bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Islet Autoantibodies in Whole Blood by Antibody Detection by Agglutination-PCR (ADAP) Technology Is Sensitive and Suitable for General Population Screening Programs
Authors: Oron Tal , Cortez Felipe de Jesus , Shtaif Biana , Robinson Peter V. , Yackobovitch-Gavan Michal , Tandel Devangkumar , Seftel David , Phillip Moshe , Tsai Cheng-ting , Gat-Yablonski Galia
Published: March 2024

Background. Detection of type 1 diabetes (T1D) at the preclinical stage is possible by detecting islet autoantibodies (IAs) years before the appearance of symptomatic diabetes. The Antibody Detection Israeli Research is a general population screening program searching for children with multiple IAs who are at risk of developing T1D. IAs are measured in capillary or venous whole blood (WB) samples using the novel ultrasensitive antibody detection by agglutination-PCR (ADAP) technology. Objective. To assess the accuracy and reliability of the ADAP assay in venous and capillary WB. Materials and Methods. In total, 50 children with T1D and 50 healthy controls participated in the study. Venous and capillary blood samples were drawn from participants with T1D, while only venous blood was drawn from the controls. The ADAP assay in venous and capillary blood was compared to the currently used assays in their ability to detect glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and insulin autoantibodies (IAAs). Results. The area under the curve using the receiver operating characteristic curves was comparable between the ADAP assay in WB and standard enzyme-linked immunosorbent assay (ELISA)/radioimmunoassay (RIA) for all three IAs GADA 0.946 (95% CI: 0.900–0.991) vs. 0.949 (0.906–0.992), P=0.873; IA-2A 0.747 (0.649–0.844) vs. 0.666 (0.587–0.744), P=0.106; IAA 1.000 (1.000–1.000) vs. 1.000 (1.000–1.000), P=1.000. The correlation between the levels of IA in venous and capillary WB using ADAP was R2 = 0.958 (P <0.01), R2 = 0.943 (P <0.01), and R2 = 0.711 (P <0.01) for GADA, IA-2A, and IAA, respectively. IA levels in venous and capillary WB using ADAP were comparable without a proportional bias in Bland–Altman’s plots of agreement, suggesting the two methods may be used interchangeably. Conclusions. The ADAP assay is reliable in detecting IA in venous and capillary WB samples with comparable performance to standard RIA and ELISA. These findings open avenues for widespread use of the ADAP assay in future general population screening programs to detect children at risk of developing T1D.
The Prevalence and Associated Factors of Impaired Fasting Glucose among Children and Adolescents in Urban China: A Large-Scale Cross-Sectional Study
Authors: Huang Fenglian , Lin Zongyu , Lu Yeling , Zhou Yueqin , Zhu Lewei , Wang Xiaotong , Zhu Yanna
Published: March 2024

This study aimed to investigate the level of fasting plasma glucose (FPG), the prevalence of impaired fasting glucose (IFG), and the associated factors among children and adolescents in urban China. Based on a cross-sectional study conducted in three Chinese metropolises during 2013–2014, this analysis included 7,143 participants aged 7–18 years. Information on demographics, family environment, diet, and physical activity was collected by questionnaires. Anthropometric parameters and blood biochemical indicators were measured. Logistic regression models were applied to assess risk factors of glucose level. Results revealed that the average FPG level was 4.81 ± 0.53 mmol/L, and the prevalence of IFG was 3.3%. Trends of these two variables varied significantly with age increasing (all p<0.001), reaching double peaks at 10–12 and 15–17 years. IFG was positively associated with the male sex, age increasing, obesity, higher triglyceride (TG) levels, and living in northern China. When stratified by sex, family history of diabetes, elevated total cholesterol levels, and higher intake of sugar-sweetened beverages were positively associated with IFG only in females, suggesting these parameters were female-specific risk factors of IFG. We concluded that the prevalence of IFG among children and adolescents aged 7–18 years in urban China was higher than that reported in previous regional studies and was associated with obesity and higher levels of TG. Therefore, sex-specific lifestyle interventions should be provided to promote healthy weight and lipids and stem the upward trend of IFG.
Comorbid Anxiety and Depression among Pregnant and Postpartum Women: A Longitudinal Population-Based Study
Authors: Shen Quan , Xiao Meili , Wang Binglu , He Tan , Zhao Jinxing , Lei Jun
Published: March 2024

