bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
Authors: Hu Chunling , Nagaraj Anil Belur , Shimelis Hermela , Montalban Gemma , Lee Kun Y. , Huang Huaizhi , Lumby Carolyn A. , Na Jie , Susswein Lisa R. , Roberts Maegan E. , Marshall Megan L. , Hiraki Susan , LaDuca Holly , Chao Elizabeth , Yussuf Amal , Pesaran Tina , Neuhausen Susan L. , Haiman Christopher A. , Kraft Peter , Lindstrom Sara , Palmer Julie R. , Teras Lauren R. , Vachon Celine M. , Yao Song , Ong Irene , Nathanson Katherine L. , Weitzel Jeffrey N. , Boddicker Nicholas , Gnanaolivu Rohan , Polley Eric C. , Mer Georges , Cui Gaofeng , Karam Rachid , Richardson Marcy E. , Domchek Susan M. , Yadav Siddhartha , Hruska Kathleen S. , Dolinsky Jill , Weroha S. John , Hart Steven N. , Simard Jacques , Masson Jean Yves , Pang Yuan-Ping , Couch Fergus J.
Published: May 2023

Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers.

Significance:

Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma
Authors: Fan Fanfan , Gao Jian , Zhao Yue , Wang Jun , Meng Lu , Ma Jiaqiang , Li Teng , Han Han , Lai Jinglei , Gao Zhendong , Li Xiongfei , Guo Ran , Cao Zhiwei , Zhang Yang , Zhang Xiaoming , Chen Haiquan
Published: May 2023

Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD.

Significance:

Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.
BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: May 2023

Purpose:

Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.

Patients and Methods:

Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).

Results:

The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT–176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176–resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.

Conclusions:

BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
Abstract 1470: ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma
Authors: Wang Lu , Tan Tze King , Kim Hyoju , Kappei Dennis , Tan Shi Hao , Look A. Thomas , Sanda Takaomi
Published: May 2023

Recently, several studies have demonstrated two semi-stable and interchangeable subtypes of neuroblastoma, namely mesenchymal (MES) and adrenergic (ADRN) subtypes, which are associated with the early neural crest and committed adrenergic neural progenitor stages, respectively. Each of these subtypes is controlled by a different set of transcription factors forming the core regulatory circuit (CRC) and exhibits different enhancer and transcription profiles. However, transcription factors

that drives transition of the subtype switching and the corresponding regulated signaling pathways remain to be investigated. In this study, we demonstrate that ASCL1, a critical member of the ADRN CRC, can induce a subtype switching from MES to ADRN neuroblastoma. Our study shows that a forced expression of ASCL1 in MES neuroblastoma cells results in cell cycle arrest and cell differentiation towards the ADRN lineage with induction of ADRN gene expression, such as DLL3 and DBH. Furthermore, we have identified TCF12 as an important interaction partner of ASCL1 via SILAC analysis. ASCL1 forms a complex with TCF12 and regulates the expression of downstream target genes. On the other hand, overexpression of ASCL1 inhibits existing MES specific TGFβ-SMAD2/3 signaling pathway, while it activates BMP-SMAD1 signaling pathway. Interestingly, activation of BMP-SMAD1 signaling pathway results in the upregulation of the ID proteins, which can form dimer with TCF12 protein and sequester it away from ASCL1 protein. Thus, the BMP SMAD1-ID protein signaling cascade in turn serves as a negative feedback loop to prevent the cells from terminal differentiation via equilibration of the amount of ASCL1-TCF12 dimer. In summary, ASCL1 can induce the subtype switching and partially define the ADRN transcription program. ASCL1 serves as a lineage master initiator that characterizes ADRN neuroblastoma.

