bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Materials from CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility
Authors: Du Mulong , Xin Junyi , Zheng Rui , Yuan Qianyu , Wang Zhihui , Liu Hongliang , Liu Hanting , Cai Guoshuai , Albanes Demetrius , Lam Stephen , Tardon Adonina , Chen Chu , Bojesen Stig E. , Landi Maria Teresa , Johansson Mattias , Risch Angela , Bickeböller Heike , Wichmann H-Erich , Rennert Gad , Arnold Susanne , Brennan Paul , Field John K. , Shete Sanjay S. , Le Marchand Loïc , Liu Geoffrey , Andrew Angeline S. , Kiemeney Lambertus A. , Zienolddiny Shan , Grankvist Kjell , Johansson Mikael , Caporaso Neil E. , Cox Angela , Hong Yun-Chul , Yuan Jian-Min , Schabath Matthew B. , Aldrich Melinda C. , Wang Meilin , Shen Hongbing , Chen Feng , Zhang Zhengdong , Hung Rayjean J. , Amos Christopher I. , Wei Qingyi , Lazarus Philip , Christiani David C.
Published: February 2024

Supplementary Methods and Figures
Supplementary File S2 from Deep Learning–Based 3D Single-Cell Imaging Analysis Pipeline Enables Quantification of Cell–Cell Interaction Dynamics in the Tumor Microenvironment
Authors: Liu Bodong , Zhu Yanting , Yang Zhenye , Yan Helen H.N. , Leung Suet Yi , Shi Jue
Published: February 2024

This file contains the Supplementary Figures S1-S4 and the figure legend.
Supplementary Tables from Mesothelin Secretion by Pancreatic Cancer Cells Co-opts Macrophages and Promotes Metastasis
Authors: Luckett Teifion , Abudula Maidinaimu , Ireland Lucy , Glenn Mark , Bellomo Gaia , Stafferton Ruth , Halloran Chris , Ghaneh Paula , Jones Rob , Schmid Michael C. , Mielgo Ainhoa
Published: February 2024

Supplementary Tables
Supplementary Figure S9 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

ROC curves and AUC values for MVPs with dynamic expression and static expression, and TMBM.
Supplementary Figure S8 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

ROC curves and AUC values for MVP, MVP_32, MVP_19, and TMBM in the three validation cohorts.
Supplementary Figure S7 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

ROC curves and AUC values for MVP and MVP using ssGSEA to measure pathway activity in the three validation cohorts.
Supplementary Figure S6 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

ROC curves and AUC values for MVP, MVP_noCTL, MVP_noCXCR3, and MVP_noCTL&CXCR3 in the three validation cohorts.
Supplementary Figure S4 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

Differential expression of ICI-related biomarkers and dysregulated ligand-receptor in the breast cancer study. A. Different expression of ICI-related biomarkers in responders and non-responders in each cell type. Dot plot for IFNG, IRF1, LAG3, CXCL10, CXCL11 and CXCR3. The color intensity of each dot corresponds to gene expression level, with dot’s size indicating the percentage of cells expressing that gene. B. Dysregulated IFNG-IFNGR2, CXCL10-CXCR3 and CXCL11-CXCR3 interactions in responders compared to non-responders.
Supplementary Data from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Supplementary Methods and Materials, supplementary tables, supplementary figure legends
Figure S5 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S5
Table S9 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

Differential gene expression of K562 U2AF1-WT and U2AF1-S34F cells
Table S8 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

Alternative splicing analysis of K562 SRSF2-WT and SRSF2-P95H cells
Figure S1 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S1
Table S5 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

List of inhibitors for drug screen and IC50 summary
Table S1 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

List of antibodies
Figure S1-S8 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

Supplementary Figures S1-8
Data from Fimepinostat Impairs NF­κB and PI3K/AKT Signaling and Enhances Gemcitabine Efficacy in H3.3K27M-Diffuse Intrinsic Pontine Glioma
Authors: Wang Dan , Yan Kun , Yu Hongxing , Li Haocheng , Zhou Wei , Hong Yaqiang , Guo Shuning , Wang Yi , Xu Cheng , Pan Changcun , Tang Yujie , Liu Nian , Wu Wei , Zhang Liwei , Xi Qiaoran
Published: February 2024

