bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioavailability of Food Polyphenols: Current State of Knowledge
Authors: Williamson Gary
Published: February 2025

(Poly)phenols, including flavonoids, phenolic acids, and tannins, are a diverse class of compounds found in plant-based foods and beverages. Their bioavailability has been extensively described and detailed metabolic pathways elucidated. Although some parent (poly)phenols are absorbed intact in the small intestine, most pass to the colon where they are extensively catabolized and their microbial products absorbed into the circulation. The sum of the metabolites absorbed can reach almost 100% in some cases and in some individuals. In recent years, there have been three major areas of advancement: (a) comprehensive and systematic reviews have brought together bioavailability data, including detailed metabolic pathways in humans, and quantitative estimates of absorption and excretion; (b) the action and importance of the gut microbiota in (poly)phenol metabolism have been better defined and our understanding of the important role of the microbiota in intra- and interindividual variation has greatly expanded; and (c) strategies to improve (poly)phenol bioavailability such as encapsulation employing various nanoformulations or cyclodextrins have been developed.
Role of Scavenger Receptor B1 (SR-B1) in Improving Food Benefits for Human Health
Authors: Valacchi Giuseppe , Pecorelli Alessandra
Published: February 2025

Scavenger receptor class B member 1 (SR-B1) is a multiligand receptor with a broad range of functions spanning from the uptake of cholesteryl esters from high-density lipoproteins (HDLs) and transport of micronutrients such as fat-soluble vitamins and carotenoids across cell membranes to roles in tumor progression, pathogen recognition, and inflammatory responses. As a target of exposome factors such as environmental stressors and unhealthy lifestyle choices, as well as aging, dysregulated expression and activity of SR-B1 can negatively impact human health. Intriguingly, not only is SR-B1 a major determinant of nutrient homeostasis and, hence, metabolic health status, but these same nutrients and some phytochemicals have also demonstrated their ability to modulate SR-B1. Therefore, an integrated approach that, taking into account human health, nutrition, and food technology sciences, aims to produce foods with health-promoting effects should take advantage of the multifaceted properties of SR-B1. Improved functional foods and novel nanoparticle-based delivery systems, rich in nutrients and phytochemicals, with precise targeting to SR-B1 in specific tissues or structures could represent a strategic advance to improve human health and promote well-being.
The Effect of the Premixed Stagnation Flame Method for the Synthesis of YMnO3 based on Precursor Species on the Gas-Sensitive Performance of H2S
Authors: An Wenhao , Chang Xinru , Guo Song , Zhang Jianing , Cui Huadong , Tang Zhendong
Published: February 2025

Premixed stagnation flame method was used to synthesize Yttrium manganate (YMnO3) nanoparticles to investigate the precursor species’ effect on the resulting products’ physical phase formation. In addition, the sensitivity of sensors constructed with the most efficient combination of precursors for detecting hydrogen sulfide (H2S) was evaluated. Based on thermal breakdown and infrared spectra analysis, Y(NO3)3·6H2O and (CH3COO)2Mn·4H2O have been shown to be the best precursors. The resulting YMnO3 phase exhibited the highest purity, with numerous small tetrahedral particles averaging 20 nm in size attached to the surface of larger spherical particles. The assembled particles displayed a uniform size distribution ranging from 400 to 600 nm. The YMnO3 sensors showed the most favorable response to 30 ppm H2S gas at 220 °C, achieving a response value of 2.94. It demonstrates excellent selectivity, repeatability, and long-term stability. The premixed stagnation flame method can be used to fabricate nanoparticles with complex composition or structure at low cost, such as hollow structure, core–shell structure or multivariate metal oxide. The porous structure of the synthesized spherical YMnO3 nanoparticles has the advantages of small particle size and large specific surface area, showing excellent gas sensitive properties.
Supplementary Table S9 from Phase Ib Pharmacodynamic Study of the MNK Inhibitor Tomivosertib (eFT508) Combined With Paclitaxel in Patients With Refractory Metastatic Breast Cancer
Authors: Ferrario Cristiano , Mackey John , Gelmon Karen A. , Levasseur Nathalie , Sorensen Poul H. , Oo Htoo Zarni , Negri Gian L. , Tse Veronica W.L. , Spencer Sandra E. , Cheng Grace , Morin Gregg B. , del Rincon Sonia , Cotechini Tiziana , Gonçalves Christophe , Hindmarch Charles C.T. , Miller Wilson H. , Amiri Mehdi , Basiri Tayebeh , Villareal-Corpuz Victor , Sperry Sam , Gregorczyk Kevin , Spera Gonzalo , Sonenberg Nahum , Pollak Michael
Published: February 2025

