bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Inferred Immune-Cell Activity Is an Independent Predictor of HER2-Negative Breast Cancer Prognosis and Response to Paclitaxel-Based Therapy in the GeparSepto Trial
Authors: Fasching Peter A. , Szeto Christopher , Denkert Carsten , Benz Stephen , Weber Karsten , Spilman Patricia , Budczies Jan , Schneeweiss Andreas , Stickeler Elmar , Schmatloch Sabine , Jackisch Christian , Karn Thomas , Sinn Hans Peter , Warm Mathias , van Mackelenbergh Marion , Rabizadeh Shahrooz , Schem Christian , Heinmöller Ernst , Mueller Volkmar , Marmé Frederik , Soon-Shiong Patrick , Nekljudova Valentina , Untch Michael , Loibl Sibylle
Published: July 2023

AbstractPurpose:
Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426).
Experimental Design:
Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA “hot,” “warm,” or “cold” by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined.
Results:
iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low.
Conclusions:
Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.
Data from Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103
Authors: Shen Fei , Jiang Guanglong , Philips Santosh , Gardner Laura , Xue Gloria , Cantor Erica , Ly Reynold C. , Osei Wilberforce , Wu Xi , Dang Chau , Northfelt Donald , Skaar Todd , Miller Kathy D. , Sledge George W. , Schneider Bryan P.
Published: July 2023

AbstractPurpose:
Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed.
Experimental Design:
Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3–4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case–control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN.
Results:
Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10−6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN.
Conclusions:
Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.
Data from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer
Authors: Ricciuti Biagio , Elkrief Arielle , Alessi Joao , Wang Xinan , Li Yvonne , Gupta Hersh , Muldoon Daniel M. , Bertram Arrien A. , Pecci Federica , Lamberti Giuseppe , Di Federico Alessandro , Barrichello Adriana , Vaz Victor R. , Gandhi Malini , Lee Elinton , Shapiro Geoffrey I. , Park Hyesun , Nishino Mizuki , Lindsay James , Felt Kristen D. , Sharma Bijaya , Cherniack Andrew D. , Rodig Scott , Gomez Daniel R. , Shaverdian Narek , Rakaee Mehrdad , Bandlamudi Chaitanya , Ladanyi Marc , Janne Pasi A. , Schoenfeld Adam J. , Sholl Lynette M. , Awad Mark M. , Cheng Michael L.
Published: July 2023

AbstractPurpose:
ATM is the most commonly mutated DNA damage and repair gene in non–small cell lung cancer (NSCLC); however, limited characterization has been pursued.
Experimental Design:
Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets.
Results:
A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM–wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy.
Conclusions:
Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.
Data from Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin J.D. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: July 2023

AbstractPurpose:
Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.
Patients and Methods:
In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.
Results:
Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021–0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011–0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.
Conclusions:
NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.
Data from Patient-Reported Outcomes as Inter-Radiographic Predictors of Response in Non-Small Cell Lung Cancer
Authors: Bhatt Ambika , Schabath Matthew B. , Hoogland Aasha I. , Jim Heather S.L. , Brady-Nicholls Renee
Published: July 2023

Abstract
Purpose: Minimally-invasive biomarkers have been used as important indicators of treatment response and progression in cancers such as prostate and ovarian. Unfortunately, all biomarkers are not prognostic in all cancer types and are often not routinely collected. Patient-reported outcomes (PROs) provide a non-obtrusive, personalized measure of a patient’s quality of life and symptomatology, reported directly from the patient and are increasingly collected as part of routine care. Previous literature has shown correlations between specific PROs (i.e., insomnia, fatigue) and overall survival. Though promising, these studies often only consider single time points and ignore patient-specific dynamic changes in individual PROs, which might be early predictors of treatment response or progression. Experimental Design: In this study, PRO dynamics were analyzed to determine if they could be used as inter-radiographic predictors of tumor volume changes among 85 non-small cell lung cancer patients undergoing immunotherapy. PRO questionnaires and tumor volume scans were completed biweekly and monthly, respectively. Correlation and predictive analysis were conducted to identify specific PROs that could accurately predict patient response. Results: Changes in tumor volume over time were significantly correlated with dizziness (p<0.005), insomnia (p <0.05), and fatigue (p<0.05). Additionally, cumulative changes in insomnia could predict progressive disease with a 77% accuracy, on average 45 days prior to the next imaging scan. Conclusions: This study presents the first time that patient-specific PRO dynamics have been considered to predict how individual patients will respond to treatment. This is an important first step in adapting treatment to improve response rates.
Data from Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Subbiah Vivek , Chawla Sant P. , Conley Anthony P. , Wilky Breelyn A. , Tolcher Anthony , Lakhani Nehal J. , Berz David , Andrianov Vasily , Crago William , Holcomb Monica , Hussain Abrahim , Veldstra Carson , Kalabus James , O’Neill Brianne , Senne Lane , Rowell Emily , Heidt Analeah B. , Willis Katelyn M. , Eckelman Brendan P.
Published: July 2023