Abstract
Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci. Gemcitabine simultaneously induced a prosurvival program in DIPG through activation of RELB-mediated NF­κB signaling. Specifically, gemcitabine induced the transcription of long terminal repeat elements, activated cGAS-STING signaling, and stimulated noncanonical NF­κB signaling. A drug screen in gemcitabine-treated DIPG cells revealed that fimepinostat, a dual inhibitor of HDAC and PI3K, effectively suppressed the gemcitabine-induced NF­κB signaling in addition to blocking PI3K/AKT activation. Combination therapy comprising gemcitabine and fimepinostat elicited synergistic antitumor effects in vitro and in orthotopic H3.3K27M DIPG xenograft models. Collectively, p53 activation using gemcitabine and suppression of RELB-mediated NF­κB activation and PI3K/AKT signaling using fimepinostat is a potential therapeutic strategy for treating H3.3K27M DIPG.
Significance:
Gemcitabine activates p53 and induces apoptosis to elicit antitumor effects in H3.3K27M DIPG, which can be enhanced by blocking NF­κB and PI3K/AKT signaling with fimepinostat, providing a synergistic combination therapy for DIPG.
Data from CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility
Authors: Du Mulong , Xin Junyi , Zheng Rui , Yuan Qianyu , Wang Zhihui , Liu Hongliang , Liu Hanting , Cai Guoshuai , Albanes Demetrius , Lam Stephen , Tardon Adonina , Chen Chu , Bojesen Stig E. , Landi Maria Teresa , Johansson Mattias , Risch Angela , Bickeböller Heike , Wichmann H-Erich , Rennert Gad , Arnold Susanne , Brennan Paul , Field John K. , Shete Sanjay S. , Le Marchand Loïc , Liu Geoffrey , Andrew Angeline S. , Kiemeney Lambertus A. , Zienolddiny Shan , Grankvist Kjell , Johansson Mikael , Caporaso Neil E. , Cox Angela , Hong Yun-Chul , Yuan Jian-Min , Schabath Matthew B. , Aldrich Melinda C. , Wang Meilin , Shen Hongbing , Chen Feng , Zhang Zhengdong , Hung Rayjean J. , Amos Christopher I. , Wei Qingyi , Lazarus Philip , Christiani David C.
Published: February 2024

Abstract
Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen–metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke–exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85–0.91, P = 2.18 × 10−16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis.
Significance:
The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.
Data from Mesothelin Secretion by Pancreatic Cancer Cells Co-opts Macrophages and Promotes Metastasis
Authors: Luckett Teifion , Abudula Maidinaimu , Ireland Lucy , Glenn Mark , Bellomo Gaia , Stafferton Ruth , Halloran Chris , Ghaneh Paula , Jones Rob , Schmid Michael C. , Mielgo Ainhoa
Published: February 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, yet effective treatments to inhibit PDAC metastasis are lacking. The rich PDAC tumor microenvironment plays a major role in disease progression. Macrophages are the most abundant immune cell population in PDAC tumors and can acquire a range of functions that either hinder or promote tumor growth and metastasis. Here, we identified that mesothelin secretion by pancreatic cancer cells co-opts macrophages to support tumor growth and metastasis of cancer cells to the lungs, liver, and lymph nodes. Mechanistically, secretion of high levels of mesothelin by metastatic cancer cells induced the expression of VEGF alpha (VEGFA) and S100A9 in macrophages. Macrophage-derived VEGFA fed back to cancer cells to support tumor growth, and S100A9 increased neutrophil lung infiltration and formation of neutrophil extracellular traps. These results reveal a role for mesothelin in regulating macrophage functions and interaction with neutrophils to support PDAC metastasis.
Significance:
Mesothelin secretion by cancer cells supports pancreatic cancer metastasis by inducing macrophage secretion of VEGFA and S100A9 to support cancer cell proliferation and survival, recruit neutrophils, and stimulate neutrophil extracellular trap formation.

See related commentary by Alewine, p. 513
FATP5 Is Indispensable for the Growth of Intrahepatic Cholangiocarcinoma
Authors: Shihadih Diyala , Wang Xue , Zushin Peter-James H. , Khodakivskyi Pavlo , Park Hyo Min , Tso Emily , Shiblak Jena , Misic Angela , Louie Sharon M. , Ward Catherine , Hellerstein Marc , Nomura Daniel K. , Goun Elena , Urigo Francesco , Calvisi Diego F. , Chen Xin , Stahl Andreas
Published: February 2024