Supplementary Table S9: mRNAs affected by tomivosertib.
Supplementary Table S1 from Phase Ib Pharmacodynamic Study of the MNK Inhibitor Tomivosertib (eFT508) Combined With Paclitaxel in Patients With Refractory Metastatic Breast Cancer
Authors: Ferrario Cristiano , Mackey John , Gelmon Karen A. , Levasseur Nathalie , Sorensen Poul H. , Oo Htoo Zarni , Negri Gian L. , Tse Veronica W.L. , Spencer Sandra E. , Cheng Grace , Morin Gregg B. , del Rincon Sonia , Cotechini Tiziana , Gonçalves Christophe , Hindmarch Charles C.T. , Miller Wilson H. , Amiri Mehdi , Basiri Tayebeh , Villareal-Corpuz Victor , Sperry Sam , Gregorczyk Kevin , Spera Gonzalo , Sonenberg Nahum , Pollak Michael
Published: February 2025

Supplementary Table S1: Patient characteristics. Age, ECOG performance status, HER2 status, steroid hormone receptor status, and biopsy site data are summarized.
Figure 3 from Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Altan Mehmet , Lopes Gilberto , Hiltermann T. Jeroen N. , Govindan Ramaswamy , Villaruz Liza C. , Calvo Emiliano , Edelman Martin J. , Furqan Muhammad , Neal Joel , Felip Enriqueta , Carlisle Jennifer W. , Heymach John V. , O’Cearbhaill Róisín Eilish , Zauderer Marjorie , Chisamore Michael , Corigliano Ellie , Eleftheriadou Ioanna , Zajic Stefan , Jenkins Ben , Goodison Sophia , Suchindran Sunil , Ramos-Hernandez Natalia , Tarek Nidale , Schoenfeld Adam J.
Published: February 2025

Cellular kinetics profile by patient in the single- and multiarm studies. A, Single-arm study. Cellular kinetics profile at first infusion by patient and responder status truncated at 12 weeks (available data), mITT population. B, Multiarm study. Cellular kinetics profile by patient and treatment arm truncated at 6 months (first infusion), mITT population. AUC0–28 days, AUC from 0 to 28 days.
Figure 2 from Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Altan Mehmet , Lopes Gilberto , Hiltermann T. Jeroen N. , Govindan Ramaswamy , Villaruz Liza C. , Calvo Emiliano , Edelman Martin J. , Furqan Muhammad , Neal Joel , Felip Enriqueta , Carlisle Jennifer W. , Heymach John V. , O’Cearbhaill Róisín Eilish , Zauderer Marjorie , Chisamore Michael , Corigliano Ellie , Eleftheriadou Ioanna , Zajic Stefan , Jenkins Ben , Goodison Sophia , Suchindran Sunil , Ramos-Hernandez Natalia , Tarek Nidale , Schoenfeld Adam J.
Published: February 2025

