bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-01-05: Transcriptional signature of metastatic triple negative breast cancer in humanized mice
Authors: Yu Chun I , Wu Te-Chia , Menghi Francesca , George Joshy , Kim Kyung In , Marches Florentina , Liu Edison T , Banchereau Jacques , Palucka Karolina
Published: March 2022

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among ten PDX tumors tested, four did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastases (lung and liver). We find that different TNBC PDX tumors have different metastatic potential. Their metastatic potential is linked with differences in cellular composition and transcriptional signatures at the level of the primary tumor. Interferon Response signature is enriched in primary TNBC PDXs with metastatic potential, while non-metastatic primary tumors display a TNF signature as well as allograft rejection signature. Furthermore, liver metastases were enriched in myeloid transcripts. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis.

Citation Format: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Transcriptional signature of metastatic triple negative breast cancer in humanized mice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-05.
Abstract P5-06-13: Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen
Authors: Brown Edward , Desa Danielle , Brown Robert M , Brown Edward B , Hill Robert L , Turner Bradley M
Published: March 2022

Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects including increased appearance of the ‘tumor microenvironment of metastasis’ or TMEMs, image-based multicellular signatures which are prognostic of metastasis. In this study we explored whether NACT alters other image-based prognostic/predictive signatures, specifically second-harmonic generation (SHG) directionality, which is indicative of collagen fiber internal structure, as well as the disorganization in collagen fiber alignment. This was performed in paired biopsy/excision samples from 22 patients with HER2 overexpressing invasive ductal carcinoma as well as 22 patients with triple negative breast cancer (TNBC). We found that collagen fiber internal structure, measured using the SHG forward-to-backward-scattered ratio (F/B), is altered in the bulk of the tumor in both tumor types (p = 0.015 and 0.038, respectively), but not the adjacent tumor-stroma interface (p = 0.54 and 0.92, respectively), where F/B is prognostic of metastatic outcome. Overall disorganization in collagen fiber alignment was not significantly changed by NACT in HER2 overexpressing disease (p = 0.41) but was decreased in TNBC (p = 0.0051). These results suggest that NACT alters the collagenous extracellular matrix in diverse ways, with implications for the use of F/B and collagen fiber alignment as prognostic and predictive tools.

Citation Format: Edward Brown, Danielle Desa, Robert M Brown, Edward B Brown, Robert L Hill, Bradley M Turner. Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-13.
Abstract P5-07-07: Mapping clonal evolution and tumor heterogeneity by whole exome sequencing of tissue and plasma circulating tumor DNA in metastatic breast cancer
Authors: Kavan Stephanie , Kruse Torben A , Andersen Lars , Larsen Martin , Hildebrandt Malene G , Jylling Anne-Marie Bak , Ewertz Marianne , Vogsen Marianne , Thomassen Mads
Published: March 2022

Tumor heterogeneity in breast cancer tumors is widely recognized but evolution of the breast cancer genome is complex and not yet understood. Characterizing the evolutionary landscape of breast tumors can provide biological understanding of tumor progression and metastasis may be important for directing effective treatments. We performed copy number profiling and mutation detection based on whole exome sequencing of primary tumors, lymph node and distant metastasis as well as on plasma circulating tumor DNA from twelve metastatic breast cancer patients. Preliminary data shows diverse patterns of tumor evolution. Although linear evolution with late dissemination of metastatic cells was common, parallel evolution with early dissemination from primary tumor to distant sites was evident in some cases. Comparing tissue biopsies with plasma samples, we could detect variants mirroring primary tumor and/or metastasis, depending on the time span between the progression steps. The genomic discordance between the different stages of tumor evolution in these patients not only emphasizes the importance of molecular profiling of metastatic tissue but also the possibilities of liquid biopsies for real-time tracking of tumor clonal evolution.

Citation Format: Stephanie Kavan, Torben A Kruse, Lars Andersen, Martin Larsen, Malene G Hildebrandt, Anne-Marie Bak Jylling, Marianne Ewertz, Marianne Vogsen, Mads Thomassen. Mapping clonal evolution and tumor heterogeneity by whole exome sequencing of tissue and plasma circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-07.
Abstract P5-08-08: C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer
Authors: Rotolo Jim , Koester Mark , Ramirez Rick , Leong Siok , Ghamsari Lila , Gallagher Erin , Darvishi Emad , Merutka Gene , Kappel Barry
Published: March 2022

CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is an oncogenic transcription factor that is active in many cancers, where it drives the expression of factors that promote tumor survival and proliferation. In breast cancer, increased C/EBPβ expression is associated with a metastatic phenotype, high tumor grade and an overall poor prognosis (Zahnow, 2009). C/EBPβ forms dimers via leucine zipper domain interactions that are required for its transcriptional activity . ST101 is a novel peptide antagonist of C/EBPβ currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPβ leucine zipper domain and antagonizes it’s dimerization, resulting in increased C/EBPβ proteosomal degredation and significantly decreased target gene transactivation. Here, we describe the non-clinical anti-tumor activity of ST101 against breast cancer. In vitro studies in 4T1-luc triple-negative (TNBC) and MCF7 HRPOS BC cells demonstrate ST101 dose-dependent cytotoxicity (EC50 of 4.8 and 2.1 µM, respectively), accompanied by significant impact on C/EBPβ-mediated gene expression as determined by qPCR analysis. In contrast, normal human mammary epithelial cells were not sensitive to ST101 (EC50 >100 µM). In HR-negative BC and TNBC tumoroids in vitro, ST101 exposure resulted in a dose-dependent reduction in proliferation and viability, with EC50 values of 18.56 and 15.32 µM, respectively. In vivo experiments indicate significant anti-tumor activity. In a MCF7 subcutaneous xenograft model, 25 mg/kg ST101 resulted in tumor growth delay and a significant decrease in tumor volume (p<0.001 vs. controls). In a 4T1-luc orthotopic model, ST101 resulted in dose-dependent tumor growth inhibition, and tumor regression following 25 mg/kg ST101 (p<0.001 vs. controls). These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and triple-negative BC.

Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Siok Leong, Lila Ghamsari, Erin Gallagher, Emad Darvishi, Gene Merutka, Barry Kappel. C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-08.
Abstract P5-12-12: The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer
Authors: Sedano Melina J , Harrison Alana L , le Ine , Gadad Shrikanth S
Published: March 2022

Breast cancer is the second leading cause of cancer mortality in women after lung cancer; however, it is the primary cause of death among Hispanic women. About 10-20% of breast cancers are basal (triple-negative) subtype at the time of diagnosis, and they do not respond well to treatment regimens due to a lack of specific targets. Triple-negative breast cancer is a deadly and very aggressive tumor type associated with poor prognosis compared to other molecular subtypes of breast cancer, especially among Hispanic women. Thus, identifying novel molecules with prognostic and therapeutic value is critical to treat this ever-evolving disease. Numerous studies suggest that genes transcribed from chromosome X (X-linked genes) are implicated in cancers. The expression of these genes is tightly regulated and restricted to immune-privileged organs; however, many of them escape regulation and become aberrantly expressed in tumors.Interestingly, our genomic analysis suggests that several newly annotated X-linked genes are cancer testis-antigens (CT genes) that are highly antigenic and are located at regions previously considered to be gene deserts in the human genome. To date, very minimal is known about their expression and role in triple-negative breast cancer. In this regard, we used an integrated genomic approach to identify testis-tissue-specific genes that are differentially expressed in triple-negative breast cancer. Further, we identified a highly immunogenic cancer-testis gene by incorporating cutting-edge technology-driven (Global Run-On Sequencing) gene expression analysis. Mechanistically, by using cell-, mouse-based, and genomic approaches, we have found that candidate CT gene modulates gene expression, immune response, and tumor growth in triple-negative breast cancer. Hence, it has the potential to change the way triple-negative breast cancer is diagnosed and treated. S.S.G. is supported by a First-time Faculty Recruitment Award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation.

Citation Format: Melina J Sedano, Alana L Harrison, Ine le, Shrikanth S Gadad. The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-12.
Abstract P5-12-13: Exploring the impact of the tumor microenvironment on nuclear morphometry: Lessons learned for sensitivity to cytotoxic treatment
Authors: Chhetri Apekshya
Published: March 2022

Globally, breast cancer remains the leading cause of death in females. While systemic therapy for breast cancer may work effectively in the early phases, for more than 10% of primary and 50% of metastatic cases, the disease eventually progresses, resisting treatments. To overcome this issue, recognizing markers of resistance as early as possible is critical. Microenvironmental factors influence tumors, and increased stiffness of the extracellular matrix (ECM) is associated with cancer progression. Additionally, neighboring cells such as non-neoplastic epithelial cells(that may constitute an important portion of the tumor microenvironment -TME) are suspected to affect tumors, but details on their impact are lacking. Here, we asked whether the response to increased ECM stiffness differed depending on the degree of aggressiveness of triple negative breast cancers (TNBC) and the presence of the non-neoplastic epithelium. We investigated two morphometric parameters, nuclear circularity and area (used in cancer pathology), and tumors’ sensitivity to cisplatin to assess tumor aggressiveness- with TNBC cultured at normal (770 Pa) and increased (2000 and 3300 Pa) collagen I stiffness. Reduced nuclear circularity and increased heterogeneity for this parameter in the cancer cell population resulted from higher matrix stiffness and were associated with decreased sensitivity to the cytotoxic drug, cisplatin, notably in the more invasive cancer type. Interestingly, the impact of stiffness increase was reduced by the conditioned medium from the non-neoplastic cells. These findings warrant further investigations to identify whether changes in nuclear circularity that illustrate a global nuclear reorganization affect gene expression profiles linked to cell survival.