Citation Format: Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A. Thomas Look, Takaomi Sanda. ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1470.
Abstract ND07: Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor
Authors: Cregg Jim , Nichols R J. , Yang Y C. , Schulze C J. , Wang Z , Dua R , Jiang J , Nasholm N , Knox J E. , Seamon K , Longhi M , Tomlinson A , Chou K , Li S , Wildes D P. , Singh M , Koltun E S. , Gill A L. , Smith J A.
Published: May 2023

The KRASG12C mutation occurs in 11 - 14% of non-small cell lung cancers, ~4% of colorectal cancers, and ~2% of pancreatic cancers in the U.S., and drives these cancers by shifting the cellular equilibrium of KRAS towards the GTP-bound, active state, KRASG12C(ON). The resulting increased levels of KRASG12C(ON) in turn increase signaling output to initiate and support the oncogenic state. RMC-6291 is a potent, orally bioavailable inhibitor of KRASG12C(ON) that forms a tri-complex within tumor cells along with KRASG12C(ON) and cyclophilin A (CypA), driving a near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. RMC-6291 treatment produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo. In a mouse clinical trial with a representative panel of xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, displaying a potential ‘best-in-class’ profile with an increased number of responses, greater depth of tumor regressions and improved durability of responses. Thus, RMC-6291 is a clinical stage inhibitor of KRASG12C(ON) that potentially overcomes limitations of first-generation KRASG12C(OFF) inhibitors.

Citation Format: Jim Cregg, R J. Nichols, Y C. Yang, C J. Schulze, Z Wang, R Dua, J Jiang, N Nasholm, J E. Knox, K Seamon, M Longhi, A Tomlinson, K Chou, S Li, D P. Wildes, M Singh, E S. Koltun, A L. Gill, J A. Smith. Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND07.
Abstract ND09: M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity
Authors: Czauderna Frank , Schneider Richard , Ramaswamy Shivapriya , Brandstetter Susanne , Drouin Elise , Bogatyrova Olga , Mazur Johanna , Sun Qing , Jorand-Lebrun Catherine , Sherbetjian Eva , Nachtigall Jonny , Wing Carolyn , Hildebrand Christian , Ellinghaus Peter , Lemoine Isabelle , Johnson Mac , Hoover Russell , Clark Michael , Lindemann Ralph
Published: May 2023

Therapeutic strategies based on exacerbated stress signaling may represent novel and effective treatment paradigms in oncology. Here, we disclose for the first time the endoplasmic reticulum (ER) stress modulator (ERSM) M3913 that was discovered and developed following a phenotypic screening campaign. Mechanistically, M3913 engages an ER transmembrane protein not yet implicated in cancer biology to induce a Ca2+ shift from the ER towards the cytoplasm, resulting in an unfolded protein response and subsequent antitumor activity in sensitive preclinical models. We detected concurrent elevation of bona fide ER stress markers by several methods including qRT-PCR, Western Blotting analysis, and unbiased transcriptome analysis. Genetic removal of M3913’s putative ER transmembrane target abrogated the M3913-mediated, but not the Thapsigargin-mediated, ER stress response. PK/PD studies confirmed a dose- and time-dependent upregulation of ER stress markers in preclinical cancer models in vivo. As a monotherapy, M3913 induced full and partial tumor regression in preclinical models of multiple myeloma, non-small-cell lung cancer, triple-negative breast cancer, and other cancers. An in vitro combination screen indicated combination potential of M3913 with standard-of-care agents and novel candidate drugs. IND-enabling toxicology and additional mechanism-of-action studies in rat and minipig uncovered specific target organs for M3913 in line with expression of the target in human tissues. This presentation details mechanistic profiling data from M3913, reveals its putative ER-resident target and discusses forward translation studies that support M3913 as a novel therapeutic option for hard-to-treat subtypes of a variety of cancers.

Citation Format: Frank Czauderna, Richard Schneider, Shivapriya Ramaswamy, Susanne Brandstetter, Elise Drouin, Olga Bogatyrova, Johanna Mazur, Qing Sun, Catherine Jorand-Lebrun, Eva Sherbetjian, Jonny Nachtigall, Carolyn Wing, Christian Hildebrand, Peter Ellinghaus, Isabelle Lemoine, Mac Johnson, Russell Hoover, Michael Clark, Ralph Lindemann. M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND09.
Abstract ND10: Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers
Authors: Wallace Owen B. , Gavory Gerald , Ghandi Mahmoud , d’Alessandro Anne-Cecile , Bonenfant Debora , Cabanski Maciej , Cantagallo Lisa , Chicas Agustin , Chen Qian , Diesslin Anna , King Christopher , Massafra Vittoria , Narayan Rajiv , Osmont Arnaud , Peck Dave , Ortiz Carolina Perdomo , Schillo Martin , Singh Ambika , Tiedt Ralph , Tortoioli Simone , Buonamici Silvia , Warmuth Markus , Janku Filip , Fasching Bernhard
Published: May 2023