Patient tumor responses in the single- and multiarm studies. A, Best overall response in the single- and multiarm studies (confirmed). In the single-arm study, data following first infusion only. One patient did not have measurable target lesions at baseline and does not appear in this plot; one patient received a transduced cell dose below the required dose level, per protocol, due to waiver granted. In the multiarm study, *arm A: one patient (M65) had unconfirmed PR. **Arm C: one patient (M1) had unequivocal progression due to new lesion and one patient died prior to first post-treatment scan and does not appear in this plot. B, Percent change from baseline in target lesion diameter in the multiarm study. Arm A patients are shown at left, and arm C is shown at right. Red circles indicate new target lesions. C, Median PFS and OS for each study. D, Radiographic images of case study patient S5, single-arm study. One patient from the single-arm study (S5) received two separate infusions, achieving best overall responses of confirmed PR from first infusion and SD from the second, per RECIST 1.1. The top left image is baseline before the first infusion, and top right is after 9 months. The bottom left image is baseline before the second infusion, and the bottom right is at week 11 after second infusion. E, Peak persistence and tumor shrinkage of case study patient S5, single-arm study. CR, complete response; LLOD, lower limit of detection; NA, not available; NE, not evaluable; PD, progressive disease; SD, stable disease.
Supplementary Table S1 from The Landscape of ctDNA in Appendiceal Adenocarcinoma
Authors: White Michael G. , Zeineddine Mohammad A. , Fallon Eleanor A. , Zeineddine Fadl A. , Dansby Julia , Chowdhury Saikat , Hornstein Nicholas , Yousef Abdelrahman , Yousef Mahmoud , Bhutiani Neal , Gu Yue , Kee Bryan , Dasari Arvind , Overman Michael J. , Raghav Kanwal , Kopetz Scott , Uppal Abhineet , Taggart Melissa , Newhook Timothy , Fournier Keith , Helmink Beth , Drusbosky Leylah M. , Shen John Paul
Published: February 2025

Supplementary Table 1: Actionable mutations noted in ctDNA of AA patients
Supplementary Figure 4 from Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies
Authors: Haffner Michael C. , Morris Michael J. , Ding Chien-Kuang C. , Sayar Erolcan , Mehra Rohit , Robinson Brian , True Lawrence D. , Gleave Martin , Lotan Tamara L. , Aggarwal Rahul , Huang Jiaoti , Loda Massimo , Nelson Peter S. , Rubin Mark A. , Beltran Himisha
Published: February 2025

Supplementary Figure 4. Example case 4.
Data from Antitumor Activity and Biomarker Analysis for TROP2 Antibody–Drug Conjugate Datopotamab Deruxtecan in Patient-Derived Breast Cancer Xenograft Models
Authors: Meric-Bernstam Funda , Yuca Erkan , Evans Kurt W. , Zhao Ming , Maejima Takanori , Karibe Tsuyoshi , Raso Maria Gabriela , Tang Ximing , Zheng Xiaofeng , Rizvi Yasmeen Qamar , Akcakanat Argun , Scott Stephen M. , Wang Bailiang , Byers Lauren A. , Tripathy Debu , Okajima Daisuke , Damodaran Senthil
Published: February 2025

AbstractPurpose:
Datopotamab deruxtecan (Dato-DXd) is a humanized anti–trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.
Experimental Design:
The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.
Results:
Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd–sensitive models. In isogenic cell lines derived from Dato-DXd–resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd–sensitive BCXs but not in a Dato-DXd–resistant BCX. In Dato-DXd–sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.
Conclusions:
Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.
Data from Aberrantly Expressed Mitochondrial Lipid Kinase, AGK, Activates JAK2–Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy
Authors: Mamidi Murali K. , Sinha Sutapa , Mendez Mariana T. , Sanyal Tapojyoti , Mahmud Hasan , Kay Neil E. , Gupta Mamta , Xu Chao , Vesely Sara K. , Mukherjee Priyabrata , Holter Chakrabarty Jennifer , Ghosh Asish K.
Published: February 2025

AbstractPurpose:
Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined.
Experimental Design:
Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism.
Results:
We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton’s tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells.
Conclusions:
These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL.
Mitochondria Targeting of Oxidative Phosphorylation Inhibitors to Alleviate Hypoxia and Enhance Anticancer Treatment Efficacy
Authors: Beerkens Anne P.M. , Heskamp Sandra , Reinema Flavia V. , Adema Gosse J. , Span Paul N. , Bussink Johan
Published: February 2025

