bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Impact of Germline Alterations in Appendiceal Adenocarcinoma
Authors: Foote Michael B. , Walch Henry , Kemel Yelena , Vakiani Efsevia , Johannet Paul , Sheehan Margaret , Chatila Walid , Chung Sebastian , Nash Garrett M. , Maio Anna , Shia Jinru , Mandelker Diana , Berger Michael , Schultz Nikolaus , Diaz Luis A. , Cercek Andrea , Stadler Zsofia K.
Published: June 2023

AbstractPurpose:
More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants.
Experimental Design:
We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated.
Results:
Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma–specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable.
Conclusions:
Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.
Data from Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)
Authors: Wang Qiao-Li , Ma Chao , Yuan Chen , Shi Qian , Wolpin Brian M. , Zhang Yin , Fuchs Charles S. , Meyer Jeffrey , Zemla Tyler , Cheng En , Kumthekar Priya , Guthrie Katherine A. , Couture Felix , Kuebler Philip , Kumar Pankaj , Tan Benjamin , Krishnamurthi Smitha , Goldberg Richard M. , Venook Alan , Blanke Charles , Shields Anthony F. , O'Reilly Eileen M. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: June 2023

AbstractPurpose:
To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association.
Experimental Design:
Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2).
Results:
Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events.
Conclusions:
Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.
Table S2 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Genes deferentially expressed in EGR2 compared to AAVS1 knockout CD8+ CAR T-cells. The corresponding log2 fold change values and statistical significance are provided for the listed genes.
Table S1 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Genes comprising the TCF7 regulon, the type I IFN signature, and the EGR2 Co-expression signatures. Gene names and symbols are listed.
Figure S9 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Epigenetic remodeling of CAR T-cells by EGR2 knockout and effect of type I IFN signaling on the development of memory and exhaustion. A, Volcano plots showing differentially accessible chromatin regions within genes between KLF2+ and MKI67+ CD8+ T-cells. B, Volcano plots depicting differentially accessible chromatin regions within genes between EGR2 and AAVS1 knockout (KO) CD8+ CAR T-cells. C, Representative contour plots showing frequencies of TIM3- and LAG3-expressing CD8+ CAR-T cells after exposure to IFNβ (1ng/mL) following chronic CAR stimulation. D, Proportions of CD27+ (left) or CD62L+ (right) CD8+ CAR-T cells after exposure to IFNβ. E, Representative contour plots showing frequencies of CD45RO+CD27+ CD8+ CAR-T cells after IFNAR blockade (Anifrolumab, 1µg/mL) during chronic antigen stimulation. F, Frequencies of TIM3+LAG3+ CD8+ CAR-T cells after IFNAR blockade. G, Cytolytic capacity of CAR T-cells as measured by normalized cell index kinetics using the xCELLigence real-time cytotoxicity assay following chronic stimulation with target cancer cells in the setting of either IFNβ or IFNAR blockade. H, Normalized cell index at 75 hours after challenge with target cancer cells. All experiments were conducted using healthy donor T-cells from independent donors (Mann-Whitney test, n = 4). *P < 0.05, *P < 0.01, ***P < 0.001, ns.: not significant.
Figure S6 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Pathways regulated by EGR2 in CD8+ CAR T-cells. (A-C) Top pathways differentially expressed in EGR2 knockout CD8+ CAR-T cells compared to AAVS1 knockout CAR T-cells. Libraries used in this enrichment analysis: A, Reactome 2016. B, NCI-Nature Pathway Interaction Database 2015. C, ARCHS4 transcription factor (TF) co-expression.
Figure S3 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Impact of EGR2 knockout on different T-cell subsets and CD28-based CAR T-cells. A, Naive, central memory, effector memory, and effector T-cells were magnetically isolated. PSMA CAR-T cells with AAVS1 and EGR2 knockout (KO) were then generated from the T-cell subsets and restimulation experiments were conducted to examine the development of exhaustion and memory. B, Expression of exhaustion markers (TIM3+LAG3+), C, cytotoxicity and D, expression of early memory markers (CD45RO+CD27+) after chronic CAR stimulation. (E-H) EGR2 was deleted in PSMA-CD28 based CAR T-cells, and the immunophenotype of CAR T-cells was assessed during the restimulation assay. E, Expression of exhaustion markers (TIM3+LAG3+), F, cytotoxicity, G, expression of early memory markers (CD45RO+CD27+) after chronic CAR stimulation and H, CAR T-cell expansion capacity during restimulation. All experiments were conducted using T-cells from two independent healthy donors, and panels (A-H) are representative data from one donor. (Mann-Whitney test, n = 4). *P < 0.05, **P < 0.01, ***P < 0.001, ns.: not significant.
Figure S2 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Impact of EGR2 knockout on CD8+/CD4+ ratio and Th2 cytokine production in the setting of chronic tumor antigen stimulation. A, Comparison of CD8+/CD4+ ratio in control and EGR2 knockout (KO) CAR T-cells after chronic CAR stimulation. B, Th2 cytokine production by control and EGR2 KO CAR T-cells after 24 hours of CAR stimulation (Mann-Whitney test, n = 4). All experiments were performed using T-cells from three independent healthy donors. Panel B is representative data from one donor. *P < 0.05, **P < 0.01, ***P < 0.001, ns: not significant.
Figure S11 from Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A.
Published: June 2023

