bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S2 from Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RASmut Disease Models
Authors: Wu Jin , Wang Jianxin , O’Connor Thomas N. , Tzetzo Stephanie L. , Gurova Katerina V. , Knudsen Erik S. , Witkiewicz Agnieszka K.
Published: December 2024

Supplementary Figure S2. A. Immunofluorescent analysis of RB expression in HT1080-sgCtrl and sgRB cells. Scale bar = 50 μm. B. Relative mouse body mass for each cohort. HT1080-sgCtrl-vehicle (n = 4), HT1080-sgCtrl-CDK4/6i + MEKi (palbociclib (100 mg/kg) + trametinib (0.5 mg/kg), n = 4), HT1080-sgRB-vehicle (n = 4), HT1080-sgRB- CDK4/6i + MEKi (palbociclib (100 mg/kg) + trametinib (0.5 mg/kg), n = 3). C. Excised tumor representative images from each cohort following the final treatment. Scale bar = 1 cm. D. Violin plot displaying tumor mass from each cohort plotted as mean ± SD. **p < 0.01, ***p < 0.001 as determined by two-way ANOVA.
Supplementary Tables from Targeting the Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer
Authors: Triboulet Robinson , Sadykov Khikmet , Harvey Darren M. , Wilson David M. , Steinbaugh Michael J. , Mayo Christopher B. , Hawley Dillon , Madanjian Andrew , Fyfe Corey , Bracken Christina , Rivera-Rivera Izarys , Ericsson Anna , Snyder Andrew R. , Knutson Sarah K. , Stein Ross L. , Gibaja Veronica , Ghosh Shomir , Campbell Robert M.
Published: December 2024

Supplementary tables
Supplemental Fig. S3 from Trametinib Potentiates Anti-PD-1 Efficacy in Tumors Established from Chemotherapy-Primed Pancreatic Cancer Cells
Authors: Pham Thao D. , Metropulos Anastasia E. , Mubin Nida , Becker Jeffrey H. , Shah Dhavan , Spaulding Christina , Shields Mario A. , Bentrem David J. , Munshi Hidayatullah G.
Published: December 2024

Supplemental Fig. S3. KPC-FIO cells display reduced sensitivity to 5FU. A-D. The parental KPC and KPC-FIO cells were treated with increasing doses of 5FU (F; 2, 4, 8, 16 µM). After 72 hours, the effects of drug treatments on cell proliferation were evaluated by WST1 assay and analyzed by GraphPad. Error bars ± SEM from 3 biological replicates. One-way ANOVA, followed by Dunnett multiple comparison test. *, p<0.05 **, p<0.01 ***, p<0.001 ****, p<0.0001 ns, non-significant.
Supplementary Figure S2 from Integrated Imaging Probe and Bispecific Antibody Development Enables In Vivo Targeting of Glypican-3–Expressing Hepatocellular Carcinoma
Authors: Habibollahi Peiman , Gurevich Alexey , Hui James Z. , Weinfurtner Kelly , McClung George , Adler Justin , Soulen Michael C. , Kaplan David E. , Nadolski Gregory J. , Hunt Stephen J. , Tsourkas Andrew , Gade Terence P.
Published: December 2024

Supplementary Figure S2: GPC3 expression in HCC samples and normal adjacent liver. Sample images from immunostaining showing nearly absent GPC3 expression in normal adjacent liver (n=41) (A, B) and high GPC3 expression in HCC tumors (n=47) (C,D). 79% of the tumors (79%) stained strongly positive for GPC3 expression (Grade 3 and 4) (E). Within normal adjacent liver samples only 2 (5%) had grade 3/4 GPC3 expression compared to 79% among HCC tumor samples (F).
Data from Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RASmut Disease Models
Authors: Wu Jin , Wang Jianxin , O’Connor Thomas N. , Tzetzo Stephanie L. , Gurova Katerina V. , Knudsen Erik S. , Witkiewicz Agnieszka K.
Published: December 2024

Abstract
The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TANK-binding kinase 1 inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcomas.
Supplementary Figure-7 from TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation
Authors: Zhang Yahui , Ren Yidan , Dong Guoying , Jiao Qinlian , Guo Nan , Gao Ping , Li Ya , Wang Yunshan , Zhao Wei
Published: December 2024

Supplementary Figure-7
Supplementary Figure-2 from TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation
Authors: Zhang Yahui , Ren Yidan , Dong Guoying , Jiao Qinlian , Guo Nan , Gao Ping , Li Ya , Wang Yunshan , Zhao Wei
Published: December 2024

Supplementary Figure-2
Figure 4 from Ruthenium Drug BOLD-100 Regulates BRAFMT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation
Authors: Griffin Daryl , Carson Robbie , Moss Debbie , Sessler Tamas , Lavin Deborah , Tiwari Vijay K. , Karelia Shivaali , Kennedy Richard , Savage Kienan I. , McDade Simon , Carie Adam , Pankovich Jim , Bazett Mark , Van Schaeybroeck Sandra
Published: December 2024