Background. Longitudinal studies investigating the prevalence of comorbid anxiety and depression (CAD) and its risk factors during the perinatal period are limited. The objective of this longitudinal study was to describe the prevalence and risk factors of CAD among pregnant and postpartum women in China. Methods. From the Population Health Data Archive of the National Population Health Data Center, 1,941 Chinese pregnant or postpartum women who were surveyed for both depressive and anxiety symptoms during and after pregnancy were included in the study. This population-based longitudinal study was conducted between March 2017 and March 2022. The self-rating anxiety scale and self-rating depression scale were used to assess anxiety and depression symptoms at four time points throughout the perinatal period. The generalized estimation equation model was used to identify sociodemographic, obstetric, and mental health factors for CAD. Results. The prevalence of CAD was 15.67%, 8.36%, 11.64%, and 13.24% in the first, second, and third trimesters and postpartum, respectively. A higher proportion of women reporting, compared to women with single anxiety or depression, CAD during and after pregnancy were primiparas (OR=1.32, 95% CI 1.06-1.65), having a smoking history (OR=1.51, 95% CI 1.05-2.18), and having dissatisfied marital relationship (OR=1.97, 95% CI 1.28-3.06). Women conceived with assisted reproductive treatment were reported to be less likely to have CAD (OR=0.69, 95% CI 0.55-0.86). Conclusions. These findings highlight that CAD is relatively common in pregnant and postpartum women and recommend targeted interventions for higher risk women, specifically primiparas with a history of smoking and dissatisfied marital relationships.
Accuracy‐Improved Fault Diagnosis Method for Rolling Bearing Based on Enhanced ESGMD‐CC and BA‐ELM Model
Authors: Yuan Wei , Liu Fuzheng , Gu Hongbin , Miao Fei , Zhang Faye , Jiang Mingshun
Published: March 2024

The current methods for early fault diagnosis of rolling bearing have some flaws, such as poor fault feature information and insufficient fault feature extraction capability, which makes it challenging to guarantee fault diagnosis accuracy. In order to increase the accuracy of fault diagnosis, it proposes a new fault diagnosis method based on enhanced Symplectic geometry mode decomposition with cosine difference factor and calculus operator (ESGMD‐CC) and bat algorithm (BA) optimized extreme learning machine (ELM). The vibration signal is first decomposed into a number of Symplectic geometry components (SGCs) by SGMD. The number of iterations is reduced by the cosine difference factor, which also successfully separates the noise components from the effective components. The calculus operator is adopted to strengthen the weak fault features, making it simple to extract. The fault feature vectors are calculated by the power spectrum entropy‐weighted singular values. Finally, the ELM model optimized by BA iteratively is performed as the final classifier for fault classification. The simulation and experiments demonstrate that the proposed method has a better degree of fault diagnostic accuracy and is effective at extracting the rich fault information from vibration signals.
Supplemental Table 5 from A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma
Authors: Hwang Grace H. , Pazyra-Murphy Maria F. , Seo Hyuk-Soo , Dhe-Paganon Sirano , Stopka Sylwia A. , DiPiazza Marina , Sutter Nizhoni , Gero Thomas W. , Volkert Alison , Ombelets Lincoln , Dittemore Georgia , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Agar Nathalie Y.R. , Scott David A. , Segal Rosalind A.
Published: March 2024

Supplemental Table 5
Supplemental Table 3 from A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma
Authors: Hwang Grace H. , Pazyra-Murphy Maria F. , Seo Hyuk-Soo , Dhe-Paganon Sirano , Stopka Sylwia A. , DiPiazza Marina , Sutter Nizhoni , Gero Thomas W. , Volkert Alison , Ombelets Lincoln , Dittemore Georgia , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Agar Nathalie Y.R. , Scott David A. , Segal Rosalind A.
Published: March 2024