MYC transcription factors have been demonstrated to be drivers of many cancers, yet have remained recalcitrant to new drug development. We hypothesized that MYC-driven cancer cell lines are addicted to protein translation, and therefore are vulnerable to the loss of the translation termination factor, GSPT1. We have discovered MRT-2359, a selective GSPT1 molecular glue degrader, that demonstrates potent and preferential antiproliferative activity in MYC-driven cell lines, such as high N- and L-MYC mRNA expressing non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) lines. MRT-2359 has been optimized for differential toxicity between MYC- and non-MYC-driven cancer cell lines, kinetics and depth of degradation, oral bioavailability, and in vivo efficacy. The anti-tumor activity of MRT-2359 was assessed in more than 80 lung patient-derived xenografts (PDXs) that confirmed the preferential anti-tumor activity in N- and L-MYC high NSCLC and SCLC PDXs when dosed orally daily or intermittently. Similar levels of activity were also observed in neuroendocrine lung cancer PDXs and lymphoma models. Oral MRT-2359 is currently in a Phase 1/2 clinical trial in selected cancer patients with MYC-driven NSCLC, SCLC, high grade neuroendocrine cancers and diffuse large B-cell lymphoma (NCT05546268).

Citation Format: Owen B. Wallace, Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Maciej Cabanski, Lisa Cantagallo, Agustin Chicas, Qian Chen, Anna Diesslin, Christopher King, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Dave Peck, Carolina Perdomo Ortiz, Martin Schillo, Ambika Singh, Ralph Tiedt, Simone Tortoioli, Silvia Buonamici, Markus Warmuth, Filip Janku, Bernhard Fasching. Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND10.
TABLE 1 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Univariate and multivariate Cox analysis of risk factors
Supplementary Methods from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Additional methods for Coxnet models
Supplementary Figure S2 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Different cross-validation results of Coxnet model using fragmentomics profiles
FIGURE 6 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Evaluating fragmentomics model prediction and ctDNA mutation profile status in the cohort. A and B, Venn diagrams of model prediction and ctDNA status for 7 days and 6 months postsurgical timings. C, Barplots of sensitivity and specificity in the cohort. The error bars represent 95% CIs.
FIGURE 4 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Fragmentomics model prediction ahead of radiographic confirmed recurrence. Swim plot illustrating the fragmentomics model–predicted risk status, adjuvant therapy and pathologic events of cases in which relapse occurred (A) and not yet occurred (B) during the follow-up.
FIGURE 3 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Progression-free survival analysis using fragmentomics model–predicted risk status and ctDNA mutation profile. A and B, 7 days and 6 months postsurgical prognosis based on fragmentomics model–predicted risk status. C and D, 7 days and 6 months postsurgical prognosis based on ctDNA mutation profile–predicted risk status. E and F, 7 days and 6 months postsurgical prognosis based on combination of fragmentomics model and ctDNA mutation profile–predicted risk status. A combined high-risk patient was defined as being model-predicted high risk or ctDNA positive.
FIGURE 2 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Leave-one-out cross-validation (LOOCV) results of Coxnet model using fragmentomics profiles. A, ROC curves for both 7 days and 6 months postsurgical models. B and C, Barplots for model-predicted risk scores for 7 days and 6 months postsurgical models.
FIGURE 1 from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Study design and flow chart of methodology. A, Cohort and study design. B, Fragmentomics feature extraction and modeling details.
Data from Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer Using Cell-free DNA Fragmentomics
Authors: Wang Siwei , Xia Zhijun , You Jing , Gu Xiaolan , Meng Fanchen , Chen Peng , Tang Wanxiangfu , Bao Hua , Zhang Jingyuan , Wu Xue , Shao Yang , Wang Jie , Zuo Xianglin , Xu Lin , Yin Rong
Published: May 2023