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity have hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared with healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243, and IACS-010759 and the potential of mitochondria-targeted OXPHOSi and their influence on reactive oxygen species production. Furthermore, the effect of the mitochondria-targeting moiety triphenylphosphonium on mitochondria is discussed as it affects mitochondrial bioenergetics.
Supplemental Table 6 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative
Authors: Karra Prasoona , Hardikar Sheetal , Winn Maci , Anderson Garnet L. , Haaland Benjamin , Shadyab Aladdin H. , Neuhouser Marian L. , Seguin-Fowler Rebecca A. , Thomson Cynthia A. , Coday Mace , Wactawski-Wende Jean , Stefanick Marcia L. , Zhang Xiaochen , Cheng Ting-Yuan David , Karanth Shama , Sun Yangbo , Saquib Nazmus , Pichardo Margaret S. , Jung Su Yon , Tabung Fred K. , Summers Scott A. , Holland William L. , Jalili Thunder , Gunter Marc J. , Playdon Mary C.
Published: February 2025

Supplemental Table 6. Association between metabolic phenotypes defined by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 23,232).
Supplemental Table 3 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative
Authors: Karra Prasoona , Hardikar Sheetal , Winn Maci , Anderson Garnet L. , Haaland Benjamin , Shadyab Aladdin H. , Neuhouser Marian L. , Seguin-Fowler Rebecca A. , Thomson Cynthia A. , Coday Mace , Wactawski-Wende Jean , Stefanick Marcia L. , Zhang Xiaochen , Cheng Ting-Yuan David , Karanth Shama , Sun Yangbo , Saquib Nazmus , Pichardo Margaret S. , Jung Su Yon , Tabung Fred K. , Summers Scott A. , Holland William L. , Jalili Thunder , Gunter Marc J. , Playdon Mary C.
Published: February 2025

Supplemental Table 3. Association between metabolic phenotypes defined by ATP III criteria with obesity-related cancer risk in the Women’s Health Initiative cohort (N= 23,915).
Supplemental Figure 3 from Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women’s Health Initiative
Authors: Karra Prasoona , Hardikar Sheetal , Winn Maci , Anderson Garnet L. , Haaland Benjamin , Shadyab Aladdin H. , Neuhouser Marian L. , Seguin-Fowler Rebecca A. , Thomson Cynthia A. , Coday Mace , Wactawski-Wende Jean , Stefanick Marcia L. , Zhang Xiaochen , Cheng Ting-Yuan David , Karanth Shama , Sun Yangbo , Saquib Nazmus , Pichardo Margaret S. , Jung Su Yon , Tabung Fred K. , Summers Scott A. , Holland William L. , Jalili Thunder , Gunter Marc J. , Playdon Mary C.
Published: February 2025

Supplemental Figure 3. Kaplan–Meier cumulative incidence curves for obesity-related cancer risk among Women’s Health Initiative (WHI) participants according to metabolic phenotype defined by (A) Wildman criteria, (B) ATP III criteria, (C) HOMA-IR, and (D) hs-CRP ≥ 3 mg/L.
Figure S6 from TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids
Authors: Sun Yi , Maggs Luke , Panda Apekshya , Wright Samuel J. , Cicerchia Angelina M. , Jenney Anne , Perricone Matthew D. , Mills Caitlin E. , Cattaneo Giulia , Ventin Marco , Chen Feng , Rasmussen Martin Q. , Miranda Alex , Revach Or-Yam , Fang Jacy , Fu Amina , Bowling Peter J. , Sharova Tatyana , Lawless Aleigha , Sorger Peter K. , Bardeesy Nabeel , Wang Xinhui , Flaherty Keith T. , Boland Genevieve M. , Mehta Arnav , Sade-Feldman Moshe , Ferrone Cristina R. , Jenkins Russell W.
Published: February 2025

Supplemental Figure S6 | Supporting data that targeting TBK1 prevents CAR-T cell dysfunction.
Table S2 from Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko
Published: February 2025

Table S2
Table S1 from The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment
Authors: Tsuge Ayaka , Watanabe Sho , Kawazoe Akihito , Togashi Yosuke , Itahashi Kota , Masuda Mari , Sai Atsuo , Takei Shogo , Muraoka Hiromi , Ohkubo Shuichi , Sugiyama Daisuke , Yan Yue , Fukuoka Shota , Doi Toshihiko , Shitara Kohei , Koyama Shohei , Nishikawa Hiroyoshi
Published: February 2025