Supplemental Table 3
Supplemental Table 1 from A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma
Authors: Hwang Grace H. , Pazyra-Murphy Maria F. , Seo Hyuk-Soo , Dhe-Paganon Sirano , Stopka Sylwia A. , DiPiazza Marina , Sutter Nizhoni , Gero Thomas W. , Volkert Alison , Ombelets Lincoln , Dittemore Georgia , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Agar Nathalie Y.R. , Scott David A. , Segal Rosalind A.
Published: March 2024

Supplemental Table 1
Figure S5 from FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma
Authors: Huang Jiao , Tsang Wai Ying , Fang Xiao-Na , Zhang Yu , Luo Jie , Gong Lan-Qi , Zhang Bai-Feng , Wong Ching Ngar , Li Zhi-Hong , Liu Bei-Lei , Huang Jin-Lin , Yang Yu-Ma , Liu Shan , Ban Liu-Xian , Chan Yiu Hong , Guan Xin-Yuan
Published: March 2024

Figure S5
Figure S4 from FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma
Authors: Huang Jiao , Tsang Wai Ying , Fang Xiao-Na , Zhang Yu , Luo Jie , Gong Lan-Qi , Zhang Bai-Feng , Wong Ching Ngar , Li Zhi-Hong , Liu Bei-Lei , Huang Jin-Lin , Yang Yu-Ma , Liu Shan , Ban Liu-Xian , Chan Yiu Hong , Guan Xin-Yuan
Published: March 2024

Figure S4
Supplementary Fig. S6 from AKT1 interacts with DHX9 to Mitigate R Loop–Induced Replication Stress in Ovarian Cancer
Authors: Huang Tzu-Ting , Chiang Chih-Yuan , Nair Jayakumar R. , Wilson Kelli M. , Cheng Ken , Lee Jung-Min
Published: March 2024

Supplementary Fig. S6
Figure S5 from N6-Methyladenosine Reader YTHDF1 Promotes Stemness and Therapeutic Resistance in Hepatocellular Carcinoma by Enhancing NOTCH1 Expression
Authors: Zhang Xinyue , Su Tianhong , Wu Yifan , Cai Yuhong , Wang Lina , Liang Cong , Zhou Lei , Wang Shiyan , Li Xiao-Xing , Peng Sui , Kuang Ming , Yu Jun , Xu Lixia
Published: March 2024

Figure S5
Data from AKT1 interacts with DHX9 to Mitigate R Loop–Induced Replication Stress in Ovarian Cancer
Authors: Huang Tzu-Ting , Chiang Chih-Yuan , Nair Jayakumar R. , Wilson Kelli M. , Cheng Ken , Lee Jung-Min
Published: March 2024

Abstract
PARP inhibitor (PARPi)–resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop–mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop–mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status.
Significance:
Inhibition of the AKT and ATR pathways cooperatively induces R loop–associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations.

See related commentary by Ramanarayanan and Oberdoerffer, p. 793
Data from N6-Methyladenosine Reader YTHDF1 Promotes Stemness and Therapeutic Resistance in Hepatocellular Carcinoma by Enhancing NOTCH1 Expression
Authors: Zhang Xinyue , Su Tianhong , Wu Yifan , Cai Yuhong , Wang Lina , Liang Cong , Zhou Lei , Wang Shiyan , Li Xiao-Xing , Peng Sui , Kuang Ming , Yu Jun , Xu Lixia
Published: March 2024

Abstract
N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of HCC spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSC). Stem cell–specific conditional Ythdf1 knockin (CKI) mice treated with diethylnitrosamine showed elevated tumor burden as compared with wild-type mice. YTHDF1 promoted CSCs renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. Multiomic analysis, including RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1-deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through an YTHDF1–m6A–NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC.
Significance:
Inhibition of YTHDF1 expression suppresses stemness of hepatocellular carcinoma cells and enhances sensitivity to targeted therapies, indicating that targeting YTHDF1 may be a promising therapeutic strategy for liver cancer.
Supplementary Table S2 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

