bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S12 from Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation
Authors: Guo Xiaofan , Qiu Wei , Li Boyan , Qi Yanhua , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Pan Ziwen , Zhao Shulin , Qiu Jiawei , Li Gang , Xue Hao
Published: March 2024

Figure S12. DUSP9 knockdown promotes the microglia M2 polarization.
Figure S10 from Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation
Authors: Guo Xiaofan , Qiu Wei , Li Boyan , Qi Yanhua , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Pan Ziwen , Zhao Shulin , Qiu Jiawei , Li Gang , Xue Hao
Published: March 2024

Figure S10. miR-200c-3p promotes the microglial M2 polarization by targeting ZC3H13.
Supplementary Table S6 from Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non–small Cell Lung Cancer: TORG1937 (DATE Study)
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Kondo Tetsuro , Murakami Shuji , Shiraishi Yoshimasa , Imai Hisao , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Furuya Naoki , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: March 2024

Phase III clinical trials with a combination of immunotherapy and radiotherapy
Supplementary Table S4 from Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non–small Cell Lung Cancer: TORG1937 (DATE Study)
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Kondo Tetsuro , Murakami Shuji , Shiraishi Yoshimasa , Imai Hisao , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Furuya Naoki , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: March 2024

Treatment delivery
Supplementary Table S3 from Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non–small Cell Lung Cancer: TORG1937 (DATE Study)
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Kondo Tetsuro , Murakami Shuji , Shiraishi Yoshimasa , Imai Hisao , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Furuya Naoki , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: March 2024

Comparison of the background between this study and the PACIFIC study
Supplementary Table S2 from Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non–small Cell Lung Cancer: TORG1937 (DATE Study)
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Kondo Tetsuro , Murakami Shuji , Shiraishi Yoshimasa , Imai Hisao , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Furuya Naoki , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: March 2024

Representativeness of Study Participants
Supplementary Table S3 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

DEG for myeloid clusters
Supplementary Figure S9 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Spatial analysis of tumors with high CD8 infiltration did not show different in the proximity or clustering of myeloid cells markers or phenotypes near CD8 T cells between the response groups.
Supplementary Figure S7 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Higher levels of MSDC-Mac cells relative to CD8 T cells in MCC tumors, and especially in tumors with high CD8 T cells infiltration, are associated with worse prognosis.
Supplementary Figure S6 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Multivariate models resemble similar results to univariate model: Higher levels of TAMs markers relative to CD8 T cells are associated with worse prognosis.
Supplementary Figure S5 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Results of ROC space comparing CD8 percentage, MDSC-Mac/CD8 and Mono-Mac ratios as a in three patients groups stratified by CD8 levels.
Supplementary Figure S3 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Expression levels of immune checkpoint molecules across the immune landscape of MCC.
Supplementary Figure S2 from Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade
Authors: Tabachnick-Cherny Shira , Pulliam Thomas , Rodriguez Haroldo J. , Fan Xinyi , Hippe Daniel S. , Jones Daniel C. , Moshiri Ata S. , Smythe Kimberly S. , Kulikauskas Rima M. , Zaba Lisa C. , Paulson Kelly G. , Nghiem Paul
Published: March 2024

Transcriptomics analysis demonstrate differences between TAMs and DCs.
Data from Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide
Authors: Abida Wassim , Hahn Andrew W. , Shore Neal , Agarwal Neeraj , Sieber Paul , Smith Matthew R. , Dorff Tanya , Monk Paul , Rettig Matthew , Patel Rupal , Page Anne , Duff Maureen , Xu Rongda , Wang Jian , Barkund Shravani , Pankov Aleksandr , Wang Amber , Junttila Melissa R. , Multani Pratik S. , Daemen Anneleen , Chow Maneval Edna , Logothetis Christopher J. , Morris Michael J.
Published: March 2024