Combined ATR inhibition with BOLD-100 results in apoptosis in BRAFMT colorectal cancer. A, CTG cell viability assays in BRAFMT colorectal cancer cells co-treated with BOLD-100 and ATR inhibitors (AZD6738, M4344, M6620) for 72 hours. CI values were calculated to evaluate the nature of interaction. B, PARP, cleaved PARP and cleaved caspase-3 (top), and caspase-3/7 activity levels (bottom) in BRAFMT cells co-treated with BOLD-100 and ATR inhibitors for 48 hours. C, HT29 and VACO432 cells were co-treated with BOLD-100 and ATR inhibitors for 48 hours, and apoptosis was assessed using PI or annexin-V/PI staining. The graph indicates the percentage of positive stained cells. D, VACO432 and HT-29 cells were transfected with 10 nmol/L of SC or two different siRNA sequences targeting ATR for 24 hours, followed by treatment with BOLD-100 for 48 hours and apoptosis assessed by WB for PARP, Cleaved PARP (left) and Caspase 3/7 activity assay (right). Expression of pATRT1989, ATR, pCHK1S345, CHK1, pKAP1S824, and KAP was also determined.
Supplementary Table 3 from EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell–Dependent Manner
Authors: Nguyen Lily L. , Watson Zachary L. , Ortega Raquel , Woodruff Elizabeth R. , Jordan Kimberly R. , Iwanaga Ritsuko , Yamamoto Tomomi M. , Bailey Courtney A. , To Francis , Lin Shujian , Villagomez Fabian R. , Jeong Abigail D. , Guntupalli Saketh R. , Behbakht Kian , Gibaja Veronica , Arnoult Nausica , Chuong Edward B. , Bitler Benjamin G.
Published: December 2024

Hallmark pathways enriched in ID8-OR cells compared to ID8 cells.
Supplementary Table 1 from EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell–Dependent Manner
Authors: Nguyen Lily L. , Watson Zachary L. , Ortega Raquel , Woodruff Elizabeth R. , Jordan Kimberly R. , Iwanaga Ritsuko , Yamamoto Tomomi M. , Bailey Courtney A. , To Francis , Lin Shujian , Villagomez Fabian R. , Jeong Abigail D. , Guntupalli Saketh R. , Behbakht Kian , Gibaja Veronica , Arnoult Nausica , Chuong Edward B. , Bitler Benjamin G.
Published: December 2024

Multispectral IHC antibody list
Supplementary Figure 5 from EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell–Dependent Manner
Authors: Nguyen Lily L. , Watson Zachary L. , Ortega Raquel , Woodruff Elizabeth R. , Jordan Kimberly R. , Iwanaga Ritsuko , Yamamoto Tomomi M. , Bailey Courtney A. , To Francis , Lin Shujian , Villagomez Fabian R. , Jeong Abigail D. , Guntupalli Saketh R. , Behbakht Kian , Gibaja Veronica , Arnoult Nausica , Chuong Edward B. , Bitler Benjamin G.
Published: December 2024

Gating strategy and necropsy images following CD8T cell depletion
Raw Data Excel File S1 from Targeting BTN2A1 Enhances Vγ9Vδ2 T-Cell Effector Functions and Triggers Tumor Cell Pyroptosis
Authors: Le Floch Anne-Charlotte , Imbert Caroline , Boucherit Nicolas , Gorvel Laurent , Fattori Stéphane , Orlanducci Florence , Le Roy Aude , Archetti Lorenzo , Crescence Lydie , Panicot-Dubois Laurence , Dubois Christophe , Vey Norbert , Briantais Antoine , Anastasio Amandine , Cano Carla , Guittard Geoffrey , Frechin Mathieu , Olive Daniel
Published: December 2024

Supplementary Raw Data Excel File S1
Figure S1 from CAR T Cells Engineered to Secrete IFNκ Induce Tumor Ferroptosis via an IFNAR/STAT1/ACSL4 Axis
Authors: Gao Yaoxin , Liu Shasha , Huang Yifan , Wang Hui , Zhao Yuyu , Cui Xuyang , Peng Yajing , Li Feng , Zhang Yi
Published: December 2024

IFNK was a key mediator for tumor ferroptosis.
Figure S2 from Targeting BTN2A1 Enhances Vγ9Vδ2 T-Cell Effector Functions and Triggers Tumor Cell Pyroptosis
Authors: Le Floch Anne-Charlotte , Imbert Caroline , Boucherit Nicolas , Gorvel Laurent , Fattori Stéphane , Orlanducci Florence , Le Roy Aude , Archetti Lorenzo , Crescence Lydie , Panicot-Dubois Laurence , Dubois Christophe , Vey Norbert , Briantais Antoine , Anastasio Amandine , Cano Carla , Guittard Geoffrey , Frechin Mathieu , Olive Daniel
Published: December 2024

Supplementary Figure S2. BTN2A1 is broadly expressed in normal and tumor cells.
Supplementary Table 4 from Cannabidiol Enhances Atezolizumab Efficacy by Upregulating PD-L1 Expression via the cGAS–STING Pathway in Triple-Negative Breast Cancer Cells
Authors: Kim Bu Gyeom , Kim Bo Ram , Kim Dae Yeong , Kim Woo Young , Kang Sanghee , Lee Sun Il , Oh Sang Cheul
Published: December 2024

Antibodies for IHC staining
Figure S8 from Integrated Germline and Somatic Features Reveal Divergent Immune Pathways Driving Response to Immune Checkpoint Blockade
Authors: Sears Timothy J. , Pagadala Meghana S. , Castro Andrea , Lee Ko-han , Kong JungHo , Tanaka Kairi , Lippman Scott M. , Zanetti Maurizio , Carter Hannah
Published: December 2024