AbstractPurpose:
Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933).
Patients and Methods:
INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS.
Results:
In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%).
Conclusions:
INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Supplementary Figure S5 from Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model Via Induction of Apoptosis
Authors: Unachukwu Uchenna , Sonett Jarrod , Woode Denzel , Shiomi Takayuki , Chada Kiran , D'Armiento Jeanine M.
Published: July 2023

Western blots of whole cell extracts obtained from drug-treated renal AML cells stained with anti-cytochrome C antibodies.
Data from Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy
Authors: Borek Bartlomiej , Nowicka Julita , Gzik Anna , Dziegielewski Marek , Jedrzejczak Karol , Brzezinska Joanna , Grzybowski Marcin , Stanczak Paulina , Pomper Paulina , Zagozdzon Agnieszka , Rejczak Tomasz , Matyszewski Krzysztof , Golebiowski Adam , Olczak Jacek , Lisiecki Kamil , Tyszkiewicz Magdalena , Kania Magdalena , Piasecka Sylwia , Cabaj Anna , Dera Paulina , Mulewski Krzysztof , Chrzanowski Jacek , Kusmirek Damian , Sobolewska Elzbieta , Magdycz Marta , Mucha Lukasz , Masnyk Marek , Golab Jakub , Nowotny Marcin , Nowak Elzbieta , Napiorkowska-Gromadzka Agnieszka , Pikul Stanislaw , Jazwiec Radoslaw , Dzwonek Karolina , Dobrzanski Pawel , Meyring Michael , Skowronek Krzysztof , Iwanowski Piotr , Zaslona Zbigniew , Blaszczyk Roman
Published: July 2023

Abstract
Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer.
Significance:
We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.
Supplementary Table 4 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: July 2023

Transcription Factor Enrichment Analysis of Differentially Downregulated Genes by The Drug Combination Previously Identified as Depleting Genes in a Genome-Wide CRISPR Dropout Screen
Supplementary Table 18 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: July 2023

Single Cell ATAC Cell Type Populations
Supplementary Figure Legends from Tumor-Derived CCL5 Recruits Cancer-Associated Fibroblasts and Promotes Tumor Cell Proliferation in Esophageal Squamous Cell Carcinoma
Authors: Dunbar Karen J. , Karakasheva Tatiana A. , Tang Qiaosi , Efe Gizem , Lin Eric W. , Harris Michael , Sahu Varun , Sachdeva Uma M. , Hu Jianhua , Klein-Szanto Andres J. , Henick Brian , Diehl J. Alan , Nakagawa Hiroshi , Rustgi Anil K.
Published: July 2023

Supplementary Figure Legends 1-4
Supplementary Table 18 from Associations between Physical Activity and Incidence of Cancer among Overweight Adults in Korea: Results from the Health Examinees-G Study
Authors: Choi Jaesung , Park JooYong , Kim Ji-Eun , Lee Miyoung , Kang Daehee , Shin Aesun , Choi Ji-Yeob
Published: July 2023

Supplementary Table 18 shows comparison of the basic characteristics between the included and excluded population
Data from Associations between Physical Activity and Incidence of Cancer among Overweight Adults in Korea: Results from the Health Examinees-G Study
Authors: Choi Jaesung , Park JooYong , Kim Ji-Eun , Lee Miyoung , Kang Daehee , Shin Aesun , Choi Ji-Yeob
Published: July 2023