AbstractPurpose:
Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.
Patients and Methods:
Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).
Results:
A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65–38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
Conclusions:
Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
Data from Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM)
Authors: Fan Huishou , Wang Bing , Shi Lihui , Pan Ni , Yan Wenqiang , Xu Jingyu , Gong Lixin , Li Lingna , Liu Yuntong , Du Chenxing , Cui Jian , Zhu Guoqing , Deng Shuhui , Sui Weiwei , Xu Yan , Yi Shuhua , Hao Mu , Zou Dehui , Chen Xiequn , Qiu Lugui , An Gang
Published: March 2024

AbstractPurpose:
We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma.
Experimental Design:
A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10−5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated.
Results:
Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26–7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12–0.52) and overall survival (HR, 0.16; 0.06–0.40).
Conclusions:
EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.
Data from The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide
Authors: Halabi Susan , Guo Siyuan , Park Joseph J. , Nanus David M. , George Daniel J. , Antonarakis Emmanuel S. , Danila Daniel Costin , Szmulewitz Russell Zelig , McDonnell Donald P. , Norris John D. , Lu Changxue , Luo Jun , Armstrong Andrew J.
Published: March 2024

AbstractPurpose:
HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide.
Experimental Design:
We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide. CTC detection and HOXB13 complementary DNA (cDNA) expression was measured using a modified Adnatest, grouping patients into 3 categories: CTC 0 (undetectable); CTC+ HOXB13 CTC low (<4 copies); or CTC+ HOXB13 CTC high. The HOXB13 threshold was determined by maximally selected rank statistics for prognostic associations with overall survival (OS) and progression-free survival (PFS).
Results:
We included 102 men with sufficient CTC HOXB13 cDNA, identifying 25%, 31%, and 44% of patients who were CTC 0, CTC+ HOXB13 low, and CTC+ HOXB13 high, respectively. Median OS were 25.7, 27.8, and 12.1 months whereas the median PFS were 9.0, 7.7, and 3.8 months, respectively. In subgroup analysis among men with CellSearch CTCs ≥5 copies/mL and adjusting for prior abi/enza treatment and Halabi clinical risk score, the multivariate HR for HOXB13 CTC detection was 2.39 (95% CI, 1.06–5.40) for OS and 2.78 (95% CI, 1.38–5.59) for PFS, respectively. Low HOXB13 CTC detection was associated with lower CTC PSA, PSMA, AR-FL, and AR-V7 detection, and more liver/lung metastases (41% vs. 25%).
Conclusions:
Higher CTC HOXB13 expression is associated with AR-dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC.
Data from Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer
Authors: Wang Yinu , Situ Xiaolei , Cardenas Horacio , Siu Ellie , Alhunayan Sayedabdulrazzaq A. , Keathley Russell , Tanner Edward , Wei Jian-Jun , Tan Yuying , Prabhu Dessai Chinmayee Vallabh , Cheng Ji-Xin , Matei Daniela
Published: March 2024

AbstractPurpose:
DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development.
Experimental Design:
The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy.
Results:
Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1–3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301–induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301–treated xenografts.
Conclusions:
NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.
Data from An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer
Authors: Lukovic Jelena , Pintilie Melania , Han Kathy , Fyles Anthony W. , Bruce Jeffrey P. , Quevedo Rene , Pugh Trevor J. , Fjeldbo Christina S. , Lyng Heidi , Milosevic Michael F.
Published: March 2024

AbstractPurpose:
To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM).
Experimental Design:
Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA).
Results:
The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4).
Conclusions:
The immune metastatic risk score addresses important challenges in the treatment of cervical cancer—identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a “cold,” immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.
Data from Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non–small Cell Lung Cancer: TORG1937 (DATE Study)
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Kondo Tetsuro , Murakami Shuji , Shiraishi Yoshimasa , Imai Hisao , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Furuya Naoki , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: March 2024