Fig S8. A. MHC-I reliant patients in TCGA with melanoma, non-small cell lung cancer or renal cell carcinoma stratified by CD4/CD8 T Cell infiltration ratio. B. MHC-II reliant patients in TCGA with melanoma, non-small cell lung cancer or renal cell carcinoma stratified by CD4/CD8 T Cell infiltration ratio. P Values generated via log-rank test. C. Immune infiltrate adjusted HLA DRB1 expression is associated with prolonged survival in MHC-II Reliant TCGA patients. D. Immune infiltrate adjusted HLA DRB1 expression is not protective in MHC-I Reliant TCGA patients.
Figure S2 from Integrated Germline and Somatic Features Reveal Divergent Immune Pathways Driving Response to Immune Checkpoint Blockade
Authors: Sears Timothy J. , Pagadala Meghana S. , Castro Andrea , Lee Ko-han , Kong JungHo , Tanaka Kairi , Lippman Scott M. , Zanetti Maurizio , Carter Hannah
Published: December 2024

Fig S2. A-C. Recursive feature elimination analysis. Mean squared error for each model is shown for a range of total number of features included in a given model. Optimal model size is indicated by a dashed red line. D-E. Pearson correlation matrices of features respective to germline and somatic models.
Figure S9 from CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors
Authors: Nayak Devanshi A. , Sedlacek Abigail L. , Cillo Anthony R. , Watkins Simon C. , Binder Robert J.
Published: December 2024

Supplementary Figure 9. Gating on lymph node resident and migratory antigen presenting cells under inflammatory conditions.
Figure S8 from CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors
Authors: Nayak Devanshi A. , Sedlacek Abigail L. , Cillo Anthony R. , Watkins Simon C. , Binder Robert J.
Published: December 2024

Supplementary Figure 8. Accumulation of tumor-derived gp96-EGFP in the draining lymph nodes.
Table S7 from Peripheral Blood–Derived PD-1/CD28–CD19 CAR–Modified PD-1+ T-Cell Therapy in Patients with Solid Tumors
Authors: Zhang Zhen , Zhao Xuan , Zhao Qitai , Chen Xinfeng , Li Congcong , Liu Yaqing , Shen Chunyi , Song Lijie , Miao Lijun , Guo Fuyou , Mou Xiaoning , Zhao Jie , Gu Weiyue , Zhang Yi
Published: December 2024

Treatment-emergent adverse events of patients.
Figure S6 from CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors
Authors: Nayak Devanshi A. , Sedlacek Abigail L. , Cillo Anthony R. , Watkins Simon C. , Binder Robert J.
Published: December 2024

Supplementary Figure 6. cDC1-specific deletion of CD91 affects frequency and quality of CD8+ T cells.
Figure S14 from CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors
Authors: Nayak Devanshi A. , Sedlacek Abigail L. , Cillo Anthony R. , Watkins Simon C. , Binder Robert J.
Published: December 2024

Supplementary Figure 14. Antigen presenting cells within sorted and adoptively transferred cells. Lymph nodes from mice challenged with gp96-EGFP+ tumor were processed and sorted on live CD19- CD3- CD45+ CD11c+/- CD11b+/- gp96+ as shown in Supplementary figure 7A. Sorted cells were further stained using additional markers to further subset the sorted populations of cells transferred in Fig. 5.
Supplementary Tables S2 from Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun
Published: December 2024

Characteristics of patients with lung cancer treated with immune checkpoint inhibitor (RNA-seq cohort)
Figure S1 from PTPRZ1-Targeting RNA CAR T Cells Exert Antigen-Specific and Bystander Antitumor Activity in Glioblastoma
Authors: Martinez Bedoya Darel , Marinari Eliana , Davanture Suzel , Castillo Cantero Luis , Erraiss Sarah , Dockerill Millicent , Barluenga Sofia , Winssinger Nicolas , Schaller Karl , Bijlenga Philippe , Momjian Shahan , Voize Christel , Tissot Stéphanie R. , Kandalaft Lana E. , Hammel Philippe , Cosson Pierre , Walker Paul R. , Dutoit Valérie , Migliorini Denis
Published: December 2024

PTPRZ1 expression at the mRNA level according to different GBM clinicopathologic features
Supplementary Table S5 from Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun
Published: December 2024

List of genes in various T cell status signatures
Supplementary Table S10 from Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun
Published: December 2024

The most up- or downregulated gene sets in immune cells between IF_PDL1H and ID_PDL1H
Table S2 from Hyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti–PD-1 in Murine Non–Small Cell Lung Cancer
Authors: Du Yushen , Salehi-Rad Ramin , Zhang Tian-hao , Crosson William P. , Abascal Jensen , Chen Dongdong , Shi Yuan , Jiang Hong , Tseng Yen-Wen , Ma Xi , Hong Mengying , Wang Sihan , Wang Xijuan , Tang Kejun , Hu Shiyao , Li Yuting , Ni Shaokai , Cai Yiqi , Tappuni Shahed , Shen Yong , Liu Bin , Sun Ren
Published: December 2024

Flow antibodies and Fixable Viability dye
Supplementary Figure S1 from Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun
Published: December 2024