Citation Format: Apekshya Chhetri. Exploring the impact of the tumor microenvironment on nuclear morphometry: Lessons learned for sensitivity to cytotoxic treatment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-13.
Abstract P5-13-31: Pik3ca mutations and myc amplification are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment
Authors: Shi Qiyun , Xuhong Juncheng , Ge Jia , Liu Feng , Lan Yang , Zhang Yi , Tao Luo , BIan Xiuwu , Qi Xiaowei , Jiang Jun
Published: March 2022

Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods:To date, a total of 162 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results:. Among the cohort of 162 cases, a total of 43 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 25 of them achieved total pCR. The most frequently mutated driver genes were TP53 (80%), PIK3CA (46%), ERBB2 (10%), NF1 (8%), NBN (8%), ATRX (8%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (66%), MYC (24%), CKD12 (14%), CCND1 (12%) and ZNF217 (12%), respectively. The median tumor mutation burden (TMB) was 4.76 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had higher median TMB but not statistically significant (5.29 vs 3.85 mut/Mb, P=0.141). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (80.0% vs 27.8%, P = 0.001), and those with amplified MYC are more likely to achieve pCR (22.2% vs 67.6%, P = 0.023). Conclusions:Preliminary results suggested that HER2-positive breast cancer patients with activating mutations in PIK3CA and amplified MYC are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate.

Citation Format: Qiyun Shi, Juncheng Xuhong, Jia Ge, Feng Liu, Yang Lan, Yi Zhang, Luo Tao, Xiuwu BIan, Xiaowei Qi, Jun Jiang. Pik3ca mutations and myc amplification are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-31.
Abstract P5-17-06: P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer
Authors: Rajan Priyanka , Zonneville Justin , Colligan Sean , Abrams Scott , Bakin Andrei
Published: March 2022

The immune suppressive tumor microenvironment (TME) in metastatic breast cancer (MBC) limits the benefits of immunotherapy with immune checkpoint inhibitors (ICIs). In particular, the primary TME drives the expansion and recruitment of immune suppressive myeloid cell populations, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Treatments targeting these populations can potentially improve the efficacy of ICI therapy. To that end, our published and new findings have revealed that the p38 Mitogen-Activated Protein Kinase (MAPK) contributes to the expansion and mobilization of TAMs and MDSCs. Further, we found that pharmacological blockade of p38 decreased metastasis and increased the levels of CD8+ T cells while decreasing TAMs in the primary TME. Depletion of PMN-MDSCs, a major MDSC subset, was accompanied by reduced TAM infiltration and phenocopied the anti-metastatic effects of p38 blockade. Next, we explored the impact of p38 blockade on the composition and functionality of the immune populations in the primary TME by using single-cell RNA-sequencing. We found that p38 blockade increased levels of Irf8+ monocytic populations, indicating a decrease in immune-suppressive properties of the TME. Notably, p38 blockade increased the expression of factors related to the activation of CD8+ cytotoxic T lymphocytes, i.e., Jchain, Icos, and Cd137. Thus, our data indicate that p38 blockade alters the immune landscape within the primary TME and favors an antitumor immune response. Our data also suggest that the p38 kinase controls the production of tumor-derived factors (TDFs) which facilitate the recruitment of those pro-tumor myeloid populations. Thus, we explored this p38-TDF-myeloid axis by using trans-well migration assays. We tested the migration of the monocyte-like cell line RAW 264.7 in response to tumor-conditioned media prepared from tumor cells treated with or without the p38 inhibitor, Ralimetinib. Our data showed that the migration of RAW 264.7 cells was significantly diminished towards the conditioned media from tumor cells treated with the p38 inhibitor or from tumor cells with a genetic inactivation of p38α by CRISPR/Cas9 compared to the corresponding controls. Altogether, our studies demonstrate that p38 kinase is a potential therapeutic target, which reshapes the immune suppressive contexture of TME in MBC to improve antitumor immunity.