AbstractPurpose:
Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non–small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC.
Patients and Methods:
This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT.
Results:
From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0–80.0 and 95% CI, 59.4–85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%.
Conclusions:
Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.
Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series
Authors: Anselmino Nicolas , Labanca Estefania , Shepherd Peter D.A. , Dong Jiabin , Yang Jun , Song Xiaofei , Nandakumar Subhiksha , Kundra Ritika , Lee Cindy , Schultz Nikolaus , Zhang Jianhua , Araujo John C. , Aparicio Ana M. , Subudhi Sumit K. , Corn Paul G. , Pisters Louis L. , Ward John F. , Davis John W. , Vazquez Elba S. , Gueron Geraldine , Logothetis Christopher J. , Futreal Andrew , Troncoso Patricia , Chen Yu , Navone Nora M.
Published: March 2024

Purpose:

Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

Experimental Design:

We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy.

Results:

The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response–associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets.

Conclusions:

We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.
Vasorin Exocytosed from Glioma Cells Facilitates Angiogenesis via VEGFR2/AKT Signaling Pathway
Authors: Zhong Ying , Kang Hui , Ma Ziqing , Li Jiayu , Qin Zixi , Zhang Zixuan , Li Peiwen , Zhong Ying , Wang Lihui
Published: March 2024

Glioma is a highly vascularized tumor of the central nervous system. Angiogenesis plays a predominant role in glioma progression and is considered an important therapeutic target. Our previous study showed that vasorin (VASN), a transmembrane protein, is overexpressed in glioma and promotes angiogenesis; however, the potential mechanism remains unclear. In this study, we found that human vascular endothelial cells (hEC) co-cultured with VASN-overexpressing glioma cells exhibited accelerated migration ability and increased expression of VASN originated from glioma cells. VASN was found in exosomes secreted by glioma cells and could be taken up by hECs. hECs showed more edge filopodia and significantly upregulated expression of endothelial tip cell marker gene and protein levels after co-culture with VASN-overexpressing glioma cells. In clinical glioma tissue and orthotopic transplantation glioma tissue, the vascular density and the number of vascular endothelial cells with a tip cell phenotype in VASN-overexpressed tissues were significantly higher than in tissues with low expression. At the molecular level, VASN interacted with VEGFR2 and caused internalization and autophosphorylation of VEGFR2 protein, and then activated the AKT signaling pathway. Our study collectively reveals the function and mechanism of VASN in facilitating angiogenesis in glioma, providing a new therapeutic target for glioma.

Implications:

These findings demonstrate that VASN exocytosed from glioma cells enhanced the migration of vascular endothelial cells by VEGFR2/AKT signaling pathway.
Figure S4 from Nanoparticle-mediated Photodynamic Therapy as a Method to Ablate Oral Cavity Squamous Cell Carcinoma in Preclinical Models
Authors: Sahovaler Axel , Valic Michael S. , Townson Jason L. , Chan Harley H.L. , Zheng Mark , Tzelnick Sharon , Mondello Tiziana , Pener-Tessler Alon , Eu Donovan , El-Sayes Abdullah , Ding Lili , Chen Juan , Douglas Catriona M. , Weersink Robert , Muhanna Nidal , Zheng Gang , Irish Jonathan C.
Published: March 2024

Supplementary figure 4 and legend.
Utricular Dysfunction and Hearing Impairment Affect Spatial Navigation in Community-Dwelling Healthy Adults: Analysis from the Baltimore Longitudinal Study of Aging
Authors: Grove Colin R. , Anson Eric R. , Agrawal Yuri , Simonsick Eleanor M. , Schubert Michael C.
Published: March 2024