Flow chart for patient selection and inclusion and exclusion criteria for DSP analysis of this study
Data from PTPRZ1-Targeting RNA CAR T Cells Exert Antigen-Specific and Bystander Antitumor Activity in Glioblastoma
Authors: Martinez Bedoya Darel , Marinari Eliana , Davanture Suzel , Castillo Cantero Luis , Erraiss Sarah , Dockerill Millicent , Barluenga Sofia , Winssinger Nicolas , Schaller Karl , Bijlenga Philippe , Momjian Shahan , Voize Christel , Tissot Stéphanie R. , Kandalaft Lana E. , Hammel Philippe , Cosson Pierre , Walker Paul R. , Dutoit Valérie , Migliorini Denis
Published: December 2024

Abstract
The great success of chimeric antigen receptor (CAR) T-cell therapy in the treatment of patients with B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but efforts to develop more effective anti-GBM CAR T cells are ongoing. In this study, we selected protein tyrosine phosphatase receptor type Z (PTPRZ1) as a target for GBM treatment. We isolated six anti-human PTPRZ1 single-chain variable fragments from a human phage display library and produced second-generation CAR T cells in an RNA format. Patient-derived GBM PTPRZ1–knockin cell lines were used to select the CAR construct that showed high cytotoxicity while consistently displaying high CAR expression (471_28z). CAR T cells incorporating 471_28z were able to release IFNγ, IL2, TNFα, granzyme B, IL17A, IL6, and soluble FasL and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype after in vitro killing. In addition, 471_28z CAR T cells displayed strong bystander killing against PTPRZ1-negative cell lines after preactivation by PTPRZ1-positive tumor cells but did not kill antigen-negative nontumor cells. In an orthotopic xenograft tumor model using NOD/SCIDγ mice, a single dose of anti-PTPRZ1 CAR T cells significantly delayed tumor growth. Taken together, these results validate PTPRZ1 as a GBM target and prompt the clinical translation of anti-PTPRZ1 CAR T cells.
In vivo Study to Evaluate an Intelligent Algorithm for Time Efficient Detection of Malignant Melanoma Using Dermatofluoroscopy
Authors: Weihmann Karl , Schleusener Johannes , Eigentler Thomas K. , Ghoreschi Franziska C. , Moritz Rose K.C. , Szyc Lukasz , Dronnik Eduard , Meinke Martina C.
Published: December 2024

Introduction: Dermatofluoroscopy is an optical noninvasive method of melanoma/nevus differentiation that has shown 89% sensitivity and 45% specificity in clinical trials, but long measurement duration hinders clinical use. An intelligent algorithm was developed to shorten the measurement time without compromising its diagnostic accuracy. It uses dermoscopic images of the skin lesions to be measured to select measurement points based on the assessment of color values. Methods: 27 patients with a total of 29 lesions suggestive of cutaneous melanoma were included in a clinical study and measured with both methods, conventional dermatofluoroscopy and the newly developed intelligent algorithm. The results were compared to the independent findings of two histopathologists to evaluate diagnostic accuracy and time saved. Results: There was a median reduction of measurement points from 265 to 158 (40%). Meanwhile, the intelligent algorithm showed a higher diagnostic accuracy than conventional dermatofluoroscopy (area under the curve of 72% vs. 63%). Conclusion: The intelligent algorithm did not perform inferior to the conventional method while saving 40% of time. However, measurement times remain long compared to other noninvasive methods of diagnosing malignant melanoma. Further studies are needed to evaluate clinical suitability.
Culture-Negative Peritonitis and the Latest Diagnostic Techniques
Authors: Ye Jiajia , Sun Jing , Chen Dan , Cao Huanhuan , Lv Yi , Ye Chen , Wang Yumei , Jiang Huajun
Published: December 2024

Background: Peritonitis is a common and serious complication of peritoneal dialysis that results in considerable morbidity, mortality, and increased healthcare costs. A positive culture-based microorganism test is one of the main criteria for the diagnosis of peritonitis. However, the rates of positive bacterial culture remain quite low. Summary: Peritonitis is a frequently encountered and consequential complication of peritoneal dialysis that poses a significant clinical burden in terms of morbidity, mortality, and healthcare expenditure. The reliance on culture-positive microbiological tests as a cornerstone of peritonitis diagnosis often results in a relatively low rate of positive results. Key Messages: This article aimed to present a comprehensive synthesis and critical analysis of the most recent diagnostic modalities used to identify peritonitis-associated pathogens in peritoneal dialysis. Emphasis was placed on both direct diagnostic tools for pathogen identification and rapid detection methodologies that facilitate expedited pathogen diagnosis in peritonitis.
Impact of Smokeless Oral Nicotine Products on Cardiovascular Disease: Implications for Policy, Prevention, and Treatment: A Policy Statement From the American Heart Association
Authors: Dennison Himmelfarb Cheryl R. , Benowitz Neal L. , Blank Melissa D. , Bhatnagar Aruni , Chase Paul J. , Davis Esa M. , Fetterman Jessica L. , Keller-Hamilton Brittney , Ogungbe Oluwabunmi , Page Robert L. , Rezk-Hanna Mary , Robertson Rose Marie , Whitsel Laurie P. ,   on behalf of the American Heart Association Advocacy Coordinating Committee
Published: December 2024