Analysis of survival outcomes and EGR2 gene expression in CD19 CAR T-cell products. The figure presents the P values and hazard ratio of different EGR2 molecular marker stratification points in relation to A, overall survival and B, event-free survival The black arrows indicate the stratification points used in the study. C, EGR2-targeted gene expression scores in CD19 CAR T-cell products from responders and non-responders in pediatric ALL. D, Summary of how EGR2 regulates resistance to CAR T-cell therapy through the type I IFN pathway.
Supplementary Table 2 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A , Durecki Diane E , Eder Joseph P , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

A full list of all adverse events.
Supplementary Figure 3 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A , Durecki Diane E , Eder Joseph P , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Progression free survival and overall survival curves.
Supplementary Figure 2 from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A , Durecki Diane E , Eder Joseph P , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Waterfall plot for best response by RECIST version 1.1.
Supplementary Figure S3 from Targeting the clear cell sarcoma oncogenic driver fusion gene EWSR1:ATF1 by HDAC inhibition
Authors: Mae Hirokazu , Outani Hidetatsu , Imura Yoshinori , Chijimatsu Ryota , Inoue Akitomo , Kotani Yuki , Yasuda Naohiro , Nakai Sho , Nakai Takaaki , Takenaka Satoshi , Okada Seiji
Published: June 2023

Fig. S3
Mivebresib (ABBV-075) inhibited cell viability of CCS cells and lowered expression of EWSR1::ATF1.
Supplementary Figure S2 from Targeting the clear cell sarcoma oncogenic driver fusion gene EWSR1:ATF1 by HDAC inhibition
Authors: Mae Hirokazu , Outani Hidetatsu , Imura Yoshinori , Chijimatsu Ryota , Inoue Akitomo , Kotani Yuki , Yasuda Naohiro , Nakai Sho , Nakai Takaaki , Takenaka Satoshi , Okada Seiji
Published: June 2023

Fig. S2
The gene-silencing efficiency and its effect on cell proliferation.
TABLE 3 from A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma
Authors: Kessler Elizabeth R. , Callihan Eryn , Hu Junxiao , Eule Corbin , Srivastava Geetika , Kemme Douglas J. , Iruku Praveena , Rana Vishal , Moore James , Schuster Steven R. , Amirault Mali , Flaig Thomas W. , Lam Elaine T.
Published: June 2023

Best response by RECIST in evaluable patients treated at RP2D (pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily).
TABLE 1 from A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma
Authors: Kessler Elizabeth R. , Callihan Eryn , Hu Junxiao , Eule Corbin , Srivastava Geetika , Kemme Douglas J. , Iruku Praveena , Rana Vishal , Moore James , Schuster Steven R. , Amirault Mali , Flaig Thomas W. , Lam Elaine T.
Published: June 2023

Baseline characteristics
FIGURE 2 from A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma
Authors: Kessler Elizabeth R. , Callihan Eryn , Hu Junxiao , Eule Corbin , Srivastava Geetika , Kemme Douglas J. , Iruku Praveena , Rana Vishal , Moore James , Schuster Steven R. , Amirault Mali , Flaig Thomas W. , Lam Elaine T.
Published: June 2023