Altered lipid metabolism is a common hallmark of various cancers, including intrahepatic cholangiocarcinoma (ICC), a highly lethal carcinoma that lacks effective treatment options. To elucidate the lipid metabolism changes in ICC, we coupled the expression of the firefly luciferase gene (FFL) to AKT1 (AKT-FFL) via an IRES linker, and then hydrodynamically injected mice with AKT-FFL and Notch1 intracellular cytoplasmic domain (NICD) to establish a luciferase-positive ICC model. This model not only enabled us to monitor and quantify tumor growth by injecting the mice with luciferin, but also allowed us to assess the fatty acid uptake rate by injecting the mice with free fatty acid luciferin (FFA-Luc). The ICC model exhibited robust uptake of exogenous fatty acids compared with the HCC model induced by AKT-FFL/ neuroblastoma Ras (Ras). Lipidomics analysis showed a dramatically higher level of fatty acid in ICC, further supporting the increased fatty acids uptake. Mechanistic studies identified FATP5 as the predominant mediator of fatty acid uptake required for ICC growth using Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5. Our study discovered a novel therapeutic target for the treatment of ICC and shed light on the contributions of lipid metabolism to ICC development.

Implications:

This study provides the first in vivo evidence that FATP5 is a potential therapeutic target for treating ICC.
Supplementary Figure 5 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Supplementary Figure 5. CD4+, CD8+ T cells and Tregs expression in mice with sham lingual denervation surgery before or after MOC1 tumor cell inoculation or without surgery.
Supplementary Figure 4 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Supplementary Figure 4. CD4+, CD8+ T cells and Tregs expression in naïve tongues, tongues 10, 20 and 30 days post sham lingual denervation surgery and tongues 7 days post lingual denervation surgery in mice.
Supplementary Figure 2 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Supplementary Figure 2. (A) Representative immunofluorescence of neuritogenesis in different coculture groups. (B) Heatmaps displaying DEGs between coculture groups and the control group. (C) Volcano maps displaying DEGs between coculture groups and the control group. (D) The expression levels of PD-L1 in different coculture groups and control group.
FIGURE 5 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

A, LD decreased tumor proliferation and downregulated TGFβ1 and PD-L1 expression. B–F, The expression levels of β3-tubulin, Ki-67, caspase-3, TGFβ1, and PD-L1 in each group [each bar represents mean ± SD (n = 5–7); ***, P < 0.001 versus MOC1+IgG; ###, P < 0.001 vs. MOC1+αPD-1; $,$$,$$$, P < 0.05, 0.01, 0.001 for αPD-1 vs. IgG].
FIGURE 4 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Galunisertib reserves the tumor cell aggressiveness and downregulates TGFβ signaling and PD-L1 expression of tumor cells in the neuron-tumor coculture system. A, SCC-15 cell viability after treated with different concertation of galunisertib (**,***,****, P < 0.01, 0.001, 0.0001 vs. 0 µmol/L group) at each timepoint, top; MOC1 cell viability in complete DMEM/F12 (control group) or coculture medium from coculture group 1 (coculture group 2) after treated with 10 µmol/L galunisertib (*, P < 0.05, bottom). B–F, Migration and invasion activity of SCC-15 cells detected by migration assay, invasion assay, and wound healing assay (quantitative data from three independent experiments are shown in the right, respectively, **,***, P < 0.01, 0.001). G–J, Expression levels of TGFβ1, p-SMAD2, SMAD2, and PD-L1 determined by Western blot analysis (*,**, P < 0.05, 0.01).
Data from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

AbstractPurpose:
Intratumoral nerve infiltration relates to tumor progression and poor survival in oral squamous cell carcinoma (OSCC). How neural involvement regulates antitumor immunity has not been well characterized. This study aims to investigate molecular mechanisms of regulating tumor aggressiveness and impairing antitumor immunity by nerve-derived factors.
Experimental Design:
We performed the surgical lingual denervation in an immunocompetent mouse OSCC model to investigate its effect on tumor growth and the efficacy of anti-PD-1 immunotherapy. A trigeminal ganglion neuron and OSCC cell coculture system was established to investigate the proliferation, migration, and invasion of tumor cells and the PD-L1 expression. Both the neuron-tumor cell coculture in vitro model and the OSCC animal model were explored.
Results:
Lingual denervation slowed down tumor growth and improved the efficacy of anti-PD-1 treatment in the OSCC model. Coculturing with neurons not only enhanced the proliferation, migration, and invasion but also upregulated TGFβ-SMAD2 signaling and PD-L1 expression of tumor cells. Treatment with the TGFβ signaling inhibitor galunisertib reversed nerve-derived tumor aggressiveness and downregulated PD-L1 on tumor cells. Similarly, lingual denervation in vivo decreased TGFβ and PD-L1 expression and increased CD8+ T-cell infiltration and the expression of IFNγ and TNFα within tumor.
Conclusions:
Neural involvement enhanced tumor aggressiveness through upregulating TGFβ signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, downregulated TGFβ signaling, enhanced activities of CD8+ T cells, and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC.
Significance:
This study revealed the specific mechanisms for nerve-derived cancer progression and impaired antitumor immunity in OSCC, providing a novel insight into the cancer-neuron-immune network as well as pointing the way for new strategies targeting nerve-cancer cross-talk as a potential adjuvant therapeutic approach for OSCC.
Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils
Authors: Fetit Rana , McLaren Alistair S. , White Mark , Mills Megan L. , Falconer John , Cortes-Lavaud Xabier , Gilroy Kathryn , Lannagan Tamsin R.M. , Ridgway Rachel A. , Nixon Colin , Naiker Varushka , Njunge Renee , Clarke Cassie J. , Whyte Declan , Kirschner Kristina , Jackstadt Rene , Norman Jim , Carlin Leo M. , Campbell Andrew D. , Sansom Owen J. , Steele Colin W.
Published: February 2024