Introduction: Spatial navigation, the ability to move through one’s environment, is a complex skill utilized in everyday life. The effects of specific vestibular end-organ deficits and hearing impairments on spatial navigation have received little to no attention. We hypothesized that hearing impairment adversely affects spatial navigation and that bimodal impairments (vestibular and hearing) further impair navigation ability. Methods: Data from 182 participants in the Baltimore Longitudinal Study of Aging who had interpretable results for the video head impulse test (vHIT), cervical vestibular evoked myogenic potentials (cVEMP) and ocular vestibular evoked myogenic potentials (oVEMP), audiometric testing, and the triangle completion test (TCT) were retrospectively analyzed. Multiple linear regression, controlling for age, sex, and cognition, was employed to identify predictors of TCT performance in terms of end-point error, angle deviation, and distance walked. Results: oVEMP abnormalities were associated with larger end-point error (p = 0.008) and larger angle deviation (p = 0.002) but were not associated with distance walked (p = 0.392). Abnormalities on cVEMP testing and vHIT were not associated with distance walked (p = 0.835, p = 0.300), end-point error (p = 0.256, p = 0.808), or angle deviation (p = 0.192, p = 0.966). Compared with normal-hearing adults, hearing-impaired adults walked a shorter distance during the TCT (p = 0.049) but had a similar end-point error (p = 0.302) and angle deviation (p = 0.466). There was no interaction between vestibular and hearing function for predicting spatial navigation ability. Conclusion: In this cohort analysis, utricular dysfunction and hearing impairment were associated with poorer spatial navigation performance. We postulate that hearing impairment negatively affects one’s ability to use real-time, intrinsic auditory cues and/or prior experience to guide navigation.
Morphometric assessment remodeling features of ventricular artery at
postresection portal hypertension
Authors: Hnatjuk Mykhailo , Monastyrska Nataliia , Hdanska Natalia M. , Tatarchuk Liudmyla , Yasinovskyi Oleg B.
Published: March 2024

Summary. Structural and functional reconstruction of arterial bed of
heart chambers may be due to various changes in hemodynamics in the great
and small circles and the portal hepatic vein system, which is most often
caused by portal hypertension, which can occur at removing large volumes of
liver. Angioarchitectonics of the intraorganic channel of heart muscle in
portal hypertension has not been fully studied. The aim of the study –
morphometrically study the features of remodeling of the arteries of
ventricles of heart in conditions of postresection portal hypertension.
Materials and Methods. Ventricular arteries of the heart of 94 white rats,
divided into 3 groups were morphologically examined. Group 1 consisted of 15
animals, group 2 – 63 rats with simulated postresection portal hypertension,
group 3 – 16 animals with a combination of postresection portal hypertension
and multiorgan failure. Euthanasia of rats was performed by bloodletting
under thiopental anesthesia. Histological micronutrients were made of the
ventricles of heart, which determined the outer and inner diameters of the
arteries of left and right ventricles of small caliber, the thickness of
media and adventitial membrane, Wagenworth and Kernogan indices, endothelial
cell height, diameter of their nuclei, nuclear-cytoplasmic relation,
relative volume of damaged endothelial cells. Quantitative indicators were
processed statistically. Results. Postresection portal hypertension leads to
structural reconstruction of small ventricular arteries, which is
characterized by thickening of the wall of studied vessels, narrowing of
their lumen, marked changes in Wagenworth and Kernogan indices,
deterioration of blood supply, nuclear-cytoplasmic relation disorders in
endotheliocytes. The relative volume of damaged endothelial cells in
conditions of postresection portal hypertension in the left ventricle was
(19.20±0.30) %, in the right – (15.30±0.27) %, in case of multiple organ
failure, respectively – (34.5±0.4) % and (24.30±0.36) %. Conclusions.
Postresection portal hypertension leads to severe remodeling of the small
arteries of left and right ventricles, which is characterized by thickening
of their wall, narrowing of lumen, changes in the Kernogan and Wagenworth
indices, damage to endothelial cells, endothelial trophic dysfunction and
dystrophy and necrobyosis cellulae, tissues, foci of cellular infiltration
and sclerosis. The revealed structural changes dominated in the left
ventricle and in the combination of postresection portal hypertension with
multiorgan failure
Microscopic analysis of herbal teas against flu and cold
Authors: Pencheva R.S. , Danyliv S.I.
Published: March 2024