Abstract
Although the protective effects of physical activity against several cancers are well established, evidence is inconsistent concerning Asian populations. Therefore, we assessed the association between the characteristics of physical activity and overall and type-specific cancer incidence in Koreans and examined the differences in association according to obesity status. Using prospective data from 112,108 participants in the Health Examinees study-G from 2004 to 2013, we evaluated the association between leisure-time physical activity (LTPA) and the incidence of overall and type-specific cancers using the Cox proportional hazards model. Self-reported LTPA participation, duration per week, intensity, type, and diversity were assessed. The incidence of overall and type-specific cancers, including colorectal, gastric, lung, breast, and prostate cancer and 13 obesity-related cancers, was identified using the Korea Central Cancer Registry from 1999 to 2018. Analyses were also stratified according to obesity status. In overweight males, participation in vigorous LTPA [HR, 0.84; 95% confidence interval (CI), 0.72–0.97] and walking (HR, 0.84; 95% CI, 0.72–0.98) were associated with a lower risk of cancer overall. Regarding cancer types, climbing was marginally associated with a lower risk of colorectal cancer in overweight males (HR, 0.61; 95% CI, 0.37–1.00). In normal-weight females, although there was an increased risk in those performing recreational activities, this risk was attenuated when those diagnosed with thyroid cancer were excluded. In the analysis for 13 obesity-related cancers, consistent associations were found. These findings suggest the need for greater public awareness regarding physical activity among overweight individuals within the Asian population.
Prevention Relevance:
Overall cancer risk is associated with leisure-time physical activity such as duration, intensity, type, and diversity in overweight males, but not in the general population. The decreased risk was most noticeable for colorectal cancer. Our results suggest that physical activity may reduce the risk of cancer among overweight Asian males.
Supplemental Table 3 from mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity
Authors: Nirschl Christopher J. , Brodkin Heather R. , Domonkos Celesztina , Dwyer Connor J. , Hicklin Daniel J. , Ismail Nesreen , Seidel-Dugan Cynthia , Steiner Philipp , Steuert Zoe , Sullivan Jenna M. , Winston William M. , Salmeron Andres
Published: July 2023

Differential Gene Expression Analysis of EMT-6 Tumor Infiltrating CD8+ T cells
Data from IL12/18/21 Preactivation Enhances the Antitumor Efficacy of Expanded γδT Cells and Overcomes Resistance to Anti–PD-L1 Treatment
Authors: Teo Huey Yee , Song Yuan , Yong Kylie Su Mei , Liu Yonghao , Mei Yu , Hanafi Zuhairah Binte , Zhu Ying , Chua Yen Leong , Gascoigne Nicholas R.J. , Chen Qingfeng , Liu Haiyan
Published: July 2023

Abstract
γδT cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current γδT cell-based cancer immunotherapy has limited efficacy, and novel strategies are needed to improve clinical outcomes. Here, we report that cytokine pretreatment with IL12/18, IL12/15/18, IL12/18/21, and IL12/15/18/21 effectively enhanced the activation and cytotoxicity of in vitro–expanded murine and human γδT cells. However, only adoptive transfer of IL12/18/21 preactivated γδT cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL12/18/21 preactivated antibody-expanded and zoledronate-expanded human γδT cells effectively controlled tumor growth in a humanized mouse model. IL12/18/21 preactivation promoted γδT cell proliferation and cytokine production in vivo and enhanced IFNγ production and activation of endogenous CD8+ T cells in a cell–cell contact- and ICAM-1–dependent manner. Furthermore, the adoptive transfer of IL12/18/21 preactivated γδT cells could overcome the resistance to anti–PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced antitumor function of adoptively transferred IL12/18/21 preactivated γδT cells was largely diminished in the absence of endogenous CD8+ T cells when administered alone or in combination with anti–PD-L1, suggesting a CD8+ T cell–dependent mechanism. Taken together, IL12/18/21 preactivation can promote γδT cell antitumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy.
Data from KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2–CXCL10 Axis in Colorectal Cancer
Authors: Liang Wenfeng , Liu Huashan , Zeng Ziwei , Liang Zhenxing , Xie Hao , Li Wenxin , Xiong Li , Liu Zhihang , Chen Mian , Jie Haiqing , Zheng Xiaobin , Huang Liang , Kang Liang
Published: July 2023

Abstract
Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) “reader” YTHDF2. KRT17 synergized with anti–PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.
Data from Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia
Authors: Kotini Andriana G. , Carcamo Saul , Cruz-Rodriguez Nataly , Olszewska Malgorzata , Wang Tiansu , Demircioglu Deniz , Chang Chan-Jung , Bernard Elsa , Chao Mark P. , Majeti Ravindra , Luo Hanzhi , Kharas Michael G. , Hasson Dan , Papapetrou Eirini P.
Published: July 2023

Abstract
The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.
Significance:
We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation.