Currently, approximately 30%–55% of the patients with non–small cell lung cancer (NSCLC) develop recurrence due to minimal residual disease (MRD) after receiving surgical resection of the tumor. This study aims to develop an ultrasensitive and affordable fragmentomic assay for MRD detection in patients with NSCLC. A total of 87 patients with NSCLC, who received curative surgical resections (23 patients relapsed during follow-up), enrolled in this study. A total of 163 plasma samples, collected at 7 days and 6 months postsurgical, were used for both whole-genome sequencing (WGS) and targeted sequencing. WGS-based cell-free DNA (cfDNA) fragment profile was used to fit regularized Cox regression models, and leave-one-out cross-validation was further used to evaluate models’ performance. The models showed excellent performances in detecting patients with a high risk of recurrence. At 7 days postsurgical, the high-risk patients detected by our model showed an increased risk of 4.6 times, while the risk increased to 8.3 times at 6 months postsurgical. These fragmentomics determined higher risk compared with the targeted sequencing–based circulating mutations both at 7 days and 6 months postsurgical. The overall sensitivity for detecting patients with recurrence reached 78.3% while using both fragmentomics and mutation results from 7 days and 6 months postsurgical, which increased from the 43.5% sensitivity by using only the circulating mutations. The fragmentomics showed great sensitivity in predicting patient recurrence compared with the traditional circulating mutation, especially after the surgery for early-stage NSCLC, therefore exhibiting great potential to guide adjuvant therapeutics.
Significance:
The circulating tumor DNA mutation-based approach shows limited performance in MRD detection, especially for landmark MRD detection at an early-stage cancer after surgery. Here, we describe a cfDNA fragmentomics–based method in MRD detection of resectable NSCLC using WGS, and the cfDNA fragmentomics showed a great sensitivity in predicting prognosis.
Cuerpo travesti en Las malas de Camila Sosa Villada
Authors: Leonardo-Loayza Richard
Published: May 2023

El artículo estudia Las malas (2019), de Camila Sosa Villada y se propone analizar los diferentes significados que en dicha novela se le otorga al cuerpo travesti. En la diégesis dicho cuerpo es considerado como un cuerpo abyecto y, por lo tanto, es repudiado, proscrito, violentado. Pero, también, se trata de un cuerpo que permite agencia, cierta autonomía, a la vez que se convierte en un objeto que incomoda, perturba, las bases del sistema sexo-género, por eso es sometido a diversas violencias que intentan disciplinarlo, silenciarlo, normalizarlo. En este sentido, el cuerpo travesti se erige como un simulacro, pero que, asimismo, se manifiesta como algo inédito, único.
Spatial Multiplexed Protein Profiling of Cardiac Ischemia-Reperfusion Injury
Authors: Yao Luyan , He Funan , Zhao Quanyi , Li Dandan , Fu Shufang , Zhang Mingzhi , Zhang Xingzhong , Zhou Bingying , Wang Li
Published: May 2023

Background:

Reperfusion therapy is critical to myocardial salvage in the event of a myocardial infarction but is complicated by ischemia-reperfusion injury (IRI). Limited understanding of the spatial organization of cardiac cells, which governs cellular interaction and function, has hindered the search for targeted interventions minimizing the deleterious effects of IRI.

Methods:

We used imaging mass cytometry to characterize the spatial distribution and dynamics of cell phenotypes and communities in the mouse left ventricle following IRI. Heart sections were collected from 12 cardiac segments (basal, mid-cavity, apical, and apex of the anterior, lateral, and inferior wall) and 8 time points (before ischemia [I-0H], and postreperfusion [R-0H, R-2H, R-6H, R-12H, R-1D, R-3D, R-7D]), and stained with 29 metal-isotope-tagged antibodies. Cell community analysis was performed on reconstructed images, and the most disease-relevant cell type and target protein were selected for intervention of IRI.

Results:

We obtained a total of 251 multiplexed images, and identified 197 063 single cells, which were grouped into 23 distinct cell communities based on the structure of cellular neighborhoods. The cellular architecture was heterogeneous throughout the ventricular wall and exhibited swift changes following IRI. Analysis of proteins with posttranslational modifications in single cells unveiled 13 posttranslational modification intensity clusters and highlighted increased H3K9me3 (tri-methylated lysine 9 of histone H3) as a key regulatory response in endothelial cells during the middle stage of IRI. Erasing H3K9 methylation, by silencing its methyltransferase
Suv39h1
or overexpressing its demethylase
Kdm4d
in isolated endothelial cells, attenuated cardiac dysfunction and pathological remodeling following IRI. in vitro, H3K9me3 binding significantly increased at endothelial cell function-related genes upon hypoxia, suppressing tube formation, which was rescued by inhibiting H3K9me3.