Neutrophils are a highly heterogeneous cellular population. However, a thorough examination of the different transcriptional neutrophil states between health and malignancy has not been performed. We utilized single-cell RNA sequencing of human and murine datasets, both publicly available and independently generated, to identify neutrophil transcriptomic subtypes and developmental lineages in health and malignancy. Datasets of lung, breast, and colorectal cancer were integrated to establish and validate neutrophil gene signatures. Pseudotime analysis was used to identify genes driving neutrophil development from health to cancer. Finally, ligand–receptor interactions and signaling pathways between neutrophils and other immune cell populations in primary colorectal cancer and metastatic colorectal cancer were investigated. We define two main neutrophil subtypes in primary tumors: an activated subtype sharing the transcriptomic signatures of healthy neutrophils; and a tumor-specific subtype. This signature is conserved in murine and human cancer, across different tumor types. In colorectal cancer metastases, neutrophils are more heterogeneous, exhibiting additional transcriptomic subtypes. Pseudotime analysis implicates IL1β/CXCL8/CXCR2 axis in the progression of neutrophils from health to cancer and metastasis, with effects on T-cell effector function. Functional analysis of neutrophil-tumoroid cocultures and T-cell proliferation assays using orthotopic metastatic mouse models lacking Cxcr2 in neutrophils support our transcriptional analysis. We propose that the emergence of metastatic-specific neutrophil subtypes is driven by the IL1β/CXCL8/CXCR2 axis, with the evolution of different transcriptomic signals that impair T-cell function at the metastatic site. Thus, a better understanding of neutrophil transcriptomic programming could optimize immunotherapeutic interventions into early and late interventions, targeting different neutrophil states.

Significance:

We identify two recurring neutrophil populations and demonstrate their staged evolution from health to malignancy through the IL1β/CXCL8/CXCR2 axis, allowing for immunotherapeutic neutrophil-targeting approaches to counteract immunosuppressive subtypes that emerge in metastasis.
Reduced Proliferative Capacity and Defense against Staphylococcus aureus in Human Nasal Mucosal Epithelium Lacking ZNF365
Authors: Du Xiaoyun , Yu Longgang , Wang Lin , Yan Xudong , Xu Bingqing , Chai Fangyu , Li Danyang , Zi Jiajia , Zhang Jisheng , Jiang Yan
Published: February 2024

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common chronic inflammatory disease of the nose characterized by barrier disruption and environmental susceptibility, and the deletion of ZNF365 may be a factor inducing these manifestations. However, there is no study on the mechanism of action between CRSwNP and ZNF365. Therefore, this study focuses on the effect of the zinc finger protein ZNF365 on the proliferation of nasal mucosal epithelial cells and their defense against Staphylococcus aureus (S. aureus). Methods: Immunohistochemistry and Western blot were applied to verify the changes of ZNF365 expression in nasal polyp tissues and control tissues, as well as in primary epithelial cells. ZNF365 was knocked down in human nasal mucosa epithelial cell line (HNEpc), and the proliferation, migration, and transdifferentiation of epithelium were observed by immunofluorescence, QPCR, CCK8, and cell scratch assay. The changes of mesenchymal markers and TLR4-MAPK-NF-κB pathway were also observed after the addition of S. aureus. Results: ZNF365 expression was reduced in NP tissues and primary nasal mucosal epithelial cells compared to controls. Knockdown of ZNF365 in HNEpc resulted in decreased proliferation and migration ability of epithelial cells and abnormal epithelial differentiation (decreased expression of tight junction proteins). S. aureus stimulation further inhibited epithelial cell proliferation and migration, while elevated markers of epithelial-mesenchymal transition and inflammatory responses occurred. Conclusion: ZNF365 is instrumental in maintaining the proliferative capacity of nasal mucosal epithelial cells and defending against the invasion of S. aureus. The findings suggest that ZNF365 may participate in the development of CRSwNP.
Addressing the Binning Problem in Calibration Assessment through Scalar Annotations
Authors: Jiang Zhengping , Liu Anqi , Durme Benjamnin Van
Published: February 2024