Citation Format: Priyanka Rajan, Justin Zonneville, Sean Colligan, Scott Abrams, Andrei Bakin. P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-06.
Abstract PD5-09: Work status changes and associated factors in a nation-wide sample of 1324 Norwegian long-term breast cancer survivors
Authors: Bøhn Synne-Kristin Hoffart , Vandraas Kathrine , Kiserud Cecilie E , Dahl Alv A , Ewertz Marianne , Lie Hanne Cathrine , Falk Ragnhild , Reinertsen Kristin Valborg
Published: March 2022

Background: Little is known about work participation in breast cancer survivors (BCSs) beyond two years after diagnosis. This study aims to report work status at diagnosis and at eight years post-diagnosis in a nation-wide sample of BCSs, investigate factors associated with reduced work status, and report on self-perceived reasons for reduced work status or disability pension. Material and Methods: Women diagnosed with stage I-III BC at the age of 20-65 years in 2011 or 2012 were invited to participate (n=2,803), of which 49 % (n=1361) responded. The response rate was 49 % (n=1361). A final sample of 1324 BCSs with complete questionnaire information regarding work status were included in the present study. Logistic regression analyses were applied to identify factors associated with reduced work status. Results At diagnosis, 78% (n=1038) of the BCSs were in paid work, 12% received disability pension and 4 % held early retirement. At survey, 42% of the BCSs were in paid work, 26% held disability pension and 28% were retired. Of the 845 survivors who were in paid work at diagnosis and within working age at survey, 63% maintained their work status, while 37% reduced their work status. Living with children (OR 0.4, p=.007), older age (OR 1.2, p<.001), chemotherapy (OR 2.9, p=.013), three or more comorbid conditions (OR 2.2, p=.016), higher level of fatigue (OR 1.02, p<.001), symptoms of cognitive dysfunction (OR 0.9, p=.038) and higher degree of neuroticism (OR 1.2, p=.012) were associated with reduced work status. BC, complaints and late effects after BC were reported as the main or partial reason for reduced work status and disability. Conclusion Almost two thirds of BCSs in working age who were in paid work at diagnosis remained in the paid work force eight years later. Individual characteristics and various health complaints including fatigue end cognitive dysfunction were associated with reduced work status from diagnosis to survey. Evaluation and treatment of these conditions are warranted, with the ultimate aim of improving work maintenance in long-term BCSs.

Citation Format: Synne-Kristin Hoffart Bøhn, Kathrine Vandraas, Cecilie E Kiserud, Alv A Dahl, Marianne Ewertz, Hanne Cathrine Lie, Ragnhild Falk, Kristin Valborg Reinertsen. Work status changes and associated factors in a nation-wide sample of 1324 Norwegian long-term breast cancer survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-09.
Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy
Authors: Zuo Qianying , Mogol Ayca Nazli , Liu Yu-Jeh , Santaliz Casiano Ashlie , Chien Christine , Drnevich Jenny , Imir Ozan Berk , Kulkoyluoglu-Cotul Eylem , Park Nicole Hwajin , Shapiro David J. , Park Ben Ho , Ziegler Yvonne , Katzenellenbogen Benita S. , Aranda Evelyn , O'Neill John D. , Raghavendra Akshara Singareeka , Tripathy Debu , Madak Erdogan Zeynep
Published: March 2022

Estrogen receptor–positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer–related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared with other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung, and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to fulvestrant. Furthermore, differential ER± activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of fulvestrant treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment.

Implications:

These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

Watch the interview with Zeynep Madak-Erdogan, PhD, recipient of the 2024 MCR Michael B. Kastan Award for Research Excellence: https://vimeo.com/992993791
IDH1 Inhibition Reawakens the Immune Response against Cholangiocarcinoma
Authors: Zhu Yan , Kwong Lawrence N.
Published: March 2022

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma, but their exact mechanisms in cholangiocarcinoma initiation and maintenance are unclear. In this issue of Cancer Discovery, Wu and colleagues identify immune suppression via TET2 inactivation as the primary means by which mIDH1 maintains cholangiocarcinoma survival, leading to an efficacious new combination of mIDH1 inhibitors and immune checkpoint blockade targeting regulatory T cells.