Summary. The common cold and flu are caused by common respiratory
viruses, sometimes leading to hospitalization and even death. Among viral
infections, influenza viruses have spread around the world with a major
impact on public health. Changes in the antigenic structures of influenza
viruses lead to a lack of effective treatments. Therefore, the use of herbal
remedies is an alternative way to treat flu and colds. For this purpose, you
can use both individual medicinal plants and their collections. The aim of
the study – to learn the anatomical structure against cold herbal teas from
two manufacturers (Ukraine and Bulgaria) to establish microscopic diagnostic
features. Materials and Methods. Gripophytol tea (Liktravy Ukraine) and Pri
Stud i Zima herbal tea (Bioprograma, Bulgaria) were selected for analysis.
The manufacture of drugs was performed according to the method described in
the SPU. Results. When examining phytotea remedies, fragments of the upper
and lower epidermis of leaves, stomata complex and its types, fragments of
large hairs, numerous simple hairs on the edges of leaves, densely pubescent
inner epidermis, probably fertile rose hips, druze of calcium oxalate, etc
were found. Particles of herbal teas made it possible to identify their
composition and make a general picture of the microscopic structure of the
studied samples. Conclusions. Thus, a microscopic study was conducted and
the anatomical structure of herbal teas Gripofitol (Ukraine) and "Pri Stud i
Zima" (Bulgaria) was established. The main microscopic diagnostic features
of the anatomical structure of the components of these fees, which can be
used in the future to diagnose these herbal teas, have been identified
Diagnostic significance of leptin in patients with ischemic heart
disease on the basis of metabolic syndrome
Authors: Schurko Mariia M. , Lapovets Lyubov Ye. , Boikiv Natalya D.
Published: March 2024

Summary. This article presents changes in leptin, carbohydrate and
lipid metabolism in patients with coronary heart disease and complicated by
metabolic syndrome (MS). Obesity is positively correlated with loss of
health and reduced life expectancy, as it contributes to a high risk of many
pathological processes, such as coronary heart disease, stroke, liver
cirrhosis, type 2 diabetes and a number of different cancers. Obesity and
insulin resistance are major components of the metabolic syndrome and major
risk factors for cardiovascular disease. High leptin levels are positively
associated with systemic markers of inflammation. The aim of the study – to
research the levels of leptin, glucose, triacylglycerols (TG), glycated
hemoglobin (HbA1c) in the blood of patients with coronary heart disease and
patients with coronary heart disease on the background of metabolic
syndrome. Materials аnd Methods. 120 patients with verified coronary heart
disease were examined, including 60 patients with coronary heart disease
without MS (30 men, 30 women) and 60 patients with coronary heart disease on
the background of MS (29 men, 31 women). The mean age of patients was (50±5)
years. Control group – 30 healthy people of appropriate age and sex.
Results. Studies have shown that obesity is accompanied by high levels of
leptin, which deepens insulin resistance and is a trigger for coronary heart
disease. Also, more pronounced changes in carbohydrate and lipid metabolism
in patients with coronary heart disease on the background of metabolic
syndrome, which indicates the severity of the clinical course of coronary
heart disease on the background of MS. Conclusions. Studies have shown that
leptin resistance can be a potential cause of insulin resistance and
therefore obesity, which ultimately leads to metabolic syndrome and the
development of coronary heart disease. The data indicate a greater tendency
to obesity in women with coronary heart disease complicated by MS
Morphological features of heart remodeling in the postcompression period
of crush syndrome
Authors: Yuryk Yaroslav I.
Published: March 2024