Antibodies used for flow cytometry.
Supplementary Figure 1 from Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy
Authors: Tintelnot Joseph , Paschold Lisa , Goekkurt Eray , Schultheiss Christoph , Matschl Urte , Santos Cruz Mariana , Bauer Marcus , Wickenhauser Claudia , Thuss-Patience Peter , Lorenzen Sylvie , Ettrich Thomas J. , Riera-Knorrenschild Jorge , Jacobasch Lutz , Kretzschmar Albrecht , Kubicka Stefan , Al-Batran Salah-Eddin , Reinacher-Schick Anke , Pink Daniel , Bokemeyer Carsten , Sinn Marianne , Lindig Udo , Hinke Axel , Hegewisch-Becker Susanna , Stein Alexander , Binder Mascha
Published: February 2025

Supplementary Figure 1: The duration of response to various therapy lines for patients in the Ipi arm is depicted. For each line of therapy, the duration of response (DOR) is indicated if applicable. Active therapy is represented by an arrow, and dashed arrows are used for patients who were lost to follow-up. Monotherapy with trastuzumab (T), ramucirumab (R), radiotherapy (#), or surgery (*) is also indicated.
Supplementary Table S1 from Hyperthermic Intrathoracic Chemotherapy Modulates the Immune Microenvironment of Pleural Mesothelioma and Improves the Impact of Dual Immune Checkpoint Inhibition
Authors: Hao Yameng , Gkasti Aspasia , Managh Amy J. , Dagher Julien , Sifis Alexandros , Tiron Luca , Chriqui Louis-Emmanuel , Marie Damien N. , De Souza Silva Olga , Christodoulou Michel , Peters Solange , Joyce Johanna A. , Krueger Thorsten , Gonzalez Michel , Abdelnour-Berchtold Etienne , Sempoux Christine , Clerc Daniel , Teixeira-Farinha Hugo , Hübner Martin , Meylan Etienne , Dyson Paul J. , Cavin Sabrina , Perentes Jean Y.
Published: February 2025

Supplementary Table S1: Termination criteria used for animal experiments
Data from A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer
Authors: Phung Shee Kwan , Zorko Nicholas A. , Soignier Yvette , Waller Rhett L. , Shackelford Madison , Walker Joshua T. , Nelson Trygve D. , Selleck Carly , Bendzick Laura E. , Kotz Laura E. , Kile Quinlan M. , Bozicevich Asha J. , Miller Sarah E. , Khaw Melissa , Shetty Mihir , Hinderlie Peter , Ehrhardt Michael , Li Yingming , Luo Xianghua , Dehm Scott M. , Antonarakis Emmanuel S. , Kennedy Philippa R. , Miller Jeffrey S. , Felices Martin
Published: February 2025

Abstract
NK cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with coactivation may enhance NK cell function in mCRPC. We describe a tri-specific killer engager (TriKE) construct that engages with the activating receptor CD16 on NK cells and prostate-specific membrane antigen (PSMA) on mCRPC cells and has an IL15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation, and cytokine production of NK cells derived from healthy donors or patients with prostate cancer. Bystander killing of PSMA-negative tumor cells was also achieved with PSMA TriKE treatment when cocultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment, NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or myeloid-derived suppressor cells maintained their potent function whereas IL15-treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared with IL15-treated and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their antitumor potential in prostate cancer, especially in the setting of a hostile tumor microenvironment.
Data from Combination CXCR4 and PD-1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma
Authors: Morita Satoru , Lei Pin-Ji , Shigeta Kohei , Ando Tomofumi , Kobayashi Tatsuya , Kikuchi Hiroto , Matsui Aya , Huang Peigen , Pittet Mikael J. , Duda Dan G.
Published: February 2025