See related article by Wu et al., p. 812 (9).
Retained Medullary Cord Associated with Terminal Myelocystocele and Intramedullary Arachnoid Cyst
Authors: Kurogi Ai , Murakami Nobuya , Mukae Nobutaka , Shimogawa Takafumi , Shono Tadahisa , Suzuki Satoshi O. , Morioka Takato
Published: March 2022

Introduction: The retained medullary cord (RMC) is a newly defined entity of closed spinal dysraphism that is thought to originate from regression failure of the medullary cord during the last phase of secondary neurulation. The terminal myelocystocele (TMC) is an unusual type of closed spinal dysraphism, characterized by localized cystic dilatation of the terminal part of the central canal that then herniates through a posterior spinal bifida. The co-occurrence of RMC and TMC is extremely rare. Case Presentation: We treated a baby girl with a huge sacrococcygeal meningocele-like sac with two components. Untethering surgery and repair surgery for the sac revealed that RMC, associated with intramedullary arachnoid cyst (IMAC), was terminated at the bottom of the rostral cyst, forming the septum of the two cystic components, and the caudal cyst was TMC derived from the central canal-like ependymal lining lumen (CC-LELL) of the RMC at the septum. IMAC within the RMC communicated with TMC, and both contained xanthochromic fluid with the same properties. Conclusion: We speculated that the mass effect of the coexistent IMAC impeded the flow of cerebrospinal fluid in the CC-LELL within the RMC and eventually formed a huge TMC. In surgical strategies for such complex pathologies, it is important to identify the electrophysiological border between the functional cord and nonfunctional RMC and the severe RMC to untether the cord, as with a typical or simple RMC.
Challenges of Neural Machine Translation for Short Texts
Authors: Wan Yu , Yang Baosong , Wong Derek Fai , Chao Lidia Sam , Yao Liang , Zhang Haibo , Chen Boxing
Published: March 2022

Short texts (STs) present in a variety of scenarios, including query, dialog, and entity names. Most of the exciting studies in neural machine translation (NMT) are focused on tackling open problems concerning long sentences rather than short ones. The intuition behind is that, with respect to human learning and processing, short sequences are generally regarded as easy examples. In this article, we first dispel this speculation via conducting preliminary experiments, showing that the conventional state-of-the-art NMT approach, namely, Transformer (Vaswani et al. 2017), still suffers from over-translation and mistranslation errors over STs. After empirically investigating the rationale behind this, we summarize two challenges in NMT for STs associated with translation error types above, respectively: (1) the imbalanced length distribution in training set intensifies model inference calibration over STs, leading to more over-translation cases on STs; and (2) the lack of contextual information forces NMT to have higher data uncertainty on short sentences, and thus NMT model is troubled by considerable mistranslation errors. Some existing approaches, like balancing data distribution for training (e.g., data upsampling) and complementing contextual information (e.g., introducing translation memory) can alleviate the translation issues in NMT for STs. We encourage researchers to investigate other challenges in NMT for STs, thus reducing ST translation errors and enhancing translation quality.
Assessing Corpus Evidence for Formal and Psycholinguistic Constraints on Nonprojectivity
Authors: Yadav Himanshu , Husain Samar , Futrell Richard
Published: March 2022

Formal constraints on crossing dependencies have played a large role in research on the formal complexity of natural language grammars and parsing. Here we ask whether the apparent evidence for constraints on crossing dependencies in treebanks might arise because of independent constraints on trees, such as low arity and dependency length minimization. We address this question using two sets of experiments. In Experiment 1, we compare the distribution of formal properties of crossing dependencies, such as gap degree, between real trees and baseline trees matched for rate of crossing dependencies and various other properties. In Experiment 2, we model whether two dependencies cross, given certain psycholinguistic properties of the dependencies. We find surprisingly weak evidence for constraints originating from the mild context-sensitivity literature (gap degree and well-nestedness) beyond what can be explained by constraints on rate of crossing dependencies, topological properties of the trees, and dependency length. However, measures that have emerged from the parsing literature (e.g., edge degree, end-point crossings, and heads’ depth difference) differ strongly between real and random trees. Modeling results show that cognitive metrics relating to information locality and working-memory limitations affect whether two dependencies cross or not, but they do not fully explain the distribution of crossing dependencies in natural languages. Together these results suggest that crossing constraints are better characterized by processing pressures than by mildly context-sensitive constraints.
On the Road: Poor Travelers in Mid-Seventeenth-Century Friesland
Authors: de Vries Jan
Published: March 2022

Outsiders—some traveling to a possible place of employment or refuge and some wandering as vagabonds with an eye on the main chance—were a constant presence in early modern Europe. But their stories are faint to nonexistent in most of the archival records available to historians. Such records illuminate the lives of the permanent, rooted, populations but rarely reveal much about those who stood outside the local communities through which they passed on their journeys. Analysis of a large, unusual data set compiled in the small Dutch city of Franeker in the mid-seventeenth century, however, uncovers the circumstances and motives of poor travelers and indigent wayfarers who passed through the city, providing a glimpse into the lives of a population otherwise largely hidden.
Assembling Path Dependency and History: An Actor-Network Approach
Authors: De Munck Bert
Published: March 2022