Clinical activity of pembrolizumab and cabozantinib. A, Best percent change from baseline as measured by RECIST 1.1 in all evaluable patients from both phase I and phase II (N = 43). B, Swimmer plot of time on treatment in months for in all evaluable patients from both phase I and phase II (N = 43). ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
Data from NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Authors: Cecchini Michael , Walther Zenta , Wei Wei , Hafez Navid , Pilat Mary Jo , Boerner Scott A , Durecki Diane E , Eder Joseph P , Schalper Kurt A. , Chen Alice P. , LoRusso Patricia
Published: June 2023

Abstract
Purpose: Veliparib is a Poly (ADP-ribose) polymerase inhibitor (PARPi) with activity in BRCA 1/2/PALB2 deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi.

Patients and Methods NCI 7977 was a multi-cohort phase 1 clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles.

Results Fifteen patients enrolled, 8/15 (53%) received ≥ 4 prior systemic treatments. At DL1, 1/6 patients experienced a dose limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2/6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the maximum tolerated dose (MTD). No objective responses were observed, although 4 patients had progression free survival > 6 months.

Conclusions The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely.
Data from Targeting the clear cell sarcoma oncogenic driver fusion gene EWSR1:ATF1 by HDAC inhibition
Authors: Mae Hirokazu , Outani Hidetatsu , Imura Yoshinori , Chijimatsu Ryota , Inoue Akitomo , Kotani Yuki , Yasuda Naohiro , Nakai Sho , Nakai Takaaki , Takenaka Satoshi , Okada Seiji
Published: June 2023

Abstract
Clear cell sarcoma (CCS), a rare but extremely aggressive malignancy with no effective therapy, is characterized by the expression of the oncogenic driver fusion gene EWSR1::ATF1. In this study, we performed a high-throughput drug screening, finding that the histone deacetylase inhibitor vorinostat exerted an antiproliferation effect with the reduced expression of EWSR1::ATF1. We expected the reduced expression of EWSR1::ATF1 to be due to the alteration of chromatin accessibility; however, ATAC sequencing and a CUT&RUN assay revealed that chromatin structure was only slightly altered, despite histone deacetylation at the EWSR1::ATF1 promoter region. Alternatively, we found that vorinostat treatment reduced the level of BRD4, a member of the bromodomain and extraterminal motif protein family, at the EWSR1::ATF1 promoter region. Furthermore, the BRD4 inhibitor JQ1 downregulated EWSR1::ATF1 according to western blotting and q-PCR analyses. In addition, motif analysis revealed that vorinostat treatment suppressed the transcriptional factor SOX10, which directly regulates EWSR1::ATF1 expression and is involved in CCS proliferation. Importantly, we demonstrate that a combination therapy of vorinostat and JQ1 synergistically enhances antiproliferation effect and EWSR1::ATF1 suppression. These results highlight a novel fusion gene suppression mechanism achieved using epigenetic modification agents and provide a potential therapeutic target for fusion gene-related tumors.
Data from A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma
Authors: Kessler Elizabeth R. , Callihan Eryn , Hu Junxiao , Eule Corbin , Srivastava Geetika , Kemme Douglas J. , Iruku Praveena , Rana Vishal , Moore James , Schuster Steven R. , Amirault Mali , Flaig Thomas W. , Lam Elaine T.
Published: June 2023