Conclusions:

We mapped the spatiotemporal heterogeneity of cellular phenotypes in the adult heart upon IRI, and uncovered H3K9me3 in endothelial cells as a potential therapeutic target for alleviating pathological remodeling of the heart following myocardial IRI.
Can hubs of the human connectome be identified consistently with diffusion MRI?
Authors: Gajwani Mehul , Oldham Stuart , Pang James C. , Arnatkevičiūtė Aurina , Tiego Jeggan , Bellgrove Mark A. , Fornito Alex
Published: May 2023

Recent years have seen a surge in the use of diffusion MRI to map connectomes in humans, paralleled by a similar increase in processing and analysis choices. Yet these different steps and their effects are rarely compared systematically. Here, in a healthy young adult population (n = 294), we characterized the impact of a range of analysis pipelines on one widely studied property of the human connectome: its degree distribution. We evaluated the effects of 40 pipelines (comparing common choices of parcellation, streamline seeding, tractography algorithm, and streamline propagation constraint) and 44 group-representative connectome reconstruction schemes on highly connected hub regions. We found that hub location is highly variable between pipelines. The choice of parcellation has a major influence on hub architecture, and hub connectivity is highly correlated with regional surface area in most of the assessed pipelines (ρ > 0.70 in 69% of the pipelines), particularly when using weighted networks. Overall, our results demonstrate the need for prudent decision-making when processing diffusion MRI data, and for carefully considering how different processing choices can influence connectome organization.
Erasure of Unaligned Attributes from Neural Representations
Authors: Shao Shun , Ziser Yftah , Cohen Shay B.
Published: May 2023

We present the Assignment-Maximization Spectral Attribute removaL (AMSAL) algorithm, which erases information from neural representations when the information to be erased is implicit rather than directly being aligned to each input example. Our algorithm works by alternating between two steps. In one, it finds an assignment of the input representations to the information to be erased, and in the other, it creates projections of both the input representations and the information to be erased into a joint latent space. We test our algorithm on an extensive array of datasets, including a Twitter dataset with multiple guarded attributes, the BiasBios dataset, and the BiasBench benchmark. The latter benchmark includes four datasets with various types of protected attributes. Our results demonstrate that bias can often be removed in our setup. We also discuss the limitations of our approach when there is a strong entanglement between the main task and the information to be erased.1
Detecting COVID-19 Fake News on Twitter: Followers, Emotions, Relationships, and Uncertainty
Authors: Chiu Ming Ming , Morakhovski Alex , Ebert David , Reinert Audrey , Snyder Luke S.
Published: May 2023

Fake news about coronavirus disease 2019 (COVID-19) can discourage people from taking preventive measures (masks, social distancing), thereby increasing infections and deaths; thus, this study tests whether attributes of users or COVID-19 tweets can distinguish tweets of true news versus fake news. We analyzed 4,165 spell-checked English tweets with a link to 1 of 20 matched COVID-19 news stories (10 true and 10 fake), across the world during 1 year, via computational linguistics and advanced statistics. Tweets with common words, negative emotional valence, higher arousal, greater dominance, first person singular pronouns, third person pronouns or by users with more followers were more likely to be true news tweets. By contrast, tweets with second person pronouns, bald starts, or hedges were more likely to be fake news tweets. Accuracy (F1 score) was 95%. While some tweet attributes for detecting fake news might be universal (pronouns, politeness, followers), others might be topic specific (common words, emotions, hedges).
Evaluation of Lung Ultrasonography Findings of Children With Late Respiratory System Symptoms Due to COVID-19 Infection
Authors: Duksal Fatma , Keceli Avni Merter
Published: May 2023