Historians and social scientists struggling to redefine the relationship between synchrony (structure) and diachrony (events and human agency) have recently turned to the notion of path dependence, the core idea of which is that history matters. But history and path-dependence theory have less in common than might appear at first glance. Actor-network theory (ant) helps to bridge the gap between history and path dependence by incorporating the complex, layered, open, and hybrid nature of interlocked economic, symbolic, institutional-political, and socio-technical systems.
Shared Attention Amplifies the Neural Processing of Emotional Faces
Authors: Schiano Lomoriello Arianna , Sessa Paola , Doro Mattia , Konvalinka Ivana
Published: March 2022

Sharing an experience, without communicating, affects people's subjective perception of the experience, often by intensifying it. We investigated the neural mechanisms underlying shared attention by implementing an EEG study where participants attended to and rated the intensity of emotional faces, simultaneously or independently. Participants performed the task in three experimental conditions: (a) alone; (b) simultaneously next to each other in pairs, without receiving feedback of the other's responses (shared without feedback); and (c) simultaneously while receiving the feedback (shared with feedback). We focused on two face-sensitive ERP components: The amplitude of the N170 was greater in the “shared with feedback” condition compared to the alone condition, reflecting a top–down effect of shared attention on the structural encoding of faces, whereas the EPN was greater in both shared context conditions compared to the alone condition, reflecting an enhanced attention allocation in the processing of emotional content of faces, modulated by the social context. Taken together, these results suggest that shared attention amplifies the neural processing of faces, regardless of the valence of facial expressions.
Neural Activity during Story Listening Is Synchronized across Individuals Despite Acoustic Masking
Authors: Irsik Vanessa C. , Johnsrude Ingrid S. , Herrmann Björn
Published: March 2022

Older people with hearing problems often experience difficulties understanding speech in the presence of background sound. As a result, they may disengage in social situations, which has been associated with negative psychosocial health outcomes. Measuring listening (dis)engagement during challenging listening situations has received little attention thus far. We recruit young, normal-hearing human adults (both sexes) and investigate how speech intelligibility and engagement during naturalistic story listening is affected by the level of acoustic masking (12-talker babble) at different signal-to-noise ratios (SNRs). In , we observed that word-report scores were above 80% for all but the lowest SNR (−3 dB SNR) we tested, at which performance dropped to 54%. In , we calculated intersubject correlation (ISC) using EEG data to identify dynamic spatial patterns of shared neural activity evoked by the stories. ISC has been used as a neural measure of participants' engagement with naturalistic materials. Our results show that ISC was stable across all but the lowest SNRs, despite reduced speech intelligibility. Comparing ISC and intelligibility demonstrated that word-report performance declined more strongly with decreasing SNR compared to ISC. Our measure of neural engagement suggests that individuals remain engaged in story listening despite missing words because of background noise. Our work provides a potentially fruitful approach to investigate listener engagement with naturalistic, spoken stories that may be used to investigate (dis)engagement in older adults with hearing impairment.
Alpha and Theta Bands Dynamics Serve Distinct Functions during Perception–Action Integration in Response Inhibition
Authors: Prochnow Astrid , Eggert Elena , Münchau Alexander , Mückschel Moritz , Beste Christian
Published: March 2022

The ability to inhibit responses is central for situational behavior. However, the mechanisms how sensory information is used to inform inhibitory control processes are incompletely understood. In the current study, we examined neurophysiological processes of perception–action integration in response inhibition using the theory of event coding as a conceptual framework. Based on theoretical considerations, we focused on theta and alpha band activity in close connection to the functional neuroanatomical level using EEG beamforming. Moreover, we performed a network-based analysis of theta and alpha band activity. We show a seesaw-like relationship between medial and superior frontal cortex theta band activity and frontoparietal cortex alpha band activity during perception–action integration in response inhibition, depending on the necessity to reconfigure perception–action associations. When perception–action integration was more demanding, because perception–action associations (bindings) have to be reconfigured, there was an increase of theta and a decrease of alpha band activity. Vice versa, when there was no need to reconfigure perception–action bindings, theta band activity was low and alpha band activity was high. However, theta band processes seem to be most important for perception–action integration in response inhibition, because only the sensor-level network organization of theta band activity showed variations depending on the necessity to reconfigure perception–action associations. When no reconfiguration was necessary, the network architecture was more small-world-like, likely enabling efficient processing. When reconfigurations were necessary, the network organization becomes more random. These differences were particularly strong for fractions of the neurophysiological signal supposed to reflect response selection processes.
Jamesian Ethics: A Working Model
Authors: Throntveit Trygve
Published: March 2022