Purpose:
Immune checkpoint inhibitor and VEGFR inhibitor combinations are effective treatments for patients with metastatic renal cell carcinoma (mRCC). This phase I/II clinical trial evaluated the safety and efficacy of pembrolizumab and cabozantinib in patients with mRCC.
Experimental Design:
Eligible patients had mRCC with clear-cell or non-clear cell histology, adequate organ function, Eastern Cooperative Oncology Group 0–1 performance status, and no prior exposure to pembrolizumab or cabozantinib. The primary endpoint was objective response rate (ORR) at the recommended phase II dose (RP2D). Secondary endpoints included safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
Results:
Forty-five patients were enrolled. A total of 40 patients were treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily, 38 of which were evaluable for response. The ORR was 65.8% [95% confidence interval (CI), 49.9–78.8] for all evaluable patients [78.6% as first-line therapy, 58.3% as second-line therapy]. The DCR was 97.4% (95% CI, 86.5–99.9). Median DoR was 8.3 months (interquartile range, 4.6–15.1). At a median follow-up of 23.54 months, the median PFS was 10.45 months (95% CI, 6.25–14.63) and median OS was 30.81 months (95% CI, 24.2–not reached). The most common grade 1 and/or 2 treatment-related adverse events (TRAE) were diarrhea, anorexia, dysgeusia, weight loss, and nausea. The most common grade 3 and/or 4 TRAEs were hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. There was one grade 5 TRAE of reversible posterior encephalopathy syndrome related to cabozantinib.
Conclusions:
Pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03149822 https://clinicaltrials.gov/ct2/show/NCT03149822
Significance:
This study evaluated the safety and effectiveness of the combination of pembrolizumab and cabozantinib in patients with mRCC. The safety profile was manageable. The combination showed promising activity with an objective response rate of 65.8%, median PFS of 10.45 months, and median OS of 30.81 months.
The Determinants of Early Investments in Urban School Systems in the United States
Authors: Schmick Ethan
Published: June 2023

Growth in per pupil education spending in the United States was mostly flat until 1918, after which it increased by almost 100 percent in a brief six-year period. This is the fastest documented increase in per pupil education spending in U.S. history. Using newly digitized biennial data on 386 of the largest urban school systems in the United States from 1900 to 1930, I investigate the origins of this spending increase. I first document that there was significant expansion in all spending and revenue categories with particularly large increases in capital expenditures, which were likely financed through borrowing. My results suggest that state education policies were largely ineffective in increasing school resources, as laws increasing state aid to local districts crowded out local receipts while compulsory schooling and English-only laws were not accompanied by increases in receipts or expenditures per pupil. Rather, I find that substantial increases in educational spending per pupil were linked to women's suffrage. Providing women with the right to vote can explain about 20 percent of the increase in per pupil spending.
From Puzzle to Paradigm: A Kuhnian Perspective on Javanese Islam
Authors: van den Boogert Jochem
Published: June 2023

Drawing on Kuhn’s understanding of scientific paradigms as exemplary ways of problem solving, this article critically assesses the current status of the study of Javanese Islam, in particular the long-standing debate on its nature. Is it a syncretist, animist religion or is it essentially Islamic? An analysis from a Kuhnian perspective indicates that both stances are actually the outcome of the same standardized theoretical approach. Consequentially, certain phenomena that are usually considered part of the Javanese religious condition now appear as anomalies of a paradigm. They will remain unsolvable, unless different theoretical approaches are developed. Locating a central assumption in the research into non-Western cultures – the universality of religion – is a step in that direction. From there, generating new descriptions and new research questions becomes a possibility.
Variability of the Deep Western Boundary Current in the Northern Philippine Sea
Authors: Xu Qinbo , Zhou Chun , Zhang Linlin , Wang Fan , Zhao Wei , Hu Dunxin
Published: June 2023

The deep western boundary current (DWBC) was studied based on a full-depth mooring east of Luzon Island in the Northern Philippine Sea deep basin during the period from January 2018 to May 2020. On average, the DWBC in the Philippine Sea flows southward with a velocity of approximately 1.18 cm s−1 at a depth of 3050 m. Significant intraseasonal and seasonal variations of the DWBC are identified. The intraseasonal variations have multiple spectral peaks in the range of 30–200 days, with the most obvious peak at approximately 120 days. On the seasonal time scale, the DWBC intensifies in summer/autumn and weakens in winter/spring, corresponding well with the seasonal variation of the ocean bottom pressure (OBP) from the Gravity Recovery and Climate Experiment. Both intraseasonal and seasonal variations have no significant correlation with the temporal variations in the upper and middle layers but have a certain correlation with transport through the Yap–Mariana Junction (YMJ). A set of experiments based on an inverted-reduced-gravity model and the OBP data reveal that the temporal variations originating from the YMJ could propagate counterclockwise along the boundary of the deep basin to the western boundary of the deep Philippine Sea, dominating the temporal variations of DWBC.
The Influence of Homelessness on the Relationship Between Clinical Risk and Protective Factors With Violent Recidivism
Authors: Francke Iris , Bogaerts Stefan , Janković Marija
Published: June 2023