Association of CTC HOXB13 expression with overall survival, univariate and multivariate analysis including adjustment for JHU CTC AR-V7 status
Supplementary Figure S1 from Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA
Authors: Liu Li-Peng , Zong Su-Yu , Zhang Ao-Li , Ren Yuan-Yuan , Qi Ben-Quan , Chang Li-Xian , Yang Wen-Yu , Chen Xiao-Juan , Chen Yu-Mei , Zhang Li , Zou Yao , Guo Ye , Zhang Ying-Chi , Ruan Min , Zhu Xiao-Fan
Published: March 2024

Figure S1. Flowchart of patient selection and enrollment. In total, 50 patients and 195 paired samples (ctDNA and BM DNA) from this population can be analyzed. In the last row, plasma samples from included patients at separate timepoint were depicted. BM, bone marrow; C2D1, Cycle 2 day 1; C3D1, Cycle 3 day 1; C4D1, Cycle 4 day 1
Supplementary Figure S5 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

NTX301 inhibits OC tumor growth in vivo.
Supplementary Figure S3 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

NTX-301 effects in OC cells
Figure S5 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 S5. Blocking GSC-induced neuronal activity reverses microglial M2 polarization in vivo.
Supplementary Figure 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

Waterfall plot of assessment
Data from Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA
Authors: Liu Li-Peng , Zong Su-Yu , Zhang Ao-Li , Ren Yuan-Yuan , Qi Ben-Quan , Chang Li-Xian , Yang Wen-Yu , Chen Xiao-Juan , Chen Yu-Mei , Zhang Li , Zou Yao , Guo Ye , Zhang Ying-Chi , Ruan Min , Zhu Xiao-Fan
Published: March 2024

AbstractPurpose:
Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML.
Experimental Design:
A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing–based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated.
Results:
In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564).
Conclusions:
Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.
Data 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

AbstractPurpose:
Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear.
Experimental Design:
By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression.
Results:
We demonstrate that hypoxia drove glioma stem cells (GSC) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes, which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization whereas cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization.
Conclusions:
These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antiepileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression.

See related commentary by Cui et al., p. 1073
Rintatolimod in Advanced Pancreatic Cancer Enhances Antitumor Immunity through Dendritic Cell–Mediated T-Cell Responses
Authors: van Eijck Casper W.F. , Haddaoui Hassana el , Kucukcelebi Songul , Vadgama Disha , Fellah Amine , Mustafa Dana A.M. , Aerts Joachim G.J.V. , van Eijck Casper H.J. , Willemsen Marcella
Published: March 2024

Purpose:

Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC.

Experimental Design:

Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models.

Results:

Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1.

Conclusions:

This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.

See related commentary by Martínez-Riaño et al., p. 3355
Figure S6 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 6 and legend.
Figure S2 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 2 and legend.
FIGURE 5 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

Antitumor treatment response to PS-PDT (10 mg/kg, 24 hour DLI, 100 J/cm2) in tumor-bearing mice models of oral cavity cancer. Representative posttreatment images in subcutaneous Cal-33 tumors (A) and in subcutaneous MOC22 tumors (B) following treatment on day 0. C, Fold change in tumor volume in subcutaneous Cal-33 tumors following treatment on day 0. N = 20 tumors (PS-PDT), 17 tumors (untreated control), nine tumors (drug control), and seven tumors (light control). D, Fold change in tumor volume in subcutaneous MOC22 tumors following treatment on day 0. N = 11 tumors (PS-PDT), and 13 tumors (untreated control). For C and D, Unitless. Mean + SD. Day 14 statistics: multiple unpaired (two-sample) t tests using Holm-Šídák correction method for multiple comparisons and ⍺ = 0.05. Additional PS-PDT efficacy data and statistical analysis are provided in Supplementary Tables S9 and S10. E, Hematologic changes in immune competent MOC22 tumor-bearing mice 24 hours post-PS administration (“Post-PS”) and 72 hours post-PS-PDT treatment (“Post-PDT”). Units given. Bar plot with mean + SD. ● represent individual replicates. Normal limits for each parameter represented by dotted lines. N = 10 Post-PS mice and 8 Post-PDT mice. Statistics: unpaired t tests without correction for multiple comparisons and ⍺ = 0.05. Additional hematology and blood chemistry analysis is provided in Supplementary Fig. S7. RBC, red blood cells (× 106 cells/µL); HCT, hematocrit (%); PLT, platelets (× 103/µL); WBC, white blood cells (× 103 cells/µL); NEUT, neutrophil count (× 103 cells/µL); NEUT%, relative neutrophil count (%).
FIGURE 3 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