Computational linguistics models commonly target the prediction of discrete—categorical—labels. When assessing how well-calibrated these model predictions are, popular evaluation schemes require practitioners to manually determine a binning scheme: grouping labels into bins to approximate true label posterior. The problem is that these metrics are sensitive to binning decisions. We consider two solutions to the binning problem that apply at the stage of data annotation: collecting either distributed (redundant) labels or direct scalar value assignment.

In this paper, we show that although both approaches address the binning problem by evaluating instance-level calibration, direct scalar assignment is significantly more cost-effective. We provide theoretical analysis and empirical evidence to support our proposal for dataset creators to adopt scalar annotation protocols to enable a higher-quality assessment of model calibration.
North Atlantic Ocean–Originated Multicentennial Oscillation of the AMOC: A Coupled Model Study
Authors: Yang Kunpeng , Yang Haijun , Li Yang , Zhang Qiong
Published: February 2024

Using a CESM1 control simulation, we conduct a follow-up study to advance our earlier theoretical research on the multicentennial oscillation (MCO) of the Atlantic meridional overturning circulation (AMOC). The modeled AMOC MCO primarily arises from internal oceanic processes in the North Atlantic, potentially representing a North Atlantic Ocean–originated mode of AMOC multicentennial variability (MCV) in reality. Specifically, this AMOC MCO is mainly driven by salinity variation in the subpolar upper North Atlantic, which dominates local density variation. Salinity anomaly in the subpolar upper ocean is enhanced by the well-known positive salinity advection feedback that is realized through anomalous advection in the subtropical to subpolar upper ocean. Meanwhile, mean advection moves salinity anomaly in the subtropical intermediate ocean northward, weakening the subpolar upper salinity anomaly and leading to its phase change. The salinity anomalies have a clear three-dimensional life cycle around the North Atlantic. The mechanism and time scale of the modeled AMOC MCO are consistent with our earlier theoretical studies. In the theoretical model, artificially deactivating either the anomalous or mean advection in the AMOC upper branch prevents it from exhibiting AMOC MCO, underscoring the indispensability of both the anomalous and mean advections in this North Atlantic Ocean–originated AMOC MCO. In our coupled model simulation, the South Atlantic and Southern Oceans do not exhibit variabilities synchronous with the AMOC MCO; the Arctic Ocean’s contribution to the subpolar upper salinity anomaly is much weaker than the North Atlantic. Hence, this North Atlantic Ocean–originated AMOC MCO is distinct from the previously proposed Southern Ocean–originated and Arctic Ocean–originated AMOC MCOs.
Chondrolipoma of the Breast: A Myofibroblastoma Variant or a Distinct Lesion?
Authors: Workman Adrienne A. , Green Donald C. , Hughes Edward G. , Shah Parth S. , Cloutier Jeffrey M. , Marotti Jonathan D.
Published: February 2024

The entity commonly referred to as chondrolipoma is a rare and enigmatic breast lesion with unclear histogenesis and a complete lack of molecular characterization. It is uncertain whether it represents a hamartoma, choristoma, or a distinct neoplasm, including possibly a variant of mammary-type myofibroblastoma. We report two additional chondrolipomatous lesions of the breast. The lesions had varying histologic and immunohistochemical features similar to myofibroblastoma, including the loss of retinoblastoma (Rb) protein expression in one lesion. Molecular analysis by chromosomal microarray analysis performed on a second lesion did not demonstrate a loss of 13q14 or 16q typical of myofibroblastoma. Our findings further support the concept that at least a subset of breast lesions that historically have been classified as chondrolipoma are related to myofibroblastoma. However, the lack of myofibroblastoma-specific molecular alterations in one lesion suggests chondrolipomas may also have varying origins.
A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome
Authors: Messana Vincenzo G. , Fascì Amelia , Vitale Nicoletta , Micillo Matilde , Rovere Matteo , Pesce Noemi A. , Martines Claudio , Efremov Dimitar G. , Vaisitti Tiziana , Deaglio Silvia
Published: February 2024