Smokeless oral nicotine products are addictive, and their use has potential adverse effects on some but not all biomarkers of cardiovascular risk. The use of some types of these products, for instance, is associated with an increased mortality risk in those with ischemic heart or cerebrovascular disease. Similarly, smokeless tobacco has the potential to increase the risk of oral cancer, but the risks depend on the chemical composition of the product. The market of smokeless oral nicotine products has transformed since the last American Heart Association smokeless tobacco policy statement. Several varieties of tobacco-free oral nicotine products—including oral nicotine pouches; nontherapeutic nicotine gums, lozenges, and tablets; and nicotine gummies—have rapidly proliferated. The sales of oral nicotine pouches, in particular, have increased substantially; however, no data are available on their cardiovascular or health risks. In addition, synthetic (compared with tobacco-derived) nicotine has been used in some brands of oral nicotine products, but its cardiovascular and health effects have been inadequately studied. Robust public policy levers are identified to support ending addiction to all commercial tobacco products. Critical components and policy initiatives include clinicians emphasizing the prevention of tobacco product initiation and supporting cessation with established pharmacological and behavioral tobacco dependence treatment therapies as primary goals for achieving an end to commercial tobacco and nicotine addiction.
In Vivo Mapping of Human Ventricular Fibrillation in Brugada Syndrome: The Role of Repolarization Heterogeneity
Authors: Pannone Luigi , Della Rocca Domenico Giovanni , Vergara Pasquale , Sorgente Antonio , Del Monte Alvise , Vetta Giampaolo , Cespon Fernandez Maria , Talevi Giacomo , Eltsov Ivan , Calburean Paul-Adrian , Overeinder Ingrid , Bala Gezim , Almorad Alexandre , Ströker Erwin , Pappaert Gudrun , Sieira Juan , de Ravel Thomy , Van Dooren Sonia , Gharaviri Ali , La Meir Mark , Brugada Pedro , Chierchia Gian Battista , Sarkozy Andrea , de Asmundis Carlo
Published: December 2024

BACKGROUND:

Brugada syndrome (BrS) is associated with ventricular fibrillation (VF). Different VF mechanisms have been described, and repolarization gradients were associated with VF in a BrS model. The aim of this study is to map VF in BrS with ECG imaging. Furthermore, spatial correlation between sinus rhythm maps and VF maps was evaluated.

METHODS:

Inclusion criteria were (1) BrS diagnosis and (2) VF mapped with ECG imaging during right ventricle outflow tract ablation. VF mechanism was classified into (1) rotational, (2) focal, and (3) irregular. For comparison, 6 controls were enrolled. The following sinus rhythm maps were performed: activation, recovery time, and activation-recovery interval time. Spatial overlap between steep repolarization gradients (cliffs) at recovery time and activation-recovery interval time maps and initiating VF rotational activity was evaluated with photogrammetry.

RESULTS:

A total of 28 VF maps in 21 patients with BrS were analyzed. In the first ≈7 seconds of VF, rotational, focal, and irregular mechanisms were found. In 19 patients with BrS (90.5%) and none of the controls, a right ventricle outflow tract repolarization cliff only was found. In all these patients, the singularity point of the first initiating rotational VF activity spatially overlapped with the right ventricle outflow tract cliff. Abolition of right ventricle outflow tract repolarization cliffs was confirmed in all but 2 patients (94.3%). In one patient with recurrence, VF was mapped on the anterior right ventricle over a cliff that was not targeted at the first ablation procedure.

CONCLUSIONS:

In patients with BrS, repolarization heterogeneity has a critical role in VF. Repolarization cliffs might be a therapeutic target in VF ablation.
Long Noncoding RNA TRIBAL Links the 8q24.13 Locus to Hepatic Lipid Metabolism and Coronary Artery Disease
Authors: Soubeyrand Sébastien , Lau Paulina , Nikpay Majid , Ma Lijiang , Bjorkegren Johan L.M. , McPherson Ruth
Published: December 2024

BACKGROUND:

Genome-wide association studies identified a 20-Kb region of chromosome 8 (8q24.13) associated with plasma lipids, hepatic steatosis, and risk for coronary artery disease. The region is proximal to
TRIB1
,

and given its well-established role in lipid regulation in animal models, TRIB1 has been proposed to mediate the contribution of the 8q24.13 locus to these traits. This region overlaps a gene encoding the primate-specific long noncoding RNA transcript
TRIBAL
/
TRIB1AL
(
TRIB1
-associated locus), but the contribution of TRIBAL to coronary artery disease risk remains untested.

METHODS:

Using recently available expression quantitative trait loci data and hepatocyte models, we further investigated this locus by Mendelian randomization analysis. Following antisense oligonucleotide targeting of TRIBAL, transcription array, quantitative reverse transcription polymerase chain reaction, and enrichment analyses were performed and effects on apoB and triglyceride secretion were determined.

RESULTS:

Mendelian randomization analysis supports a causal relationship between genetically determined hepatic
TRIBAL
expression and markers of hepatic steatosis and coronary artery disease risk. By contrast, expression data sets did not support expression quantitative trait loci relationships between coronary artery disease–associated variants and
TRIB1
.
TRIBAL
suppression reduced the expression of key regulators of triglyceride metabolism and bile acid synthesis. Enrichment analyses identified patterns consistent with impaired metabolic functions, including reduced triglyceride and cholesterol handling ability. Furthermore,
TRIBAL
suppression was associated with reduced hepatocyte secretion of triglycerides.