Summary. In the postcompression period of crush syndrome regenerative
processes develop restorative processes in target organs, in particular in
the heart. However, the dynamics of myocardial regenerative changes in the
postcompression period in crush syndrome is insufficiently covered in
professional literature and requires comprehension study and clarified. The
aim of the study – to find out features of regenerative changes in heart of
laboratory rats in the dynamics in the postcompression period of crush
syndrome. Materials and Methods. Light-optical and polarization were
performed examination of the myocardium of 48 laboratory rats after 1, 3, 7
and 14 days (12 animals in each period) after cessation of 6 hour
compression of the thigh right pelvic limb. Crush syndrome was modeled under
anesthesia by intraperitoneal input of ketamine hydrochloride (100 mg/kg
body weight) in a specially designed device, the compression force was 7
kg/cm2, the compressive surface area – 5 cm2. The control group consisted of
12 animals. Results. The stages of myocardial remodeling in the
postcompression period are noted, reflecting its structural recovery. In the
early postcompression period light-optical disorders predominated
microcirculation and alternate changes in acquired cardiomyocytes maximum
development after 3 days. After 7 days in myocardial stroma registered
cellular infiltrates in which predominate lymphocytes and fybroblasts.
Cardiomyocytes lose a compact, gait cells became fortuous, microfoci of
contractures were detected and fragmentation, there was a weak proliferation
of collagen fibers. After 14 days in the late postcompression period the
manifestation do not fade microcirculation disorders. Processes were
registered in some areas collagen formation. Conclusions. In the first three
days after the cessation of compression of compression of the lower
extremity dystrophic–necrotic changes of the myocardium persist in
combination with microcirculatory disorders. After 7 days the development of
interstitial lympho–histiocytic infiltration is observed against the
background of a gradual decrease alternative and hemodynamic processes.
After 14 days registration a restoration of myocardial histostructure with
residual processes of microfocal contracture of cardiomyocyte degeneration
and increased collagen formation are registere
Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study
Authors: Hu Yuanlong , Lin Lin , Zhang Lei , Li Yuan , Cui Xinhai , Lu Mengkai , Zhang Zhiyuan , Guan Xiuya , Zhang Muxin , Hao Jiaqi , Wang Xiaojie , Huan Jiaming , Yang Wenqing , Li Chao , Li Yunlun
Published: March 2024

BACKGROUND:

This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure.

METHODS:

A Mendelian randomization design was used to investigate the causal impact of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure on 82 cardiac magnetic resonance traits and heart failure risk. Mediation analyses were also conducted to identify potential plasma proteins mediating these effects.

RESULTS:

Genetically proxied higher SBP, DBP, and pulse pressure were causally associated with increased left ventricular myocardial mass and alterations in global myocardial wall thickness at end diastole. Elevated SBP and DBP were linked to increased regional myocardial radial strain of the left ventricle (basal anterior, mid, and apical walls), while higher SBP was associated with reduced circumferential strain in specific left ventricular segments (apical, mid-anteroseptal, mid-inferoseptal, and mid-inferolateral walls). Specific plasma proteins mediated the impact of blood pressure on cardiac remodeling, with FGF5 (fibroblast growth factor 5) contributing 2.96% (
P
=0.024) and 4.15% (
P
=0.046) to the total effect of SBP and DBP on myocardial wall thickness at end diastole in the apical anterior segment and leptin explaining 15.21% (
P
=0.042) and 23.24% (
P
=0.022) of the total effect of SBP and DBP on radial strain in the mid-anteroseptal segment. Additionally, FGF5 was the only mediator, explaining 4.19% (
P
=0.013) and 4.54% (
P
=0.032) of the total effect of SBP and DBP on heart failure susceptibility.