Owing to coronavirus disease 2019 (COVID-19), lung damage is seen as an important problem in patients after recovery. In this study, evaluation of respiratory symptoms and lung ultrasonography (LUS) findings of those who have had symptomatic and asymptomatic COVID-19 disease in children was aimed. A total of 81 patients with positive and 18 healthy children with negative COVID-19 antibodies were included to the study. The most common late presentation symptoms were cough (85.2%), shortness of breath (77.8%), and chest pain (60.5%). In LUS, 2 or less B lines, 3 or more B lines, and Z line were seen in 66.7%, 33.3%, and 9.9% of patients, respectively. There was no significant difference between control and patients in terms of these parameters ( P > .05). Pleural effusion was detected in 2 patients in the late period. Respiratory system findings may develop in the late period in patients infected with COVID-19. Therefore, patients should be followed closely.
Neurocognitive Functions in Opioid Dependence: Comparisons Between Opioid Categories
Authors: Ghosh Abhishek , Shaktan Alka , Verma Abhishek , Nehra Ritu , Basu Debasish , Rana Devender K , Ahuja Chirag K , Modi Manish , Singh Paramjit
Published: May 2023

We examined the differences in neurocognitive functions in individuals dependent on heroin ( n = 120), pharmaceutical ( n = 52), and natural opioids ( n = 66) and compared with healthy controls (HC, n = 94). We estimated independent effects of the opioid groups on cognitive tests, adjusted for effect modifiers. Pharmaceutical opioid dependent group performed worse than HC in Wisconsin Card Sorting Test in conceptual level response and trials to complete first category. Pharmaceutical and heroin groups had higher error scores than HC in verbal and visual N-Back Tests (NBTs). There was no significant difference between pharmaceutical and heroin groups, but both had higher error scores than the natural opioid users in NBTs. Time to complete Trail Making- A test was higher in pharmaceutical than in natural opioid group. The natural opioid group required more trials than HC to complete the first category. Pharmaceutical opioid group had worst cognitive impairment. Cognitive functions are relatively spared in natural opioid-dependent group.
Mifepristone Antagonization with Progesterone to Avert Medication Abortion: A Scoping Review
Authors: DeBeasi Paul L. C.
Published: May 2023

The safety and efficacy of mifepristone antagonization with progesterone to avert medication abortion, also known as abortion pill rescue, is a subject of vigorous debate. Two prominent medical associations have taken positions that either entirely reject or fully support its use. This scoping review aimed to gain insight into the safety and efficacy of its use. Analysis of 16 studies showed that the continuing pregnancy rate after ingesting mifepristone alone is ≦25 percent for gestational ages ≦49 days. Analysis of four studies showed that two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. There is no increased maternal or fetal risk from using bioidentical progesterone in early pregnancy. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. The conclusion that mifepristone antagonization with progesterone is a safe and effective treatment has implications for medication abortion informed consent. Summary: Two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. Physicians should disclose this treatment option to their patients at the time of informed consent.
The evolution of informed consent in gastroenterology
Authors: O’Neill Fallon , O’Neill Parker , Schaffer Sierra , Poullis Andrew
Published: May 2023

With medical litigation on the rise, physicians require a nuanced understanding of the legalities of consenting patients to reduce their liability while practising evidence-based medicine. This study aims to a) clarify the legal duties of gastroenterologists in the UK and USA when gaining informed consent and b) provide recommendations at the international and physician level to improve the consent process and reduce liability.

A bibliometric analysis of the Web of Science database with the MeSH terms “gastroenterology” and “informed consent” yielded 383 articles, of which 228 were excluded due to not meeting the inclusion criteria. Of the top 50 articles, 48% were from American institutions and 16% were from the UK. Thematic analysis showed 72% of the articles discussed informed consent in relation to diagnostic procedures, 14% regarding treatment, and 14% regarding research participation.

Both the USA and the UK have progressed from previously paternalistic Natanson case (1960) and Bolam test (1957), respectively, where physicians were held to the standard of a “reasonable and prudent medical doctor”. The American Canterbury case (1972) and the British Montgomery case (2015) radically shifted the standard of disclosure during the consent process by requiring physicians to explain all information pertinent to a “reasonable patient”.