CONCLUSIONS:

This work identifies
TRIBAL
as a gene bridging the genotype-phenotype relationship at the 8q24.13 locus with effects on genes regulating hepatocyte lipid metabolism and triglyceride secretion.
ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023
Authors: Batlle Daniel , Hassler Luise , Wysocki Jan
Published: December 2024

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.
Identification of Circulating Proteins Associated With Blood Pressure
Authors: Xu Siqi , Wen Simin , Zong Xizeng , Wen Shifeng , Zhu Jianwei , Zheng Weipeng , Wang Zhiqiang , Cao Peihua , Liang Zhijiang , Ding Changhai , Zhang Yan , Ruan Guangfeng
Published: December 2024

BACKGROUND:

Circulating proteins in blood are involved in various physiological processes, but their contributions to blood pressure regulation remain partially understood. In traditional observational studies, identifying circulating proteins causally associated with blood pressure is challenging because of potentially unmeasured confounding and possible reverse causality.

METHODS:

Two-sample Mendelian randomization analyses were conducted to estimate the causal effects of 2270 circulating proteins (data sourced from 8 genome-wide association studies) on diastolic blood pressure, systolic blood pressure, and pulse pressure. Colocalization analyses were then used to investigate whether the circulating proteins and blood pressure traits shared causal genetic variants. To further verify the findings, we subsequently performed Steiger filtering analyses, annotation of protein-altering variants, assessment of overlap between protein quantitative trait loci and expression quantitative trait loci, protein-protein interaction and functional enrichment analyses, and drug target evaluation. To provide more potential biomarkers, we further evaluated the epidemiological associations of 2923 circulating proteins with blood pressure and hypertension by cross-sectional and longitudinal analyses using individual data in the UK Biobank.

RESULTS:

Mendelian randomization and colocalization analyses identified 121 circulating proteins with putative causal effects on at least 1 blood pressure trait. Many of the identified proteins are enriched in the pathways relevant to blood pressure regulation, and a majority of these proteins are either known drug targets or druggable candidates.

CONCLUSIONS:

This study has uncovered numerous circulating proteins potentially causally associated with blood pressure, providing insights into the regulatory mechanisms of blood pressure and potential therapeutic targets to facilitate blood pressure management.
Enhancing MR vascular Fingerprinting with realistic microvascular geometries
Authors: Delphin Aurélien , Boux Fabien , Brossard Clément , Coudert Thomas , Warnking Jan M. , Lemasson Benjamin , Barbier Emmanuel L. , Christen Thomas
Published: December 2024

Magnetic resonance (MR) vascular Fingerprinting proposes to use the MR Fingerprinting framework to quantitatively and simultaneously map several characteristics that emerge from vascular structure much smaller than voxel size. The initial implementation assessed the local blood oxygenation saturation (SO2), blood volume fraction (BVf), and vessel averaged radius (R) in humans and rodent brains using simple 2D representations of the vascular network during dictionary generation. In order to improve the results and possibly extend the approach to pathological environments and other biomarkers, we propose in this study to use 3D realistic vascular geometries in the numerical simulations. 28,000 different synthetic voxels containing vascular networks segmented from whole-brain healthy mice microscopy images were created. A Bayesian-based regression model was used for map reconstruction. We show in 8 healthy and 9 tumor-bearing rats that realistic vascular representations yield microvascular estimates in better agreement with the literature than 2D or 3D cylindrical models. Furthermore, tumoral blood oxygenation variations observed with the proposed approach are the only ones correlating with in vivo optic-fiber measurements performed in the same animals.
Bridging Huntington’s disease research with big data science: Harmonized neuroimaging datasets from multiple studies
Authors: Pustina Dorian , Das Sandhitsu , Rozelle Dan , Johnson Hans J. , Scahill Rachael I. , Tabrizi Sarah J. , Georgiou-Karistianis Nellie , Sampaio Cristina , Wood Andrew
Published: December 2024

Multiple neuroimaging datasets from Huntington’s disease (HD) studies are publicly available, but these datasets are in various formats, omit imaging metadata, and sometimes contain corrupt scans. We have created a platform to curate, harmonize, and distribute neuroimaging datasets from eight different studies: TRACK-HD, TRACKOn-HD, PREDICT-HD, IMAGE-HD, HD-YAS, SHIELD-HD, PEARL-HD, and LONGPDE10. The platform is organized into three conceptual levels to serve the research community with both raw and processed data. Raw data are converted into Brain Imaging Data Structure (BIDS) format, while processed data are obtained from pipelines such as Freesurfer and fmriprep. Studies that had followed the same participants were combined. After combining studies, the final six BIDS datasets include a total of 2,216 participants and 7,073 sessions. We outline tools, principles, and recommendations for future data management in HD research.
Age- and sex-related differences in human α4β2* nicotinic acetylcholine receptor binding evaluated with [18F]nifene PET
Authors: McVea Andrew , Choi Jihoon , DiFilippo Alexandra , McLachlan Max , Bettcher Brecca , Zammit Matthew , Stone Charles K. , Tudorascu Dana , Mukherjee Jogeshwar , Christian Bradley T.
Published: December 2024