CONCLUSIONS:

This mediation Mendelian randomization study provides evidence supporting specific circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure.
Adverse Effects of Aldosterone: Beyond Blood Pressure
Authors: Brown Jenifer M.
Published: March 2024

Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic regulation. Classically, activation of the MR in the renal tubular epithelium is responsible for sodium retention and volume expansion, raising systemic blood pressure. However, activation of the MR across a wide distribution of tissue types has been implicated in multiple adverse consequences for cardiovascular, cerebrovascular, renal, and metabolic disease, independent of blood pressure alone. Primary aldosteronism, heart failure, and chronic kidney disease are states of excessive aldosterone production and MR activity where targeting MR activation has had clinical benefits out of proportion to blood pressure lowering. The growing list of established and emerging therapies that target aldosterone and MR activation may provide new opportunities to improve clinical outcomes and enhance cardiovascular and renal health.
Iron Status and Risk of Heart Disease, Stroke, and Diabetes: A Mendelian Randomization Study in European Adults
Authors: Liu Yunan , Clarke Robert , Bennett Derrick A. , Zong Geng , Gan Wei
Published: March 2024

Background

The relevance of iron status biomarkers for coronary artery disease (CAD), heart failure (HF), ischemic stroke (IS), and type 2 diabetes (T2D) is uncertain. We compared the observational and Mendelian randomization (MR) analyses of iron status biomarkers and hemoglobin with these diseases.

Methods and Results

Observational analyses of hemoglobin were compared with genetically predicted hemoglobin with cardiovascular diseases and diabetes in the UK Biobank. Iron biomarkers included transferrin saturation, serum iron, ferritin, and total iron binding capacity. MR analyses assessed associations with CAD (CARDIOGRAMplusC4D [Coronary Artery Disease Genome Wide Replication and Meta‐Analysis Plus The Coronary Artery Disease Genetics], n=181 522 cases), HF (HERMES [Heart Failure Molecular Epidemiology for Therapeutic Targets), n=115 150 cases), IS (GIGASTROKE, n=62 100 cases), and T2D (DIAMANTE [Diabetes Meta‐Analysis of Trans‐Ethnic Association Studies], n=80 154 cases) genome‐wide consortia. Observational analyses demonstrated J‐shaped associations of hemoglobin with CAD, HF, IS, and T2D. In contrast, MR analyses demonstrated linear positive associations of higher genetically predicted hemoglobin levels with 8% higher risk per 1 SD higher hemoglobin for CAD, 10% to 13% for diabetes, but not with IS or HF in UK Biobank. Bidirectional MR analyses confirmed the causal relevance of iron biomarkers for hemoglobin. Further MR analyses in global consortia demonstrated modest protective effects of iron biomarkers for CAD (7%–14% lower risk for 1 SD higher levels of iron biomarkers), adverse effects for T2D, but no associations with IS or HF.

Conclusions

Higher levels of iron biomarkers were protective for CAD, had adverse effects on T2D, but had no effects on IS or HF. Randomized trials are now required to assess effects of iron supplements on risk of CAD in high‐risk older people.
Intensive Blood Pressure Lowering in Individuals With Low Diastolic Blood Pressure and Elevated Troponin Levels in SPRINT
Authors: Smith Cady , Berry Jarett D. , Scherzer Rebecca , de Lemos James A. , Nambi Vijay , Ballantyne Christie M. , Kravitz Richard L. , Killeen Anthony A. , Ix Joachim H. , Shlipak Michael G. , Ascher Simon B.
Published: March 2024

Background

Among individuals with hypertension and low diastolic blood pressure (DBP), the optimal BP target remains controversial due to concerns that BP lowering may reduce coronary perfusion. We determined the impact of intensive BP control among individuals with elevated systolic BP who have low DBP and elevated hs‐cTnT (high‐sensitivity cardiac troponin T) levels.

Methods and Results

A total of 8828 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were stratified by baseline DBP. Those with low DBP (<70 mm Hg) were further stratified by elevated hs‐cTnT (≥14 ng/L) at baseline. The effects of intensive versus standard BP lowering on a cardiovascular disease composite end point, all‐cause death, and 1‐year change in hs‐cTnT were determined. The combination of low DBP/high hs‐cTnT was independently associated with a higher risk for cardiovascular disease and all‐cause death, as well as greater 1‐year increases in hs‐cTnT, compared with DBP ≥70 mm Hg. However, randomization to intensive versus standard BP lowering led to similar reductions in cardiovascular disease risk among individuals with low DBP/high hs‐cTnT (hazard ratio [HR], 0.82 [95% CI, 0.57–1.19]), low DBP/low hs‐cTnT (HR, 0.48 [95% CI, 0.29–0.79]), and DBP ≥70 mm Hg (HR, 0.73 [95% CI, 0.60–0.89];
P
for interaction=0.20). Intensive BP lowering also led to a reduction in all‐cause death that was similar across groups (
P
for interaction=0.57).