It is our recommendation that a two-pronged approach be taken; a) creation of international guidelines for consenting patients for invasive procedures in gastroenterology, and b) development of internationally standardised endoscopy consent forms containing all the details pertinent to a “reasonable patient”.
Letter Spacing Does not Affect Memory and Metamemory
Authors: Luna Karlos , Bueno Daniel , Conde Emily , Bermúdez Daniela , Gutiérrez María Fernanda , Aldana Gabriela , Botía Inés , Rodríguez Valentina , Cadavid Sara
Published: May 2023

Some perceptual manipulations, such as font size or bolding, can affect the estimations of future memorability (i.e., judgments of learning or JOLs). In two experiments, we studied the effect on JOLs of another perceptual manipulation: the interletter spacing. Spacing may decrease JOLs via beliefs on the effect of spacing on memory, or it may increase JOLs via feelings of processing fluency. In Experiment 1, we found that people do not hold any particular belief on the effect of spacing on memory for a list of words. In Experiment 2, we found that letter spacing did not affect JOLs. We also replicated the results that participants believe that words in large font size will be better remembered and that they rate words in large font size with higher JOLs. In sum, this research showed that not all the perceptual characteristics are used as cues to metamemory.
New Types of Evidence in Online Learning Spaces: A Corpus-Based Study
Authors: Ling Mayyer , Elgort Irina
Published: May 2023

Following Hyland's model of metadiscourse, evidential is defined as an expression that references information from other texts. Evidence in traditional academic writing may include peer-reviewed articles, published books and personal communication with field experts. With a sharp increase in the use of online teaching and learning environments by education providers, such as Google Classroom and Canvas, and a vast range of sources of evidence available in non-traditional forms, are types of evidence in students’ academic writing changing and, if yes, how? In this study, we analysed the use of evidentials in course discussion forums by students at the Universiti Brunei Darussalam, revealing the types of evidence included in the writing. Our findings show that students’ academic writing in online teaching environments expands what is traditionally considered academic evidence to some extent, but more targeted teaching intervention may be needed to broaden the range and quality of evidentials used by students.
Research on constrained localization of ultrasound geometric distribution based on FHN neurons
Authors: Li Weiwei , Yuan Sen , Xiaorong Zhou , Qin Long , Xi Yue
Published: May 2023

The autopilot positioning process is mainly affected by three aspects: the first is the spatial geometric distribution of positioning sensors; the second is the screening of spurious observations; and the third is the equivalent ranging error. A constrained positioning method based on the geometric distribution of FitzHugh–Nagumo (FHN) neurons is proposed. To reduce the geometric accuracy factor, a Horizontal Dilution Of Precision value algorithm with a weight factor was proposed by considering the spatial geometric distribution of base stations and the geometric relationship of anchor points. This paper proposes a geometric constraint data processing method for the error of the pseudo-observation value. Finally, considering the significant weak signal perception ability of the biological nervous system, and the stochastic resonance phenomenon caused by noise can enhance the ability of the neuronal system to detect weak signals, an ultrasonic receiving method based on the stochastic resonance characteristics of FHN neuronal system is proposed, to enhance the signal and reduce noise. The results show that under the optimized base station layout and data geometric constraint processing, the ultrasonic wave based on FHN neuron improves the accuracy of spurious observations, reduces the calculation amount of geometric constraint processing, and reduces the positioning error by 66.67%, which provides a new direction for improving the positioning accuracy.
Making Way for Men: The Gendered Processes of Graduate Hiring in Elite Professional Service Firms in China
Authors: Ren Ran
Published: May 2023

Extensive research has been conducted on the reproduction of gender inequalities in professional hiring, despite the claim of meritocracy and commitment to equality in professional sectors. While the existing literature highlights the significance of understanding gender inequalities in the context of globalisation of professional firms and their practices, it has predominantly focused on the Anglo-Saxon context. There remains a gap in the literature regarding how gender inequalities are produced in professional hiring in the context of China. Drawing on qualitative material, this study explores the gendered processes of graduate hiring in elite professional firms in China. By applying the perspective of gender practices, this article elucidates how Chinese recruiters construct male favouritism and rig the selection process. The analysis sheds light on the processes that produce gender inequalities and hinder the progress of women in the context of growing competition and lack of support for women’s participation in professional work.
Have cycling-friendly cities achieved cycling equity? Analyses of the educational gradient in cycling in Dutch and German cities
Authors: Hudde Ansgar
Published: May 2023