Pharmacokinetic profiles of PS nanoparticles in tumor-bearing mice and rabbit models of oral cavity cancer. Plasma concentration-time profiles of PS in Cal-33 and MOC22 mouse models (A) and VX-2 rabbit model (B). Units µg/mL. Additional pharmacokinetic analysis is detailed in Supplementary Table S2. Tissue concentrations of PS in Cal-33 and MOC22 mouse models (C) and VX-2 rabbit model (D) 24 hours post-injection. Units µg/g. Additional tissue distribution data are provided in Supplementary Tables S3–S5. Ratios of PS tissue concentration normalized to muscle concentration in Cal-33 and MOC22 mouse models (E) and VX-2 rabbit model (F) 24 hours post-injection. Unitless. Representative fluorescence images and ratios of PS ex vivo tissue fluorescence normalized to muscle fluorescence in Cal-33 and MOC22 mouse models (G), and VX-2 rabbit model (H) 24 hours postinjection. Unitless. Additional PS tissue selectivity data are provided in Supplementary Tables S6 and S7. For A, B, Mean ± SD. Table statistics: mean ± SE N = 5 mice/model. N = 6 rabbits. For C, D, E, and F, Tukey box-and-whisker plot with “+” denoting mean (mean value labeled above). N = 5 mice/tissue/model. N = 3 rabbits/tissue. For G and H, Bar plot with mean + SD (mean value labeled above). N = 5 mice/tissue/model. N = 3 rabbits/tissue. For G, Ex: 675 nm, Em: 720 nm, 1 second exposure time. For H, Ex: 675 nm, Em: 720 nm long pass. For mouse models: PS dose = 10 mg/kg, 400–500 MBq 64Cu/kg, i.v. For rabbit models: PS dose = 10 mg/kg, i.v.
FIGURE 2 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

Photophysical and photochemical characterization of PS nanoparticles. A, Structure and composition of PS: PEGylated porphyrin-lipid conjugate-containing nanoparticles. B, Transmission electron microscopy of negatively stained PS nanoparticle morphology. Scale bar, 0.1 µm. C, Molar attenuation coefficient (ε) profile of intact and disassembled PS in aqueous media. Intact PS are suspended in 1x PBS and disassembled PS are treated with a non-ionic surfactant (Triton X-100). Note ε reported here on basis of mols of porphyrin-lipid conjugate. D, Fluorescence spectra of intact and disassembled PS nanoparticles in aqueous media at excitation wavelength 416 nm. Note the 100-fold increase in fluorescence intensity in the disassembled PS versus the intact PS at 675-nm wavelength. E, Singlet oxygen (1O2) generation of intact and disassembled PS nanoparticles in aqueous media with increasing light dose. Note the approximately 4-fold increase in 1O2 generation in the disassembled PS versus the intact PS using 671-nm excitation wavelength (50 mW). Mean ± SD. N = 5 samples/light dose. Additional material characterizations of PS described in Supplementary Fig. S1 and Supplementary Table S1.
Data 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