In this study, we investigated the potential moderating role of instability in living arrangements in the association between 14 clinical factors of the Historical Clinical Future Revised (HKT-R) and 5-year violent recidivism. The sample included 316 male forensic psychiatric patients who were unconditionally released from Dutch forensic psychiatric institutions between 2004 and 2008. Results showed that instability in living arrangements did not moderate the association between the clinical factors and violent recidivism, however, it directly and positively predicted (OR = 3.28) violent recidivism. Likewise, hostility (OR = 4.36) and addiction (OR = 1.65) were directly and positively related to violent recidivism, while psychotic symptoms (OR = 0.25) were inversely related.
Responding to institutional plurality: Micro-politics in the rollout of a global corporate social responsibility norm in a multi-national enterprise
Authors: Gutierrez-Huerter O Gabriela
Published: June 2023

How can we make sense of the range of organizational dynamics that emerge when managers of multi-national enterprises (MNEs) seek to serve their interests as they perceive multiple demands in relation to corporate social responsibility (CSR)? In this article, I conceptualize this situation as a case of CSR institutional plurality. Drawing from the literature on MNE micro-politics, which I connect to the CSR literature, I analyze qualitative data gathered from five subsidiaries of a UK MNE to which their HQ transferred CSR reporting: a global norm with a typical explicit CSR mode. My analysis reveals that subsidiary managers responded to CSR institutional plurality by developing aligned or contested versions of the global CSR norm, that were then promoted through the deployment of discursive and symbolic tactics. I develop a grounded model that improves understanding of three power capabilities of subsidiary actors, that is, their socialization to explicit CSR norms, the exercise of employee voice and their political capital that can be deployed to support or curb the advancement of the managerial tactics. In doing so, I reveal the complex pathways through which lower-status subsidiary actors can take part in the reconfiguration of a global CSR norm.
Technology-Facilitated Continuous Professional Development During a Pandemic: A Hong Kong Primary School Case Study
Authors: Lee Jonathan , Topping Keith , Lakin Elizabeth
Published: June 2023

This article reports a case study of one local primary school in Hong Kong implementing a continuous professional development cycle for English-as-a-second-language teachers during a COVID-19 pandemic. The study focused on factors that impacted teacher continuous professional development and explored whether technology could be used to facilitate school-based professional support. An intervention implementing the technology-integrated continuous professional development cycle was conceptualised and implemented in the study. A teacher educator, together with eight English teachers, implemented the technology-integrated continuous professional development cycle. A blended approach to school-based professional support revealed that teachers valued the technological tools that facilitated professional development. These tools (such as Google Drive, Google Meets and WhatsApp) allowed for teachers to collaboratively conduct action research with the teacher educator. The study identified what factors engaged teachers in professional development as well as how technology facilitated continuous professional development. The study concluded that a mixture of different modes of continuous professional development allowed for greater teacher professional development to take place, as well as leading to applying the professional development in the classroom context.
An Analysis of the Impact of Social Networking Sites on Students’ Performance in English as a Foreign Language. The Case of Ecuadorian Polytechnic Undergraduate Students
Authors: Estrella Felix
Published: June 2023

This article aimed to identify the usefulness of using social networking sites (SNSs) in an English as a foreign language class. One hundred sixteen undergraduate students of diverse degrees from a polytechnic state-owned university in Ecuador participated in the study, which followed a quantitative design. A descriptive analysis and a linear regression model were used to analyze the data gathered through an online survey. Results reported that participants agreed on average with all the propositions, thus confirming their perception of the usefulness of the SNSs used in class. Also, it was identified that the factors “Interaction with the teacher” ( t = −0.116, p = .908) and “Engagement” ( t = 1.508, p = .133) are not statistically significant predictors of student performance. Also, the factors “Interaction with peers” ( t = 11.717, p < .001) and “Influence on cooperative learning” ( t = 10.088, p < .001) were significant predictors in the model. The results of this investigation directly impact teachers’ practice and students who will be the first recipients of the advantages of using this tool in class.
What Is Non-Inevitable?
Authors: Klassen Abigail
Published: June 2023