In German cities, higher levels of education increase people’s propensity to cycle. However, it remains unknown whether this effect is restricted to certain contexts, such as cities with low or medium cycling rates, or whether it is a more universal occurrence. This paper develops and tests competing hypotheses on how the effect of education on cycling might depend on the overall cycling level: (a) educational inequalities in cycling could increase proportionally with the overall cycling level or (b) such inequalities might diminish in high-cycling cities because their advanced pro-cycling mobility cultures encourage cycling among all social groups. I analyse about 150,000 trips made by about 50,000 residents from 143 cities in the Netherlands and Germany using multilevel regression models. Results fall in between the competing hypotheses, meaning that the effect of education is similarly large in cities with low, medium, or high overall levels of cycling. Hence, there is no automatism in the sense that higher cycling shares in general will also imply greater cycling equity.
Time Series Trend in High BMI and High Out-of-Pocket Expenditure Among Women With Disability
Authors: Shin Sun Mi
Published: May 2023

Health with disability is directly related not only to an individual’s quality of life but also to national medical finance. This study focuses on trends in BMI and out-of-pocket (OOP) expenditure of both types of indirect cost exclusion and inclusion. Participants were women with disability (n = 3200) and women without disability (n = 53 082) among adults aged 19 and older from Korea Health Panel from 2009 to 2016. Women with disability had a higher BMI (23.9) than women without disability (22.7), and this time series trend was significant for 8 years ( P < .0001). Annual OOP expenditures of both types were higher for women with disability than for women without disability ( P < .0001): excluding indirect costs, $518.9 versus $649.4; Including indirect costs, $534.5 versus $681.8. The y-intercept of disability itself and slope of one unit of BMI for both types of annual OOP expenditure is significant ( P < 0001): excluding indirect cost, $29.0 and $4.4; including indirect cost, $35.2 versus $4.6. In women with disability, annual OOP expenditure for both types were higher when they were physically inactive ( P < .05): excluding indirect cost, $714.1 versus $823.1; including indirect cost, $746.2 versus $880.0. When physical inactivity and overweight and obesity interacted, it increased more than normal weight in dose response manner ( P < .05): excluding indirect costs, $799.2 < $800.3 < $886.1; Including indirect costs, $860.2 < $845.9 < $927.5. These results suggest that women with disability are in relatively poor health. It is proposed that inequality of BMI for women with disability can be developed as an agenda from health policy.
Digital Europeanism and extending the literary Europeanist discourse: The Twitter feeds of @PulseofEurope and @mycountryeurope
Authors: Lenehan Fergal , Lietz Roman
Published: May 2023

This article argues that the study of literary Europeanism should be extended to the discourse of wider textual Europeanism, understood here as a digital Europeanism that examines digital texts, in the widest sense, contextualised within the norms of digital culture. The texts emanating on the platform Twitter from two explicitly pro-European/pro-European Union accounts, one German-language and one largely (non-native) anglophone – @PulseofEurope and @mycountryeurope – were examined from 9 May 2021 to 9 November 2021. In evidence was a type of textual Europeanism that indeed owes a degree of coherence to the norms of digital culture. This was seen in relation to referentiality, that is, the use of already existing and circulating cultural materials for one’s own cultural production. This was evident in commented and uncommented retweets, social TV practices and the Europeanisation of Internet memes. The creation of a sense of communality – the way in which meanings can be stabilised, options for action generated and resources made accessible via a collectively supported frame of reference – is also in evidence and to be seen in the distinct discursive creation of an authoritarian ‘other’. This ‘other’ consists of a temporal ‘other’ – a small number of tweets relating to authoritarianisms of the past; an inner-European Union ‘other’ – tweets relating to movements towards authoritarianism within the European Union, especially in Hungary and Poland; and an external European Union other – tweets relating to authoritarianism on the European Union’s borders, especially in Belarus and Russia.
Thomas Carlyle, François Guizot and the Brothers Ruffini: An unpublished letter
Authors: Jordan Alexander
Published: May 2023

This article presents a letter from the great Victorian man of letters Thomas Carlyle (1795–1881) to François Guizot (1787–1874), the de facto premier of France, recently discovered in the Archives Nationales in Paris. In the letter, Carlyle requests Guizot’s help in procuring visas for two of his friends, the exiled Italian revolutionaries Giovanni and Agostino Ruffini, who were hoping to visit their mother in France. The letter serves as an entry point into a wider consideration of the relationships between Carlyle, Guizot and the brothers Ruffini, all of which have been overlooked in the existing scholarship on Carlyle. In particular, the article provides an English translation of Giovanni and Agostino’s significant accounts of their relations with Carlyle (and his wife Jane), originally written in Italian.