Abstract
Photodynamic therapy (PDT) is a tissue ablation technique able to selectively target tumor cells by activating the cytotoxicity of photosensitizer dyes with light. PDT is nonsurgical and tissue sparing, two advantages for treatments in anatomically complex disease sites such as the oral cavity. We have previously developed PORPHYSOME (PS) nanoparticles assembled from chlorin photosensitizer–containing building blocks (∼94,000 photosensitizers per particle) and capable of potent PDT. In this study, we demonstrate the selective uptake and curative tumor ablation of PS-enabled PDT in three preclinical models of oral cavity squamous cell carcinoma (OCSCC): biologically relevant subcutaneous Cal-33 (cell line) and MOC22 (syngeneic) mouse models, and an anatomically relevant orthotopic VX-2 rabbit model. Tumors selectively uptake PS (10 mg/kg, i.v.) with 6-to 40-fold greater concentration versus muscle 24 hours post-injection. Single PS nanoparticle–mediated PDT (PS-PDT) treatment (100 J/cm2, 100 mW/cm2) of Cal-33 tumors yielded significant apoptosis in 65.7% of tumor cells. Survival studies following PS-PDT treatments demonstrated 90% (36/40) overall response rate across all three tumor models. Complete tumor response was achieved in 65% of Cal-33 and 91% of MOC22 tumor mouse models 14 days after PS-PDT, and partial responses obtained in 25% and 9% of Cal-33 and MOC22 tumors, respectively. In buccal VX-2 rabbit tumors, combined surface and interstitial PS-PDT (200 J total) yielded complete responses in only 60% of rabbits 6 weeks after a single treatment whereas three repeated weekly treatments with PS-PDT (200 J/week) achieved complete ablation in 100% of tumors. PS-PDT treatments were well tolerated by animals with no treatment-associated toxicities and excellent cosmetic outcomes.
Significance:
PS-PDT is a safe and repeatable treatment modality for OCSCC ablation. PS demonstrated tumor selective uptake and PS-PDT treatments achieved reproducible efficacy and effectiveness in multiple tumor models superior to other clinically tested photosensitizer drugs. Cosmetic and functional outcomes were excellent, and no clinically significant treatment-associated toxicities were detected. These results are enabling of window of opportunity trials for fluorescence-guided PS-PDT in patients with early-stage OCSCC scheduled for surgery.
Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty among Patients with Cardiometabolic Diseases
Authors: Oba Kazuhito , Ishikawa Joji , Tamura Yoshiaki , Fujita Yasunori , Ito Masafumi , Iizuka Ai , Fujiwara Yoshinori , Kodera Remi , Toyoshima Kenji , Chiba Yuko , Tanaka Masashi , Araki Atsushi
Published: March 2024

Introduction: Frailty is a crucial health issue among older adults. Growth differentiation factor 15 (GDF15) is associated with inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction, which are possible pathogeneses of frailty. However, few longitudinal studies have investigated the association between GDF15 and the incidence of frailty. Therefore, we investigated whether high serum GDF15 levels are associated with the incidence of frailty. Methods: A total of 175 older adults (mean age: 77 ± 6 years; 63% women) with cardiometabolic diseases and no frailty out of the two criteria at baseline participated. Individuals with severe renal impairment or severe cognitive impairment were excluded. Serum GDF15 levels were measured at baseline. Patients were asked to assess frailty status at baseline and annually during follow-up using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). We examined the association between GDF15 tertiles and each frailty measure during follow-up (median 38–39 months). In the multivariate Cox regression analysis, with the GDF15 tertile groups as the explanatory variables, hazard ratios (HRs) and 95% confidence intervals (CIs) for incident frailty were calculated after adjusting for covariates and using the lowest tertile group as the reference. Results: During the follow-up period, 25.6% and 34.0% of patients developed frailty, as defined by the mCHS and KCL, respectively. The highest GDF15 tertile group had a significantly higher incidence of mCHS- or KCL-defined frailty than the lowest GDF15 tertile group. Multivariate Cox regression analysis revealed that the adjusted HRs for incident mCHS- and KCL-defined frailty in the highest GDF15 tertile group were 3.9 (95% CI: 1.3–12.0) and 2.7 (95% CI: 1.1–6.9), respectively. Conclusion: High serum GDF15 levels predicted the incidence of frailty among older adults with cardiometabolic diseases and could be an effective marker of the risk for frailty in interventions aimed at preventing frailty, such as exercise and nutrition.
Heart rate variability indices in children with syncope due to
orthostatic hypotension
Authors: Kovalchuk Tetiana
Published: March 2024