In this paper, I contend that the use of the notion of non-inevitability on the part of many social constructionists and non-social constructionists alike is either vague or relies too heavily on intuition. I propose two readings, namely the Dependence and Alterability Readings, to provide a principled criterion for determining whether and to what extent something may be argued to be non-inevitable. By utilizing the examples of gender and human emotion as case studies, my ultimate goals herein are not to provide a wholly foolproof criterion to delimit the non-inevitable, but to proffer one attempt at fleshing out a structured analysis at what non-inevitability might amount to and, also, to highlight the importance of why the notion of non-inevitability must be précised in order for social constructionist or non-social constructionist programs to hold weight.
Intelligent fault classification of air compressors using Harris hawks optimization and machine learning algorithms
Authors: Afia Adel , Gougam Fawzi , Rahmoune Chemseddine , Touzout Walid , Ouelmokhtar Hand , Benazzouz Djamel
Published: June 2023

Due to their complexity and often harsh working environment, air compressors are inevitably exposed to a variety of faults and defects during their operation. Thus, condition monitoring is critically required for early fault recognition and detection to avoid any type industrial failures. In this paper, an intelligent algorithm for reciprocating air compressor fault diagnosis is developed using real-time acoustic signals acquired from an air compressor with one healthy and seven different faulty states such as leakage inlet valve (LIV), leakage outlet valve (LOV), non-return valve (NRV), piston ring, flywheel, rider-belt and bearing defects. The proposed algorithm mainly consists of three steps: feature extraction, selection, and classification. For feature extraction, experimental acoustic signals are decomposed using maximal overlap discrete wavelet packet transform (MODWPT) by six levels into 64 wavelet coefficients (nodes). Thereafter, time domain features are calculated for each node to build each air compressor’s health state feature matrix. Each feature matrix dimension is reduced by selecting the most useful features using Harris hawks optimization (HHO) in the feature selection step. Finally, for feature classification, selected features are used as inputs for random forest (RF), ensemble tree (ET) and K-nearest neighbors (KNN) to detect, identify, and classify the compressor health states with high classification accuracy. Comparative studies with several feature extraction and selection methods prove the proposed approach’s efficiency in detecting, identifying, and classifying all air compressor faults.
Revaluing Work(ers): The Role of Labor Education in the “Time of COVID”
Authors: Bussel Bob
Published: June 2023

With its rich history of supporting the advancement of the working class and the union movement, labor education has continued to evolve and change, influenced by social conditions, the needs of workers and unions, and the attitudes of the institutions in which it is anchored. This essay assesses the arguments about labor education offered by Victor Devinatz and Robert Bruno and considers how the field of labor education should respond to the challenges and opportunities offered by the “time of COVID.
Mental Health Stigma of K-12 Principals
Authors: Teahon Michael , Feusner Chelsea , Meyer Em , Ohmstede-Schmoker Tammi , Tillman Douglas , Hof David
Published: June 2023

Research shows that mental health of children is becoming a major consideration in schools across the country. The purpose of this study is to identify principals who are supportive of those with mental illness and advocate for greater access to services. Responses from 139 principals of Nebraska schools addressed mental health stigma of principals based on various factors. Results yielded that gender and school level are important influences on mental health stigma.
Learning-Centered Leadership: Exploring How Distinguished Learning-Centered Principals Apply Key Processes of Learning-Centered Leadership
Authors: Wright Jared G. , Hallam Pamela R. , Bowles W. Bryan
Published: June 2023

Research on school leadership has shown that a principal's influence on student achievement is indirect and significant. A sample of principals who earned the highest (distinguished) rating on the Vanderbilt Assessment of Leadership in Education (VAL-ED) measure responded to open-ended questions during an in-person interview. Principals in this study identified specific actions of school leadership related to the VAL-ED-defined key processes and core components of learning-centered schools. A comparative analysis was conducted to discover if a difference existed between elementary and secondary principal responses.
Trajectories of Functional Decline in Older Adults: A Latent Class Growth Curve Analysis
Authors: Dombrowsky Thomas
Published: June 2023