Conclusions

In this nonprespecified subgroup analysis of SPRINT, individuals with low DBP and elevated hs‐cTnT, low DBP and nonelevated hs‐cTnT, and DBP ≥70 mm Hg derived similar cardiovascular disease and mortality benefits from intensive BP lowering. These findings warrant confirmation in other studies.
Exercise‐Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation
Authors: Dorian David , Gustafson Dakota , Quinn Ryan , Bentley Robert F. , Dorian Paul , Goodman Jack M. , Fish Jason E. , Connelly Kim A.
Published: March 2024

Background

Atrial fibrillation (AF) is a common arrhythmia characterized by uncoordinated atrial electrical activity. Lone AF occurs in the absence of traditional risk factors and is frequently observed in male endurance athletes, who face a 2‐ to 5‐fold higher risk of AF compared with healthy, moderately active males. Our understanding of how endurance exercise contributes to the pathophysiology of lone AF remains limited. This study aimed to characterize the circulating protein fluctuations during high‐intensity exercise as well as explore potential biomarkers of exercise‐associated AF.

Methods and Results

A prospective cohort of 12 male endurance cyclists between the ages of 40 and 65 years, 6 of whom had a history of exercise‐associated AF, were recruited to participate using a convenience sampling method. The circulating proteome was subsequently analyzed using multiplex immunoassays and aptamer‐based proteomics before, during, and after an acute high‐intensity endurance exercise bout to assess temporality and identify potential markers of AF. The endurance exercise bout resulted in significant alterations to proteins involved in immune modulation (eg, growth/differentiation factor 15), skeletal muscle metabolism (eg, α‐actinin‐2), cell death (eg, histones), and inflammation (eg, interleukin‐6). Subjects with AF differed from those without, displaying modulation of proteins previously known to have associations with incident AF (eg, C‐reactive protein, insulin‐like growth factor‐1, and angiopoietin‐2), and also with proteins having no previous association (eg, tapasin‐related protein and α
2
‐Heremans‐Schmid glycoprotein).

Conclusions

These findings provide insights into the proteomic response to acute intense exercise, provide mechanistic insights into the pathophysiology behind AF in athletes, and identify targets for future study and validation.
Inferring Expectations from Observables: Evidence from the Housing Market
Authors: Ben-David Itzhak , Towbin Pascal , Weber Sebastian
Published: March 2024

We propose a method to detect shifts in housing price expectations by observing excess capacity. Anticipated future price hikes lead to increased current supply, resulting in temporary vacancies. Using a structural vector autoregression with sign restrictions, we analyze the impact of these expectations on the U.S. housing market. Our findings indicate that price expectation shocks primarily drove the 1996–2006 boom, especially in the Sand States. At the boom's peak, these shocks stemmed from unrealistic growth expectations, which reversed during the bust.
Purpose in Life: a Comparison between Communities of the Non-religious and the Religious
Authors: Robbins Mandy , Longden Gareth
Published: March 2024

Research has demonstrated that people of faith often report higher levels of purpose in life than the general population. It has been suggested this may be because they hold a meaningful world view rather than as a consequence of faith. It can be argued that humanists, like people of faith, also hold a meaningful world view, albeit one that is based upon a philosophy of naturalism. This article compares a sample of 1,042 members of Humanists UK with population norms, and a sample of religious groups, using the Purpose in Life Test to assess their reported levels of purpose in life. The data demonstrate that humanists record higher levels of purpose in life than the general population.