This works defines, to the best of our knowledge, for the first time a molecular circuit connecting nicotinamide mononucleoside phosphoribosyl transferase (NAMPT) activity to the B-cell receptor (BCR) pathway. Using 4 distinct xenograft models derived from patients with Richter syndrome (RS-PDX), we show that BCR cross-linking results in transcriptional activation of the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme NAMPT, with increased protein expression, in turn, positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all 4 models, independently of their mutational profile and the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase. The connecting link in the circuit is represented by AKT that is both tyrosine- and serine-phosphorylated by PI3K and deacetylated by sirtuin 1 and 2 to obtain full kinase activation. Acetylation (ie, inhibition) of AKT after OT-82 administration was shown by 2-dimensional gel electrophoresis and immunoprecipitation. Consistently, pharmacological inhibition or silencing of sirtuin 1 and 2 impairs AKT activation and induces apoptosis of RS cells in combination with PI3Ki or BTKi. Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas.
Serum fibroblast growth factor-2 levels complement vital biomarkers for diagnosing heart failure
Authors: Yu Z. L. , Cai Z. H. , Zheng J. T. , Jiang H. Y. , Zhou Y. Q. , Wong N. K. , Fu H. B. , Hong X. B.
Published: February 2024

Background

Early diagnosis of atrial fibrillation is important as it is crucial for improving patient outcomes. Fibroblast growth factor-2 (FGF2) may serve as a diagnostic biomarker for heart failure due to its ability to promote cardiac fibrosis and hypertrophy; however, the relationship between FGF2 concentration and heart failure is unclear. Therefore, this study aimed to explore whether FGF2 could aid in distinguishing patients with heart failure from healthy controls and those with dyspnea without heart failure. Additionally, to evaluate the possible correlation between serum FGF2 levels and its diagnostic parameters in patients with heart failure.

Methods

Plasma FGF2 concentration was measured in 114 patients with a complaint of dyspnea (enrolled in the study between January 2022 and August 2022). Based on heart failure diagnosis, the patients were assigned to three groups, as follows: heart failure (n = 80), non-heart-failure dyspnea (n = 34), and healthy controls (n = 36), following physical examination. Possible correlations between serum FGF2 levels and other prognostic parameters in patients with heart failure were analyzed.

Results

Serum FGF2 levels were higher in patients with heart failure (125.60 [88.95, 183.40] pg/mL) than in those with non-heart-failure dyspnea (65.30 [28.85, 78.95] pg/mL) and healthy controls (78.90 [60.80, 87.20] pg/mL) (p < 0.001). Receiver operating characteristic curve analysis identified FGF2 concentration as a significant predictor in heart failure diagnosis, with an area under the curve of 0.8693 (p < 0.0001). Importantly, in the heart failure group, serum FGF2 concentrations correlated with key prognostic parameters for heart failure, such as reduced left ventricular ejection fraction and elevated serum levels of N-terminal pro-B-type natriuretic peptide.

Conclusions

Elevated serum FGF2 level is strongly associated with an increased risk of heart failure and could serve as a useful biomarker to complement vital diagnostic parameters for heart failure.
Modeling heart rate of individual and team manual handling with one hand using generalized additive mixed models
Authors: Hosseini Mohammad Hamed , Heidarimoghaddam Rashid , Anbarian Mehrdad , Ilbeigi Saeed , Tapak Leili
Published: February 2024

Objectives

Despite the fact that team manual handling is common in different working environments, the previous studies in this regard, particularly those with a physiological approach are quite limited. The present study is an attempt to model the heart rate (HR) of individual and team manual handling with one hand.

Methods

Twenty-five young men (aged 21.24±1.42 year) volunteered for this study. The experiments included individual and two-person handling of the load with three different weights with and without height difference. The participants’ HR was registered at the end of the route by a chest-strap pulse monitor and a polar watch according to the manufacturer's recommendation. A multivariate Generalized Additive Mixed Model (MGAMM) was used for modeling heart rate based on explanatory variables of workload, carry method, HRrest, body weight, height, knee height, shoulder height, elbow height, and hand height. The significance level of the tests was considered as <0.05.

Results

Based on the MGAMM, the average HR (bpm) of participants increased as the workload increased (P<0.001). Handling the load with a taller person increased the HR compared to shorter partner (P<0.001). Moreover, the nonlinear associations of the resting HR (P<0.001), body weight (P<0.001), height (P<0.001), and the height of elbow, hand and knee (P<0.001) were statistically significant. The adjusted R2 of the model was 0.89 indicating that about 90 percent of the variations observed in HR could be explained by the variables in the model. This was greater than the model considering only linear effects (R2 =0.60).