In this essay I respond to critical readers of my book, William James and the Quest for an Ethical Republic. I argue that James’s ultimate preoccupations are ethical, and that his ethical and moral writings constitute a rich resource for pluralistic societies seeking democratic tools for negotiating deep ideological, cultural, and religious differences, and for building a thriving commons.
Christian Fundamentalism in Japan
Authors: Ruotsila Markku
Published: March 2022

This article examines the ultimately unfruitful attempts by U.S. Christian fundamentalists at establishing a presence within Japanese Protestantism. Almost unknown even to scholars in the field, this missionary effort was launched in 1949. It yielded several indigenous institutions, including the Tokyo Christian Theological Seminary, the Japan Bible Times, and the Christian Presbyterian Church of Japan. This uniquely American import of a fundamentalist defense of the “faith once received” is here put in regional, anti-communist and intercultural contexts.
Cymbidium purpureisepalum (Orchidaceae; Epidendroideae), a new species from China: evidence from morphological and molecular data
Authors: ZHU MENG-JIA , KE SHIJIE , ZHAO XUEWEI , WANG QIAN-QIAN , CHEN GUIZHEN , LIU ZHONG-JIAN , LAN SIREN
Published: March 2022

A new orchid species, Cymbidium purpureisepalum, from Yunnan Province, China, is described and illustrated based on morphological and molecular analyses. Detailed comparison of the newly discovered orchid with other members of Cymbidium indicated the new orchid is distinct from all other recognised species in Cymbidium. Molecular analyses based on nuclear (nrITS) and plastid DNA (matK) sequence data also support the status of C. purpureisepalum as a new species, which is sister to C. tortisepalum and C. serratum.
Chrysopogon densipaniculatus (Poaceae: Andropogoneae): a new species from India
Authors: TIWARI ARJUN PRASAD , LANDGE SHAHID NAWAZ
Published: March 2022

Chrysopogon densipaniculatus, a remarkable new species has been described and illustrated from Korba district of Chhattisgarh, India. The species is allied to C. serrulatus but may be distinguished by the dense panicle inflorescence, glandular peduncle, upper lemma and palea of the pedicelled spikelet bi-dentate to tridentate, the latter of which is reduced a minute scale. Detailed morphological description, distribution, habitat and ecology, illustration of floral parts and colour photographs, IUCN conservation status and relevant taxonomic notes of the species are provided. A key for the identification of Chrysopogon species in India is also given to facilitate the proper identification.
The Batrisini of Tibet: unveiling an enigmatic ant-loving beetle diversity at Earth’s “Third Pole” (Coleoptera, Staphylinidae, Pselaphinae)
Authors: YIN ZI-WEI
Published: March 2022