Summary. Orthostatic hypotension (OH) in children may be accompanied by
symptoms such as dizziness and syncope and is often a manifestation of
baroreflex failure due to autonomic imbalance. Heart rate variability (HRV)
is one of the most effective methods of assessing the modulation of the
autonomic nervous system and its balance. The aim of the study – to learn
the features of autonomic nervous system modulation in children with syncope
due to OH using HRV parameters. Materials and Methods. Twenty-five children
aged 8–17 with a diagnosis of syncope due to OH and 41 practically healthy
children were examined. The diagnostic criteria of the European Society of
Cardiology (ESC 2018) were used to diagnose syncope due to OH. All patients
were provided with accurate history taking, physical examination, active
standing test, electrocardiography in 12 leads, echocardiography,
electroencephalography and 24-hour Holter monitoring for HRV assessment.
Results. There were no differences in values ​​of HRV parameters SDANN,
RMSSD and pNN50 in children with syncope due to OH compared to healthy ones
(p 0.05). These results generally indicate the normal activity of humoral
influences and central oscillators against the background of balanced
parasympathetic effects on the cardiovascular system in children with
syncope. However, there were increased TP (10502.59±1526.62 ms2;
5482.44±396.87 ms2; p=0.0016), VLF (5768.27±774.29 ms2; 3906.29±269.09 ms2;
p=0.046) and LF/HF ratio (1.75±0.18; 1.29 ± 0.09; p=0.044) in the group of
syncope due to OH. Correlations were found between the number of syncope
events and SDANN (r=-0.62; p=0.002), and RMSSD (r=-0.46; p=0.03), duration
of the last presyncope event and VLF (r=0.44; p =0.04), duration of the last
syncope event and LF/HF ratio (r=0.57; p=0.006), 24-hour average interval PQ
duration and SDANN (r=0.64; p=0.001), and RMSSD (r=0.63; p=0.002), 24-hour
average interval QT duration and SDANN (r=0.43; p=0.04), and RMSSD (r=0.43;
p=0.05) in patients with syncope due to OH. Conclusions. In children with
syncope due to OH markers of pathological autonomic regulation are HRV
parameters TP, VLF, and LF/HF ratio, and their increase values is evidence
of predominance of the sympathetic circuit of heart rate regulation against
the background of increased baroreflex activity of the heart and impaired
adaptive-compensatory capabilities of the cardiovascular system including
the activity of the central circuits of heart rate regulation
Philosophical principles of ancient medicine
Authors: Naumova Uliana O. , Didukh Valeriy D. , Naumova Liudmyla V. , Milevska-Vovchuk Lyubov S.
Published: March 2024

Summary. The article describes the philosophical principles of ancient
medicine from the end of VII century B.C. to the beginning of VI century
A.D. At the beginning the ancient medicine was closely linked to
philosophical knowledge. Many personalities not only solved philosophical
problems, but also were engaged in medical practice. Doctors and
philosophers were: Galen, Heraphilus, Heraclitus, Erasistratus, Pythagoras,
Philolaus, Empedocles, Alcmaeon, Diogenes. Aristotle also had a medical
education. The aim of the study – to expand and deepen the knowledge of the
basics of ancient medicine, as well as to inspire and motivate modern
physicians to an individual-oriented approach to every patient. Materials
and Methods. Based on the Internet searching data bases, a review and
analysis of materials about ancient medicine and the role of philosophy in
its development has been made. Results. The contribution of ancient
philosophers and physicians – Greeks and Romans – in the spiritual treasury
of humankind cannot be overestimated. Hippocrates believed that "observation
at the patient's bedside" was extremely necessary, because experience alone
was "deceptive." He emphasized the need, although, complexity, at the same
time of reasoning, the participation of the mind, thinking in the process of
putting diagnosis of the disease. Hippocrates wrote: "Life is short, the
path of art is long, a convenient case is fleeting, the experience is
deceptive, and reasoning is difficult." Only by studying the
interpenetration of soul and body, you can count on the effectiveness of
treatment. Horace suggested defining mental health as a state in which a
person is satisfied with himself, treats others correctly and is able to
withstand life's troubles. Aristotle followed the principle that the soul
cannot be separated from the body, so if a person has a healthy body, he has
a healthy soul. The philosopher combined the concepts of physical and mental
health. To paraphrase Newton, if we see further than they do, it is because
we are standing on their shoulders. Conclusions. The process of history
formation and development of philosophy and medicine is inextricably linked
with the general history of humankind and science. The progress of medicine
certainly directly affects the life of each of us in particular and society
in general, and has such a social significance that it is simply impossible
not to consider it when analyzing the development of society and its
prospects
Gender-age features and possibilities of predicting the quality of life
in patients with myocardial infarction without elevation of ST-segment
Authors: Maslovskyi Valentin I.
Published: March 2024