Conclusion

The model obtained in this study can predict the heart rate of individual and team one-handed handling with high validity. The MGAMM can be used in modeling heart rate in manual handling.
An epidemiological survey of COVID-19 serology and its association with clinical infection among older adults– does antibody titer matter?
Authors: Shapiro Dvorah Sara , Ellis Refael , Zidan Jowad , Wiener-Well Yonit , Bar-Meir Maskit , Ben-Chetrit Eli
Published: February 2024

Background

Older adults are at increased risk of severe SARS-CoV-2 infection. In this study we assessed the response to COVID-19 vaccination and infection rates among nursing homes (NH) and assisted-living care home (ALCH) residents.

Methods

The study was conducted between August 2021 and January 2022, after widespread population vaccination with the third dose of Pfizer-BioNtech mRNA COVID-19 vaccine in Israel. Three groups were addressed: hospitalized older patients; NH and ALCH residents. Demographic data, COVID-19 serology (anti-spike IgG antibodies) and PCR test results were obtained to assess the dynamics of antibody titers and its correlation to infection rates.

Results

Two-hundred eighty-five individuals were evaluated; 92 hospitalized patients; 100 ALCH residents and 93 NH residents. In the latter two groups two serology surveys were conducted three months apart. Hospitalized patients were younger than ALCH and NH residents (mean age 80.4 ± 8 versus 82.6 ± 8 and 83.6 ± 5, respectively, p = 0.01), and had more comorbidities (p = 0.003). The degree of decline in the antibody level overtime was similar in ALCH and NH residents. Infection rates were higher among NH residents than ALCH residents [35/91 (38.4%) versus 11/100 (11%), p < 0.001]. Antibody level was lower among those infected [2113 (1271–3512) Au/ml versus 4113 (3364–5029) Au/ml, p < 0.001]. Adjusted analysis showed that NH residence, but not antibody levels, were significantly associated with infection.

Conclusion

Among older adults, infection rates inversely correlated with antibody level. However, only nursing home residence was significantly associated with infection, suggesting that other factors such as crowding considerably contribute to the risk of infection.
Isoenzyme characterization of Leishmania infantum toward checking the antioxidant activity of superoxide dismutase and glutathione peroxidase
Authors: Alishvandi¹ Mostafa , Bahrami Somayeh , Rashidi Sajad , Hatam Gholamreza
Published: February 2024

Background

Leishmania infantum is the major causative agent of visceral leishmaniasis in Mediterranean regions. Isoenzyme electrophoresis (IE), as a biochemical technique, is applied in the characterization of Leishmania species. The current study attempted to investigate the isoenzyme patterns of logarithmic and stationary promastigotes and axenic amastigotes (amastigote-like) of L. infantum using IE. The antioxidant activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX) was also checked in the aforementioned forms.

Method

After L. infantum cultivation and obtaining logarithmic and stationary promastigotes, axenic amastigotes were achieved by incubation of stationary promastigotes at 37 °C for 48 h. The lysate samples were prepared and examined for six enzymatic systems including glucose-6-phosphate dehydrogenase (G6PD), nucleoside hydrolase 1 (NH1), malate dehydrogenase (MDH), glucose-phosphate isomerase (GPI), malic enzyme (ME), and phosphoglucomutase (PGM). Additionally, the antioxidant activity of SOD and GPX was measured.

Results

GPI, MDH, NH1, and G6PD enzymatic systems represented different patterns in logarithmic and stationary promastigotes and axenic amastigotes of L. infantum. PGM and ME showed similar patterns in the aforementioned forms of parasite. The highest level of SOD activity was determined in the axenic amastigote form and GPX activity was not detected in different forms of L. infantum.

Conclusion

The characterization of leishmanial-isoenzyme patterns and the measurement of antioxidant activity of crucial antioxidant enzymes, including SOD and GPX, might reveal more information in the biology, pathogenicity, and metabolic pathways of Leishmania parasites and consequently drive to designing novel therapeutic strategies in leishmaniasis treatment.
Personalized decision-making for aneurysm treatment of aneurysmal subarachnoid hemorrhage: development and validation of a clinical prediction tool
Authors: de Winkel Jordi , Roozenbeek Bob , Dijkland Simone A. , Dammers Ruben , van Doormaal Pieter-Jan , van der Jagt Mathieu , van Klaveren David , Dippel Diederik W. J. , Lingsma Hester F.
Published: February 2024

Background

In patients with aneurysmal subarachnoid hemorrhage suitable for endovascular coiling and neurosurgical clip-reconstruction, the aneurysm treatment decision-making process could be improved by considering heterogeneity of treatment effect and durability of treatment. We aimed to develop and validate a tool to predict individualized treatment benefit of endovascular coiling compared to neurosurgical clip-reconstruction.