See related commentary by Doulatov, p. 252.

This article is highlighted in the In This Issue feature, p. 247
TABLE 1 from Evaluating Work Impairment as a Source of Financial Toxicity in Cancer Healthcare and Negative Impacts on Health Status
Authors: Mudaranthakam Dinesh Pal , Nollen Nicole , Wick Jo , Hughes Dorothy , Welch Danny , Calhoun Elizabeth
Published: July 2023

Participant characteristics
Data from Evaluating Work Impairment as a Source of Financial Toxicity in Cancer Healthcare and Negative Impacts on Health Status
Authors: Mudaranthakam Dinesh Pal , Nollen Nicole , Wick Jo , Hughes Dorothy , Welch Danny , Calhoun Elizabeth
Published: July 2023

How the socioeconomic factors intersect for a particular patient can determine their susceptibility to financial toxicity, what costs they will encounter during treatment, the type and quality of their care, and the potential work impairments they face. The primary goal of this study was to evaluate financial factors leading to worsening health outcomes by the cancer subtype. A logistic model predicting worsening health outcomes while assessing the most influential economic factors was constructed by the University of Michigan Health and Retirement Study. A forward stepwise regression procedure was implemented to identify the social risk factors that impact health status. Stepwise regression was done on data subsets based on the cancer types of lung, breast, prostate, and colon cancer to determine whether significant predictors of worsening health status were different or the same across cancer types. Independent covariate analysis was also conducted to cross-validate our model. On the basis of the model fit statistics, the two-factor model has the best fit, that is, the lowest AIC among potential models of 3270.56, percent concordance of 64.7, and a C-statistics of 0.65. The two-factor model used work impairment and out-of-pocket costs, significantly contributing to worsening health outcomes. Covariate analysis demonstrated that younger patients with cancer experienced more financial burdens leading to worsening health outcomes than elderly patients aged 65 years and above. Work impairment and high out-of-pocket costs were significantly associated with worsening health outcomes among cancer patients. Matching the participants who need the most financial help with appropriate resources is essential to mitigate the financial burden.
Significance:
Among patients with cancer, work impairment and out-of-pocket are the two primary factors contributing to adverse health outcomes. Women, African American or other races, the Hispanic population, and younger individuals have encountered higher work impairment and out-of-pocket costs due to cancer than their counterparts.
Procalcitonin for Detecting Culture-Positive Sepsis in Neonates: A Prospective, Multicenter Study
Authors: Chaurasia Suman , Anand Pratima , Sharma Akash , Nangia Sushma , Sivam Adhi , Jain Kajal , Gaind Rajni , Kaur Ravinder , Sastry Apurba S. , Kapil Arti , Bhatt Meenakshi , Salhan Meetu , Dudeja Ajay , Plakkal Nishad , Verma Ankit , Jain Manisha , Saxena Sonal , Mohapatra Sarita , Kashyap Archana , Goel Srishti , Sivanandan Sindhu , Arya Sugandha , Saini Savita , Pande Tapish , Saluja Sumita , Sharma Monica , Vishnubhatla Sreenivas , Chellani Harish , Sankar M. Jeeva , Agarwal Ramesh
Published: July 2023

Introduction: It is unclear if serum procalcitonin (PCT) estimated at sepsis suspicion can help detect culture-positive sepsis in neonates. We evaluated the diagnostic performance of PCT in culture-positive sepsis in neonates. Methods: This was a prospective study (February 2016 to September 2020) conducted in four level-3 units in India. We enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birth weight <750 g, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or “no sepsis” based on the culture reports and clinical course. PCT assay was performed by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. Results: The mean birth weight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32–38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9%) had culture-positive sepsis. Most (79.4%) were culture-positive within 72 h of birth. The sensitivity, specificity, and positive and negative likelihood ratios at 2 ng/mL PCT threshold were 52.3% (95% confidence interval: 44.1–60.3), 64.5% (60.7–68.1), 1.47 (1.23–1.76), and 0.74 (0.62–0.88), respectively. Adding PCT to assessing neonates with 12.9% pretest probability of sepsis generated posttest probabilities of 18% and 10% for positive and negative test results, respectively. Conclusion: Serum PCT did not reliably identify culture-positive sepsis in neonates.
Hypertrophic Pachymeningitis with Persistent Intrathecal Inflammation Secondary to Neurosarcoidosis Treated with Intraventricular Chemotherapy: A Case Report
Authors: de Almeida Marcelino Ana Luísa , Streit Simon , Homeyer Marie Alice , Bauknecht Hans-Christian , Radbruch Helena , Ruprecht Klemens , Prüss Harald
Published: July 2023