The taxonomic knowledge of the pselaphine tribe Batrisini (Coleoptera: Staphylinidae) from the Tibet Autonomous Region is summarized, with 80 species placed in 13 genera. Two genera and 68 species are described as new, aided with illustrations of habitus and diagnostic characters: Arthromelodes alpitorus sp. nov., A. angulatus sp. nov., A. aniqiao sp. nov., A. bicolor sp. nov., A. complexus sp. nov., A. cona sp. nov., A. crassicornis sp. nov., A. criniger sp. nov., A. cylindricus sp. nov., A. flosculus sp. nov., A. gyamda sp. nov., A. intricatus sp. nov., A. lage sp. nov., A. langjicuo sp. nov., A. latithorax sp. nov., A. lebus sp. nov., A. lotus sp. nov., A. markam sp. nov., A. monba sp. nov., A. nepaeformis sp. nov., A. nomurai sp. nov., A. songxiaobini sp. nov., A. speciosus sp. nov., A. torus sp. nov., A. zhangmu sp. nov., A. zhentangensis sp. nov., Batriscenaulax campestris sp. nov., Batrisiella acclivis sp. nov., Batrisiella beibeng sp. nov., Batrisiella bomea sp. nov., Batrisiella concisa sp. nov., Batrisiella curvitibialis sp. nov., Batrisiella ganma sp. nov., Batrisiella guttata sp. nov., Batrisiella zhujianqingi sp. nov., Batrisodes guoguotang sp. nov., Batrisodes hanmi sp. nov., Coryphomimus levigatus gen. et sp. nov., Coryphomodes budda sp. nov., Coryphomodes cephalicus sp. nov., Coryphomodes chenzhilini sp. nov., Gyrongita uniformis gen. et sp. nov., Sathytes aequalis sp. nov., S. asura sp. nov., S. caichenyangi sp. nov., S. dawai sp. nov., S. duojii sp. nov., S. laticornis sp. nov., S. pengzhongi sp. nov., S. proclivis sp. nov., S. pseudograndis sp. nov., S. sympatricus sp. nov., S. virupaksa sp. nov., S. yigongensis sp. nov., Tribasodites bari sp. nov., T. cellulanus sp. nov., T. constrictus sp. nov., T. dilophus sp. nov., T. elongatus sp. nov., T. grandiceps sp. nov., T. gyirong sp. nov., T. kiypu sp. nov., T. mirabilis sp. nov., T. prolixicornis sp. nov., T. pugiunculus sp. nov., T. vertexalis sp. nov., T. yatung sp. nov., and Trisinus quadrilobus sp. nov. The genus Plocamarthrus Jeannel, 1960 is proposed as a subjective junior synonym of Arthromelodes Jeannel 1954, syn. nov., resulting in Arthromelodes championi (Jeannel, 1960) comb. nov. (type species of Plocamarthrus), A. cameroni (Jeannel, 1960) comb. nov., A. planiceps (Jeannel, 1960) comb. nov., and A. abdominalis (Jeannel, 1960) comb. nov. Arthromelodes championi and Sathytes simplex Löbl, 1979 are reported to occur in Tibet, which are also new country records for China. Additional collecting data are provided for Hingstoniella lata Jeannel, 1960, Sathytes panzhaohuii Yin & Shen, 2020, Sathytes transversus Yin & Shen, 2020, and Sathytes xizangensis Yin & Shen, 2020. Keys for identification of the genera and species are presented. Maps showing the distribution of each species are provided, supplemented with habitat photos. Lists of Tibetan species of Batrisini and of other pselaphine groups are given, adding up to 95 species.
Analysing the Gig Economy in India and Exploring Various Effective Regulatory Methods to Improve the Plight of the Workers
Authors: Choudhary Vedant , Shireshi Shambhulinganand S.
Published: March 2022

Over the past decades, there has been a steady increase in the number of people involved in ‘flexible’ labour, more commonly known as ‘gig’ work. This has stimulated discussions over its various characteristics, including the lifestyle, mental health, fair treatment and overall well-being of gig workers. This article seeks to understand how the plight of gig workers can be reduced by effective regulation. For this, the authors identify seven characteristic features of the gig economy that harm the workers’ well-being. Then, the authors explain mechanisms in which the plight of these workers resulting from these seven factors can be reduced through efficient regulation. For this, the authors incorporate particular suggestions offered by some scholars outside India and modify them to suit the Indian context better. The authors also forward novel methods to regulate the gig economy. This article first defines and describes the gig economy. After that, it discusses various aspects like the quality of life, position of women and workplace dynamics of the gig economy. Then, this article recommends seven ways in which the sufferings of the workers can be reduced, and the gig economy can be better regulated in India.
Take a chance: Trust-building across identity groups
Authors: Herrera Yoshiko M , Kydd Andrew H
Published: March 2022

Mistrust is a common cause of conflict between individuals belonging to different identity groups. When can such mistrust be overcome? We present a theoretical model of trust-building across social identity groups to address this question. Trust between groups increases when individuals in one group are willing to take a chance on engaging with members of the other group, their engagement is positively reciprocated, and they are able to credibly communicate the experience to their fellow group members, thereby increasing their belief that members of the other group are trustworthy. This process is made easier if the individuals are not too hostile to the out-group, are flexible enough to change their beliefs in response to new information, and are sufficiently attached to their own group to be honest about their experiences with out-group members.
Blunt head trauma in a peculiar case of partial mummification. Murder or accidental event?
Authors: Barranco Rosario , Castelletti Lara , Fossati Francesca , Zotti Mirca , Orcioni Giulio Fraternali , Verdiani Simonetta , Ventura Francesco
Published: March 2022

The finding of a partially mummified body presenting signs of trauma requires the forensic pathologist to conduct a careful and complex examination; multidisciplinary analysis is often necessary.

We report a case where the partially mummified corpse of an elderly man was found in his own home more than seven years after death. Complete post-mortem investigation revealed a cranial fracture and an acute subdural haematoma.

An in-depth multidisciplinary analysis provided important information on the modality and cause of death but it was not possible to establish whether the trauma and death resulted from an accidental event or from an assault.