Summary. Predicting the course of acute myocardial infarction without
ST-segment elevation is one of the priority tasks of modern cardiology. The
aim of the study – to analyze gender and age features and possibilities of
predicting the quality of life in patients to assess the quality of life
with myocardial infarction without ST segment elevation. Materials and
Methods. We examined 200 patients with acute myocardial infarction without
ST-segment elevation (NSTEMI) aged 38 to 80 years. All patients were
examined according to the current treatment protocol for patients with acute
coronary syndrome without ST segment elevation. Quality of life assessment
was performed according to the valid MIDAS-35, which was conducted on the
5–7 day of hospitalization. Results. It was found that there are no
statistically significant gender differences in the overall quality of life
score on the MIDAS-35 scale. Also, there is a connection with the
deterioration of quality of life and increasing age requirements.
Conclusions. Predicting quality of life in this category of patients
encourages the use of early invasive strategy in this category of patients
Analysis of fatty oil Nigella sativa l. рroduced in Ukraine and Bulgaria
Authors: Nikolova N.S. , Danyliv S.I.
Published: March 2024

Summary. The article presents the results of the study of the fatty
acid spectrum of Nigella sativa L. seed oil grown in different geographical
regions – Ukraine and Bulgaria. The task of studying the rich chemical
composition of the plant due to the wide range of its pharmacological action
remains relevant. The aim of the study – comparative study of the fatty acid
composition of Nigella sativa L. seed oils grown in different geographical
and climatic regions. Materials and Methods. Nigella sativa L. oil samples
were obtained from 2 different geographically remote regions, Ukraine and
Bulgaria; various producers: black seed oil (Zhestor, Ukraine) and Black
seed oil (Zdravnytsia, Bulgaria).Gas chromatography was used to study the
fatty acid composition of Nigella sativa L. Results. It was found that the
composition of both studied samples includes 9 fatty acids: lauric, arachic,
palmitic, palmitoleic, myristic, pentadecene, oleic, stearic and
pentadecanoic. The content of oleic acid in the oil of the Ukrainian
producer was twice as high as in the oil of the Bulgarian production. Also,
the content of pentadecanoic acid in the oil of domestic sample was
insignificant (0.03 %). The percentage of the other seven fatty acids found
differed slightly in the oils studied. This may indicate a slight difference
in growth conditions and, as a consequence, the chemical composition of
Nigella sativa L. Conclusions. The geographical and climatic region in which
Nigella sativa L. is grown plays an important role in the formation of its
chemical composition and this leads to changes in its pharmacological
activity. However, the results obtained indicate that the difference in the
relative content of fatty acids between the studied oils of Ukrainian and
Bulgarian producers is insignificant
Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study
Authors: Plante Timothy B. , Juraschek Stephen P. , Howard George , Howard Virginia J. , Tracy Russell P. , Olson Nels C. , Judd Suzanne E. , Kamin Mukaz Debora , Zakai Neil A. , Long D. Leann , Cushman Mary
Published: March 2024

BACKGROUND:

Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1β, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension.

METHODS:

The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers.

RESULTS:

Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1β among White (1.24 [95% CI, 1.01–1.53]) but not Black participants (1.01 [95% CI, 0.83–1.23]) and higher TNF-α (1.20 [95% CI, 1.02–1.41]) and IFN-γ (1.22 [95% CI, 1.04–1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP.

CONCLUSIONS:

Higher levels of IL-1β, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.