Hypertrophic pachymeningitis (HP) is a rare immune-mediated disease characterized by thickening of the dura mater with consecutive cranial neuropathy. While HP is usually treated with systemic immunotherapies, response to therapy is variable and may be limited by insufficient drug concentrations in the brain. We report on a 57-year-old patient with HP manifesting with vision and hearing loss who had sustained clinical progression despite various systemic immunotherapies. Intraventricular chemotherapy with methotrexate, cytarabine, and dexamethasone was initiated. We present clinical, imaging and cerebrospinal fluid (CSF) findings, including cytokine levels before and after intraventricular treatment: rapid decrease of cell count, lactate and profibrotic cytokine levels in the CSF following intraventricular chemotherapy was paralleled by a mild reduction of dura thickness in MRI. The already severely impaired visual acuity and hearing loss did not progress further. Treatment was complicated by exacerbation of previously subtle psychiatric symptoms. Follow-up was terminated after 6 months as the patient suffered from a fatal ischemic stroke. Autopsy revealed neurosarcoidosis as the underlying cause of HP. This case report suggests that intrathecal chemotherapy can reduce the inflammatory milieu in the CNS and should be considered for treatment-refractory HP before irreversible damage of cranial nerves has occurred.
Top-down threat bias in pain perception is predicted by higher segregation between resting-state networks
Authors: Pak Veronika , Hashmi Javeria Ali
Published: July 2023

Top-down processes such as expectations have a strong influence on pain perception. Predicted threat of impending pain can affect perceived pain even more than the actual intensity of a noxious event. This type of threat bias in pain perception is associated with fear of pain and low pain tolerance, and hence the extent of bias varies between individuals. Large-scale patterns of functional brain connectivity are important for integrating expectations with sensory data. Greater integration is necessary for sensory integration; therefore, here we investigate the association between system segregation and top-down threat bias in healthy individuals. We show that top-down threat bias is predicted by less functional connectivity between resting-state networks. This effect was significant at a wide range of network thresholds and specifically in predefined parcellations of resting-state networks. Greater system segregation in brain networks also predicted higher anxiety and pain catastrophizing. These findings highlight the role of integration in brain networks in mediating threat bias in pain perception.
An Inference of Plot Design Method Applied to Pavilions in the Rear Garden of Changdeokgung Palace as World Cultural Heritage
Authors: Lee Ju-Won , Huh Keun Young
Published: July 2023

Background and objective: It is necessary to study traditional plot design methods or manners that the engineers in Joseon Dynasty were inferred to have conventionally applied to garden spaces or buildings. This study aimed to infer a conventional plot design method practiced by the engineers who created pavilions in Joseon Dynasty.Methods: The four pavilions were selected, whose original design drawings or documents are still unavailable to reveal the method or manner. The actual measurement plot design layouts measured and drawn on the spot by Cultural Heritage Administration (CHA) were analyzed. A geometrical approach was adopted to infer a method that drew the plot design layout on the ground using only non-gauged rulers (or strings). In the analysis, basic figure frames such as circles or lines were overlaid on the actual measurement drawings, and whether they matched was checked. Then, we inferred the sequential processes of the plot design method to implement the layout on the paper or the ground.Results: It was inferred that the plot design layouts of the four pavilions might have the same method. The results suggested that the engineers in Joseon Dynasty, without accurate numeric scale bars or protractors, might apply a geometrical method to determine the position of each pavilion pillar with the figures and intersections created in composing two identical circles overlapping by the radius. Two drawing processes implemented by the method inferred to reproduce the layout of Buyongjeong pavilions with a complex structure coincided with the actual measurement plot design drawing.Conclusion: The result could infer a plot design method and process applied to the four pavilions in the Rear Garden of Changdeokgung Palace in Joseon Dynasty. It may be a drawing method using string as a numeric scale bar or protractor, which could be used to interpret and reproduce the plot design of traditional Korean garden pavilions built in Joseon Dynasty.
Jingle Bells: How Do Bells Affect the Wellbeing, Safety, and Identity of Guide Dog Teams?
Authors: Warda Tiamat
Published: July 2023