There have been few studies examining trajectories of functional decline among older adults in the United States using large representative databases. The purpose of this study was to describe the mean trajectory of functional decline for a representative sample of US older adults, to determine the optimal number of latent classes within that sample, and to identify key differences between the classes on select variables. Through the use of link functions, non-linear trajectories can be modeled. Three classes were identified and were named Rapid Decline, Late Decline, and High Baseline. The Late Decline Group was the most numerous and was characterized by low initial functional disability with a steep rise starting around age 85. The Rapid Decline Group also had low initial functional disability, but decline started around age 80. The High Baseline Group had high initial functional disability and less steep trajectory. Age and comorbidity were the most influential factors in functional decline. Race was statistically significant but the difference disappeared when controlling for other covariates. Sex did not significantly influence the trajectory. There were significant differences among the classes for mortality during study, initial age, initial functional status, and for several specific comorbidities: arthritis, diabetes, lung disease, and stroke.
Coagulation after paediatric miniaturised versus conventional cardiopulmonary bypass: Retrospective cohort study
Authors: Ti Yunxing , Meng Baoying , Wang Yuanxiang , Liu Huaipu , Wang Pengcheng , Huang Junrong , Wu Wenzhi , Zheng Fengnan , Zhang Qing
Published: June 2023

Background

Cardiopulmonary bypass (CPB) causes coagulation disorders after surgery. This study aimed to compare the coagulation parameters after congenital cardiac surgery with miniaturised CPB (MCPB) versus conventional CPB (CCPB).

Methods

We gathered information about children who underwent cardiac surgery between 1/1/2016 and 12/31/2019. Using propensity score–matched data, we compared the coagulation parameters and postoperative outcomes of the MCPB and CCPB groups.

Results

A total of 496 patients (327 with MCPB, 169 withCCPB) underwent congenital cardiac surgery, and 160 matched pairs in each group were enrolled in the analysis. Compared with CCPB children, MCPB children had a lowermean prothrombin time (14.9 ± 2.0 vs 16.4 ± 4.1; p < 0.001)and international normalised ratio (1.3 ± 0.2 vs. 1.4 ± 0.3; p < 0.001), but higher thrombin time (23.4 ± 20.4 vs 18.2 ± 4.4; p = 0.002). The CCPB group had greaterperioperative changes inprothrombin time, international normalised ratio, fibrinogen, and antithrombin III activity (all p < 0.01) but lower perioperative changesin thrombin time ( p = 0.001) thanthe MCPB group. Ultra-fasttrack extubation and blood transfusionrates, postoperative blood loss, and intensive care unitlength of stay were considerably decreased in the MCPB group. There were no considerable intergroup differences in the activated partial thromboplastin time or platelet count.

Conclusions

Compared with CCPB, MCPB was associated with lower coagulation changes and better early outcomes, including shorter intensive care unit stay and less postoperative blood loss.
UK local government experience of COVID-19 Lockdown: Local responses to global challenges
Authors: Machin Richard
Published: June 2023

Local authorities in the United Kingdom played an integral role in responding to the COVID-19 pandemic. During a time of unprecedented crisis, local authorities acted quickly to strengthen local governance arrangements and to deliver frontline services.

The public health emergency created unparalleled challenges for local authorities. This paper reflects on the experience of Nottingham City Council, a local authority in the East Midlands of England. It draws on an in-depth interview with the then Deputy Leader of the authority and the chair of the Outbreak Control Engagement Board, and the publicly available minutes from this committee. This paper places the specific experiences of this local authority in a broader context reflecting on emergency planning, best practice, and legacy. It contributes to understanding the national impact of COVID-19 on local government.

Four key themes emerge from this analysis: first central government was too slow in responding to the emerging crisis and communication with local government was poor, second the local authority quickly moved online but there has subsequently been a return to pre-pandemic working practices, third local government played a critical role in supporting vulnerable citizens despite huge budgetary pressures, and finally relationships between partners was crucial in achieving positive outcomes.
Evaluation of the New England Office Based Addiction Treatment ECHO: A Tool for Strengthening the Addiction Workforce
Authors: Heerema Matthew R. , Ventura Alicia S. , Blakemore Samantha C. , Montoya Ivan D. , Gobel Danna E. , Kiang Mathew V. , LaBelle Colleen T. , Bazzi Angela R.
Published: June 2023

Introduction:

Reducing substance-related morbidity requires an educated and well-supported workforce. The New England Office Based Addiction Treatment Extension for Community Healthcare Outcomes (NE OBAT ECHO) began in 2019 to support community-based addiction care teams through virtual mentoring and case-based learning. We sought to characterize the program’s impact on the knowledge and attitudes of NE OBAT ECHO participants.