Neuronal α4β2* nicotinic acetylcholine receptors (nAChRs) are stimulated by nicotine and are associated with tobacco dependence. [18F]Nifene is a PET radiotracer with high specificity for α4β2* nAChRs that can be used to investigate nAChR distribution in the human brain in vivo. In this study, we investigate the dependence of sex and age on the binding of [18F]nifene in nonsmoking healthy human participants. Cognitively normal participants (n = 31) were recruited into older versus younger and male versus female cohorts to investigate sex and age differences in [18F]nifene binding. Distribution volume ratios (DVRs) were calculated for brain regions with known nAChR expression and compared using a multiparameter linear regression model. There was a significant association between age and decreasing thalamic DVR (p = 0.01), with the most notable difference coming from the anterior nucleus of the thalamus (p < 0.001). Outside of the thalamus, a higher [18F]nifene DVR was observed with increasing age in the cerebellar grey matter (p = 0.01). No significant sex differences were observed using our linear model after multi-comparison correction. These results support including age in the experimental design and analysis of the α4β2* nAChR system in research and clinical applications.
Healthy aging is associated with altered visual gamma band onset and offset responses
Authors: Springer Seth D. , Schantell Mikki , Okelberry Hannah J. , Willett Madelyn P. , Johnson Hallie J. , Wilson Tony W.
Published: December 2024

Gamma oscillations have been shown to be critical for basic sensory processing, as well as visual attention and several other higher-order cognitive functions. Aberrant gamma oscillations have also been shown in neuropsychiatric and neurodegenerative diseases. Despite the possible clinical implications of altered gamma activity and emerging stimulation-based interventions targeting gamma, research into age-related changes in gamma oscillatory activity in healthy adults remains sparse. In the current study, we examined the neural oscillations underlying basic visual processing in 87 healthy aging adults using magnetoencephalography (MEG) and a visual grating stimulus. Neural activity elicited by the visual stimulus was imaged using a time-frequency resolved beamformer, and peak voxel time series were computed to characterize the visual oscillatory dynamics underlying these responses. We found significant age-related changes in visual gamma oscillations, but not in visual theta, alpha, or beta oscillations. Specifically, we found age-related increases in gamma band amplitude and inter-trial phase-locking (ITPL) immediately following stimulus presentation (i.e., gamma onset response). Conversely, gamma band amplitude and ITPL following stimulus removal (i.e., gamma offset response) were found to be decreased as a function of healthy aging. Critically, we demonstrated that the decreases in the gamma offset response predicted slower overall processing speed across all participants. Taken together, these findings indicate that healthy aging is uniquely associated with alterations in visual gamma oscillations and that these changes predict participant processing speed.
Test–retest performance of [18F]MK-6240 tau burden
and relative delivery indices in cognitively normal older subjects using
PET/MRI
Authors: Lois Cristina , Fu Jessie Fanglu , Salvatore Andrew N. , Garimella Arun H. , Huell Derek , Sari Hasan , Garcia David Izquierdo , Mercaldo Nathaniel D. , Dickerson Bradford , Johnson Keith A. , Catana Ciprian , Price Julie C.
Published: December 2024

Accurate interpretation of quantitative positron emission tomography (PET) outcomes hinges on understanding the test–retest variability (T-RT). Previous studies of the tau-PET ligand [18F]MK-6240 reported adequate T-RT performance of tau burden estimates over a short-term 21-day and over a longer-term 6-month T-RT period, primarily involving Alzheimer’s disease (AD) and cognitively normal (CN) subjects, respectively. However, several T-RT characteristics have not yet been reported, particularly in older CN (oCN) subjects. Here, we investigate the short-term T-RT performance of dynamic [18F]MK-6240 outcomes in a group largely consisting of oCN. We report T-RT for uptake in potential reference regions, for extracerebral off-target signal, and for estimates of tau burden and relative delivery indices in tau-bearing target regions. Eight participants (7 oCN, 1 AD) underwent baseline dynamic [18F]MK-6240 PET/MRI (Biograph mMR) and a retest follow-up PET/MRI scan within approximately 3 weeks. T-RT was evaluated using absolute percentage differences and intraclass correlation coefficients (ICC) in three groups of regions: (1) potential reference regions using standardized-uptake values 90–110 minutes post-injection (SUV90–110); (2) target regions using SUV ratios (SUVR90–110), distribution volume ratios (DVR), and relative delivery (R1); and (3) extracerebral region using SUVR90–110. A voxel-based partial volume correction (PVC) was applied. T-RT was evaluated with and without PVC. In oCN subjects, the SUV90–110 T-RT in the evaluated reference regions ranged from 6 to 11% (ICC > 0.9); target region T-RT was similar for SUVR90–110 (4–9%, ICC: 0.62–0.97), DVR (3–10%, ICC: 0.66–0.92), and R1 (3–14%, ICC: 0.52–0.97). PVC had minimal impact on reference region SUV90–110 T-RT, but increased target region T-RT variability (SUVR90–110: 10–26%; DVR: 6–22%; R1: 4–20%). Extracerebral SUVR90–110 exhibited higher T-RT variability (~12%, ICC: 0.85) than other target regions (average 6%) and increased to ~15% after PVC. Our findings are consistent with previous reports and provide further evidence of acceptable [18F]MK-6240 T-RT in low-signal oCN subjects. Our results suggest [18F]MK-6240 is suitable for detecting early tau deposition and longitudinal changes over time, and further support the viability of [18F]MK-6240 R1 to evaluate longitudinal changes in perfusion. PVC increased T-RT variability in tau burden and R1 outcomes. Notably, the extracerebral signal exhibited higher T-RT variability than other target and reference regions and may affect their signal.
Resting-state functional network segregation of the default mode network predicts valence bias across the lifespan
Authors: Pierce Jordan E. , Wig Gagan S. , Harp Nicholas R. , Neta Maital
Published: December 2024