Some visually impaired individuals will attach a small bell to their guide dog’s collar to locate them acoustically, yet existing literature on this topic is lacking. This paper analyzes how bells can affect the wellbeing, welfare, and safety of guide dog teams. The ways in which bells alter personal, social, and collective identities are also explored. Results are based on autoethnographic data from the researcher’s six years as a professional guide dog mobility instructor and 12 anonymous online survey responses from participants who have lived with a guide dog. This paper concludes that although bells can offer benefits, they are not a solution for all guide dog teams. Alternatives such as collar tags, GPS devices, walking with sighted volunteers, or training guide dogs to nudge their human partner’s hand when called are addressed.
Collective Voice and Organizing in Digital Labour Platforms in Portugal
Authors: Boavida Nuno , Roque Isabel , Moniz António Brandão
Published: July 2023

The use of digital platforms for managing work grew considerably in Portugal, especially in the aftermath of the Great Recession. This new form of digital and platform work intensified the use of an on-demand workforce, not involved in the bargaining process, subject to indecent working conditions, social control and surveillance and the possibility of accessing social benefits, creating new obstacles for organising. Between 2019 and 2021, semi-structured interviews with workers, activists involved in associations and social movements, trade unionists and key informers were conducted. Also desk research involved five case-studies in Portugal, as part of a European research project. Results allowed to establish a typification of digital platform workers and to analyse collective action and voice in the country.
Polystichum napoense (Dryopteridaceae), a new cave-dwelling fern species from Guangxi, China
Authors: XIONG CHI , LI ZHENG-LONG , YANG ZI-MENG , JIANG RI-HONG , HUANG TING
Published: July 2023

Polystichum napoense, a new cave-dwelling species of Dryopteridaceae from limestone areas of Napo County, Guangxi, China, was described and illustrated in this study. This species is distinguished by the presence of scales on both surfaces of the pinnae, with scales being particularly distinct on the adaxial pinnae. It is the only known species within P. sect. Haplopolystichum that exhibits this characteristic. The new species has only been found in a single population at the type locality, with an estimated 100–150 plants. Based on the IUCN Red List Categories and Criteria (Version 3.1), P. napoense is considered Critically Endangered (CR).
Hieracium purkynei (Asteraceae): an endemic to the Sudetes rediscovered after a century
Authors: SZELĄG ZBIGNIEW
Published: July 2023

Hieracium purkynei was described from specimens collected in 1884 in the Giant Mountains, Sudetes, in Czechia. Since 1914, the species was considered extinct. In 2019, two new localities of H. purkynei were found on the Polish side of the Giant Mountains. The species is illustrated with photographs of the holotype (kept at PR) and, for the first time, living plants in the field.
Rediscovery of little-known-monotypic genus Karnataka P.K.Mukh. & Constance (Apiaceae)
Authors: GOSAVI KUMAR VINOD CHHOTUPURI , MADHAV NILESH APPASO , KHANDIGE VIKAS BHAT , CHANDORE ARUN NIVRUTTI
Published: July 2023

Karnataka (Apiaceae) is a monotypic genus rediscovered after it’s type collection around 175 years from Mudbidri area of Dakshina Kannada (South Canara) district, Karnataka. Detailed morphological description, identity notes and photoplates have been provided based on fresh material collected by authors.
Clergy and Compassionate Leadership: A Tightrope of Fatigue and Satisfaction During COVID-19
Authors: Benton Amy L. , Girdley Angela P.
Published: July 2023

The COVID-19 pandemic impacted clergy leadership by disrupting their traditional routines and roles, creating both challenges and opportunities. Using the Job Demands and Resources theory as a framework, the purpose of this study was to examine the job demands and resources that predicted compassion fatigue and satisfaction, indicators of wellbeing for the clergy, within the context of the COVID-19 pandemic. Questionnaires from 410 clergy provided the data for the study. Results indicated organizational tasks, care tasks, role conflict, and role ambiguity predicted higher compassion fatigue, and role ambiguity and organizational tasks predicted lower compassion satisfaction. Self-care predicted higher compassion satisfaction and lower compassion fatigue, and emotional support predicted higher compassion satisfaction. Findings provide information on an understudied population and add knowledge about the personal resource of self-care. The significance, implications, and limitations of the study were discussed.
No Safe Place: Violence among Unaccompanied Refugee Children Seeking Asylum in Kenya
Authors: Raddatz Rosalind , Kerby Matthew
Published: July 2023