Methods

We used randomized data (International Subarachnoid Aneurysm Trial, n = 2143) to develop models to predict 2-month functional outcome and to predict time-to-rebleed-or-retreatment. We modeled for heterogeneity of treatment effect by adding interaction terms of treatment with prespecified predictors and with baseline risk of the outcome. We predicted outcome with both treatments and calculated absolute treatment benefit. We described the patient characteristics of patients with ≥ 5% point difference in the predicted probability of favorable functional outcome (modified Rankin Score 0–2) and of no rebleed or retreatment within 10 years. Model performance was expressed with the c-statistic and calibration plots. We performed bootstrapping and leave-one-cluster-out cross-validation and pooled cluster-specific c-statistics with random effects meta-analysis.

Results

The pooled c-statistics were 0.72 (95% CI: 0.69–0.75) for the prediction of 2-month favorable functional outcome and 0.67 (95% CI: 0.63–0.71) for prediction of no rebleed or retreatment within 10 years. We found no significant interaction between predictors and treatment. The average predicted benefit in favorable functional outcome was 6% (95% CI: 3–10%) in favor of coiling, but 11% (95% CI: 9–13%) for no rebleed or retreatment in favor of clip-reconstruction. 134 patients (6%), young and in favorable clinical condition, had negligible functional outcome benefit of coiling but had a ≥ 5% point benefit of clip-reconstruction in terms of durability of treatment.

Conclusions

We show that young patients in favorable clinical condition and without extensive vasospasm have a negligible benefit in functional outcome of endovascular coiling – compared to neurosurgical clip-reconstruction – while at the same time having a substantially lower probability of retreatment or rebleeding from neurosurgical clip-reconstruction – compared to endovascular coiling. The SHARP prediction tool (https://sharpmodels.shinyapps.io/sharpmodels/) could support and incentivize a multidisciplinary discussion about aneurysm treatment decision-making by providing individualized treatment benefit estimates.
The association of E2F1 and E2F2 single nucleotide polymorphisms with laryngeal squamous cell carcinoma pathomorphological features
Authors: Jakstas Tomas , Bartnykaite Agne , Padervinskis Evaldas , Vegiene Aurelija , Juozaityte Elona , Uloza Virgilijus , Ugenskiene Rasa
Published: February 2024

Background

Laryngeal squamous cell carcinoma (LSCC) is one of the most common types of cancer in the upper respiratory tract. It is well-known that it has a high mortality rate and poor prognosis in advanced stages. There are well-known risk factors for LSCC, though new specific and prognostic blood-based markers for LSCC development and prognosis are essential. The current study aimed to evaluate the impact of four different single nucleotide polymorphisms (SNPs), E2F1 (rs3213183 and rs3213180) and E2F2 (rs2075993 and rs3820028), on LSCC development, morphological features, and patient 5-year survival rate.

Methods

A total of 200 LSCC patients and 200 controls were included in this study; both groups were matched by age and sex. In the present study, we analyzed four single nucleotide polymorphisms (SNPs) in the genes E2F1 (rs3213183 and rs3213180) and E2F2 (rs2075993 and rs3820028) and evaluated their associations with the risk of LSCC development, its clinical and morphological manifestation, and patients 5-year survival rate. Genotyping was carried out using RT-PCR.

Results

None of the analyzed SNPs showed a direct association with LSCC development. E2F2 rs2075993 G allele carriers (OR = 4.589, 95% CI 1.050-20.051, p = 0.043) and rs3820028 A allele carriers (OR = 4.750, 95% CI 1.088–20.736, p = 0.038) had a statistically significantly higher risk for poor differentiated or undifferentiated LSCC than non-carriers. E2F1 rs3213180 GC heterozygotes were found to have a 3.7-fold increased risk for lymph node involvement (OR = 3.710, 95% CI 1.452–9.479, p = 0.006). There was no statistically significant association between investigated SNPs and patient 5-year survival rate.

Conclusions

The present study indicates that E2F2 rs2075993 and rs3820028 impact LSCC differentiation, whereas E2F1 rs3213180 - on lymph node involvement.