The brain is organized into intrinsically connected functional networks that can be reliably identified during resting-state functional magnetic resonance imaging (fMRI). Healthy aging is marked by decreased network segregation, which is linked to worse cognitive functioning, but aging-related changes in emotion are less well characterized. Valence bias, which represents the tendency to interpret emotionally ambiguous information as positive or negative, is more positive in older than younger adults and is associated with differences in task-based fMRI activation in the amygdala, prefrontal cortex, and a cingulo-opercular (CO) network. Here, we examined valence bias, age, and resting-state network segregation of 12 brain networks in a sample of 221 healthy individuals from 6 to 80 years old. Resting-state network segregation decreased linearly with increasing age, extending prior reports of de-differentiation across the lifespan. Critically, a more positive valence bias was related to lower segregation of the default mode network (DMN), due to stronger functional connectivity of the DMN with CO and, to a lesser extent, the ventral attention network (VAN) in all participants. In contrast to this overall segregation effect, in participants over 39 years old (who tend to show a positive valence bias), bias was also related to weaker connectivity between the DMN and Reward networks. The present findings indicate that specific interactions between the DMN, a task control network (CO), an emotion processing network (Reward), and, to a weaker extent, an attention network (VAN), support a more positive valence bias, perhaps through regulatory control of self-referential processing and reduced emotional reactivity in aging. The current work offers further insight into the functional brain network alterations that may contribute to affective well-being and dysfunction across the lifespan.
Somewhere over the Rainbow
Authors: Baird Sophy
Published: December 2024

This research pertains to the rights of intersex children in the Global South. Kenya presents an interesting comparison as there has been litigation concerning intersex children. The 2014 case of Baby ‘A’ presents a wealth of knowledge. The jurisprudence developed in this regard touches on some of the provisions in the United Nations Convention on the Rights of the Child i.e. the four important general principles identified therein. These general principles are crucial in protecting the rights of vulnerable children and issues of gender, gender identity and sex – in particular, intersex children. In Uganda, the situation is quite dire. There are interesting questions regarding the right to health care, bodily autonomy, possible over-reach of medical professionals and legislative over-reach amongst many other issues. A comparison is made with India. In 2019 the state of Tamil Nadu, a court banned such unnecessary gender-normalising surgeries. While not an African country, it provides a comparative nuance in understanding sogiesc issues in the Global South.
Scopogonalia Young, 1977 (Insecta: Hemiptera: Cicadellidae): description of thirteen new species and phylogenetic analysis based on morphological data
Authors: Domahovski Alexandre Cruz , Alasmar Luísa , Cavichioli Rodney Ramiro
Published: December 2024

This work aims to expand the knowledge of the South American genus of sharpshooters Scopogonalia by describing 13 new species, beyond the 17 currently described, and by providing a morphology-based phylogenetic analysis. Twelve species are described from Brazil: S. gibba sp. nov., S. hama sp. nov., S. fenix sp. nov., S. nigrofasciata sp. nov., S. laticera sp. nov. and S. leali sp. nov. from Paraná State; S. personata sp. nov. and S. altomontana sp. nov. from Rio de Janeiro State; S. helenae sp. nov. from Piauí State; S. mejdalanii sp. nov. from Paraná and Piauí states; S. minima sp. nov. from Paraná and São Paulo states; and S. antonioi sp. nov. from Mato Grosso, Minas Gerais and Paraná states. The last species, S. dissimulata sp. nov. is described from Peru, Cusco District. A previous phylogenetic analysis recovered the clades named Early Green, Late Green and Yellow-Brown and the present analysis corroborated these clades, but some of the new species resulted in a new clade named Brown Clade. Images for all studied species and a new key to males are provided along with taxonomic notes for the genus and species. Additionally, the first records of parasitism by Hexacladia (Hymenoptera, Encyrtidae) and Strepsiptera are reported for Scopogonalia.
Air Pollution and Retail Vegetable Market Prices: Empirical Evidence from Korea
Authors: Ji Jeong-Hun , Lee Sang-Hyeon
Published: December 2024

Air pollution can lead to people engaging in avoidance actions. People may limit their time spent outdoors to minimize the health hazards linked with air pollution. Consequently, when severe air pollution causes these behavioral changes, both outdoor and indoor stores may experience the impacts of air pollution. This study estimated the impact of air pollutants on retail vegetable prices (i.e., the total impact of air pollutants on the demand and supply of vegetables) for large discount stores, supermarkets, department stores, and traditional markets in Korea. To this end, we examine the weekly data of 590 Korean retailers during the period from 2015 to 2019, employing both static and dynamic panel approaches. The results indicate that an increase in air pollutants, such as particulate matter, carbon monoxide, nitrogen dioxide, and sulfur dioxide, would lead to a decrease in vegetable prices in the short run and the long run across all types of stores we considered, meaning that deteriorating air pollutant levels could potentially result in decreases in vegetable prices not only in outdoor stores but also in indoor stores. Therefore, we suggest that initiatives to reduce air pollution and improve air quality should be further strengthened to prevent the adverse effects of air pollution on the food market.