This paper explores the rarely examined experiences of unaccompanied refugee minors in Nairobi, Kenya. Children are thought to comprise up to a third of Nairobi's refugee population, however, there is virtually no data on them. The paper provides a first analysis of a unique dataset to ascertain unaccompanied minor refugees’ experiences of physical, emotional, resource related, and sexual violence. Our research findings indicate widespread violence among refugee children living in Nairobi, and denote the prevalence of several kinds of violence in particular. Our results also reveal which children are most at risk and the type of abuse they are most likely to experience.
Comparison of perineal urethrostomy versus augmentation urethroplasty in anterior urethral stricture disease
Authors: Sharma Govind , Desai Sandip , Priyadarshi Shivam , Negi Saurabh
Published: July 2023

Purpose:

Perineal urethrostomy and urethroplasty are very good options for complex and long anterior urethral strictures. A perineal urethroplasty is usually a neglected option. To our knowledge, a comparative study between augmentation urethroplasty and perineal urethrostomy has been not conducted regarding subjective and patient reported outcome measures. We compared both these groups in a high volume tertiary care hospital.

Materials and methods:

A prospective comparative study of augmentation urethroplasty and perineal urethroplasty for long anterior urethral stricture. it was defined by strictures of more than 3 cm. We compared demographic data, urinary and sexual function; and quality of life using validated PROMs (patient-reported outcome measures) between both above groups.

Results:

Both groups had 40 patients each. IPSS score improvement for PU and AUP were 20 and 19.6, respectively( p = 0.1223); IIEF-5 score improvement for PU and AUP at baseline and after 6 months were 14.3 and 16.7, respectively( p = 0.1433); QOL score improvement for PU and AUP were 3.45 and 3.05, respectively; which was statistically significant ( p ⩽ 0.001).

Conclusions:

Perineal urethrostomy is a good but neglected option for complex and long anterior urethral strictures and it should be considered one of the reliable treatment option for patients with long-segment urethral strictures.
Post-truth, conspiracy, and fake news in the uncertain times of the COVID-19 pandemic in Morocco
Authors: Mifdal Mohamed
Published: July 2023

During the COVID-19 pandemic, the truth about the virus and its implications were at issue and were the object of a heated debate, nationally and globally. Because of the novelty of that experience, convergent truths emerged in Morocco, exacerbating the uncertainty that was already prevailing. This article examines these convergent truths, their epistemological bases, claims, and resources. This analysis shows the existence of different powers and strategies to which different truths are linked. The creative truth upheld by the existing dominant power, drawing, for legitimacy, on empirical scientific knowledge and claiming control over the situation. The esoteric truth based on conspiracy theories, political conflict, or the religious doctrine of fatalism and popular culture was supported and diffused through social media and gained traction among the public, already distrustful of the dominant narrative and of the scientific expertise. While other forms of truths existed in this post-truth era, this article focuses on these two kinds of truth, and examines how both were constitutive of two antagonistic discourses that used different kinds of propaganda including even fake news or alternative facts to provide (false or emotional) grounds for their claims. The scrutiny of the interactions between these discourses through media texts showed that while the government used propagandistic (pseudo)scientific messages to control the population and reinforce its authority, with little regard for people’s doubts, worries, and fears, the social media users formed different clusters of like-minded people and resisted the dominant narrative taking advantage of the growing distrust of the government among the population and the communication blunders of some public policy officials.
Endogenous military strategy and crisis bargaining
Authors: Spaniel William , İdrisoğlu Işıl
Published: July 2023

When states fight wars, they choose between multiple military strategies, e.g. whether to place boots on the ground or restrict efforts to an air campaign. We modify the standard crisis bargaining model to account for this by endogenizing a state's war strategy. Intuitively, states choose the more powerful strategy when the additional strength gained covers the additional costs of doing so. However, there is a counterintuitive second-order consequence of this. When stronger campaigns are expensive but still credible, states are more likely to reach a negotiated settlement to avoid the corresponding high costs. As the cost of the more powerful option increases, states substitute their actions with cheaper but weaker alternatives. Because of these lower costs, states become less likely to reach a settlement. In some cases, both parties may be worse off as a result.