Methods:

We conducted an 18-month prospective evaluation of the NE OBAT ECHO. Participants registered for 1 of 2 successive ECHO clinics. Each 5-month clinic included ten 1.5-hour sessions involving brief didactic lectures and de-identified patient case presentations. Participants completed surveys at Month-0, -6, -12, and -18 to assess attitudes about working with patients who use drugs and evidence based practices (EBPs), stigma toward people who use drugs, and addiction treatment knowledge. We compared outcomes using 2 approaches: (i) between-groups, which involved comparing the first intervention group to the delayed intervention (comparison) group, and (ii) within-groups, which involved comparing outcomes at different time points for all participants. In the within-group approach, each participant acted as their own control.

Results:

Seventy-six health professionals participated in the NE OBAT ECHO, representing various roles in addiction care teams. Approximately half (47% [36/76]) practiced primary care, internal, or family medicine. The first intervention group reported improved job satisfaction and openness toward EBPs compared to the delayed intervention group. Within-group analyses revealed that ECHO participation was associated with increased positive perceptions of role adequacy, support, legitimacy, and satisfaction 6 months following program completion. No changes were identified in willingness to adopt EBPs or treatment knowledge. Stigma toward people who use drugs was persistent in both groups across time points.

Conclusions:

NE OBAT ECHO may have improved participants’ confidence and satisfaction providing addiction care. ECHO is likely an effective educational tool for expanding the capacity of the addiction workforce.
Co-evolution of regional integration and green innovation under two-layer network
Authors: Wang Xianjia , Wang Can , Xue Linzhao
Published: June 2023

With global low-carbon development, green innovation has becoming a key factor for countries to obtain and maintain core competitive advantages. However, the division of scientific research resources often fails to meet the requirements of economic development. Therefore, regional integration cooperation has become an inevitable choice for innovation and development. However, the effect of the impact, direction, and interaction of regional integration policies on green innovation decision-making remains uncertain. To study the synergistic development mechanism between the two, this study constructs a two-layer network model that includes the decision and influence layers and uses a graph neural network model to map the relationship between the two-layer networks. With the help of opinion dynamics model and public goods game model, we draw the following conclusions. (1) Limited communication between regions can encourage all parties to adopt active green innovation strategies. However, excessive communication can lead to disunity of opinions among all parties, which may not be conducive to green innovation and result in an increase in free-rider behavior. (2) Regional integration development can effectively prompt all parties to choose active green innovation strategies. (3) Increasing the breadth of regional integration cooperation is more effective in promoting the active participation of all parties in green innovation, compared to increasing the depth of regional integration cooperation. This study provides theoretical support for decision-making in regional integration and green innovation development.
Metaverse in the Virtual Workplace
Authors: Šímová Tereza , Zychová Kristýna , Fejfarová Martina
Published: June 2023

The emergence of digital technologies has significantly transformed the workplace by enhancing productivity and improving employee wellbeing. One of the latest technological advancements in the workplace is the metaverse, which has tremendous potential to facilitate collaboration in virtual teams. In this study, we conducted a comprehensive bibliometric analysis to identify core research themes on applying metaverse in the workplace. Our findings reveal core themes, including an avatar, computer graphics, immersion, virtual world and virtual reality. We also developed a theoretical and conceptual framework to define a metaverse in the workplace, which includes individual, team and organizational factors as well as contextual moderators that influence its implementation. Finally, we propose a definition of a metaverse in the workplace as a 3D virtual immersive environment where employees interact with each other using their avatar identities, perform work tasks, and have autonomy and opportunities for creativity. Our study contributes to the growing body of research on the practical applications of a metaverse in the workplace. It highlights the importance of considering various factors for its successful implementation.