Abstract
Immune checkpoint inhibitors have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DC) in liver malignancies. In this study, we tested combination blockade of PD-1 and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy. In addition, we examined the effects of treatment using immunofluorescence, flow cytometric analysis of DCs in vivo and in vitro, and RNA sequencing. The combination anti-CXCR4 and anti–PD-1 therapy was safe and significantly inhibited tumor growth and prolonged survival in all murine preclinical models of HCC tested. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the potential role of conventional type 1 DCs (cDC1) in the HCC microenvironment. Moreover, DC reprogramming enhanced anticancer immunity by facilitating CD8+ T-cell accumulation and activation in the HCC tissue. The effectiveness of anti-CXCR4/PD-1 therapy was compromised entirely in Batf3 knockout mice deficient in cDC1s. Thus, combined CXCR4/PD-1 blockade can reprogram intratumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC.
Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma
Authors: Munoz-Couselo Eva , Soria Rivas Ainara , Sandhu Shahneen , Long Georgina V. , Sanmamed Miguel F. , Spreafico Anna , Buchbinder Elizabeth , Sznol Mario , Prenen Hans , Fedenko Alexander , Milhem Mohammed , Arance Fernandez Ana Maria , Grob Jean-Jacques , Demidov Lev , Robert Caroline , Habigt Christin , Evers Stefan , Sleiman Nassim , Dejardin David , Ardeshir Caroline , Martin Nicole , Boetsch Christophe , Charo Jehad , Teichgräber Volker , Kraxner Anton , Keshelava Nino , Bechter Oliver
Published: February 2025

Purpose:

This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma.

Patients and Methods:

This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced. Patients received 10 mg FAP-IL2v either continuously once every 3 weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg.

Results:

Eighty-three patients were treated: 16 patients in two safety run-in cohorts and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The pharmacokinetics of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v–related grade 3/4 adverse events were lymphopenia (23%), elevated γ-glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and 2 of 8 CPI-naïve patients (one complete response and one partial response). The median progression-free survival was 3.1 months.

Conclusions:

The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in patients with melanoma with prior CPI due to the lack of clinical activity.

Significance:

In this phase Ib study, the combination of FAP-IL2v, an immune-cytokine developed to overcome the limitations of wild-type IL2, with the CPI pembrolizumab did not show meaningful antitumor activity in patients who had progressed on prior CPI therapy, suggesting that FAP-IL2v alone cannot overcome CPI resistance or unresponsiveness.
Histopathologic spectrum and clinical management of pharyngeal and laryngeal sarcomas
Authors: Stenzl Anna K. , Mogler Carolin , Bolooki Amir , Johnson Felix , Jeleff- Wölfler Olivia , Strassen Ulrich , Hofauer Benedikt G.
Published: February 2025

Introduction: Sarcomas are rare mesenchymal malignancies (<1% of all cancer types), with 5-15% occurring in the head and neck. Common types include osteosarcoma, chondrosarcoma, and rhabdomyosarcoma. They often recur and have poor survival rates. Treatment involves surgery, radiation, and/or chemotherapy, utilizing a multidisciplinary approach. This study aims to overview sarcomas at our hospital and illustrate the interdisciplinary management of pharyngeal and laryngeal cases.
Methods: This single-center study provides a comprehensive analysis of head and neck sarcomas (HNS) and examines interdisciplinary treatment approaches for pharyngeal and laryngeal sarcomas in patients treated at the Department of Head and Neck Surgery, Technical University of Munich, from 2007 to 2022. The study encompasses data on age, gender, histopathological diagnoses, treatment modalities, follow-up, and outcomes, with an emphasis on histopathological findings and collaborative therapeutic strategies.
Results: 27 cases of HNS were identified (2007-2022). Among these, 11 were pharyngeal or laryngeal sarcomas. All pharyngeal sarcomas underwent primary resection with reconstruction based on tumor location and extent. In laryngeal sarcomas, three required laryngectomy, one had a hemilaryngectomy, and one patient opted for primary radiochemotherapy over laryngopharyngectomy. Adjuvant radiotherapy was given in 5 cases, and radiochemotherapy in 3. Diagnoses included a range of soft tissue and bone sarcomas, such as liposarcoma, synovial sarcoma, and osteosarcoma. During the study period, 4 patients survived, 5 patients were noted as deceased, and survival data for 2 patients remain unavailable. Patients exhibited an average survival of 7,6 (± 10,4) years. The survival times within this limited patient population exhibit significant variation.
Histologically, a wide spectrum of low and high-grade soft tissue and bone sarcomas were diagnosed including liposarcoma, synovial sarcoma, Ewing, osteo- or chondrosarcoma.
Conclusion: HNS are rare and challenging to treat. Surgery is the primary treatment, with postoperative radiotherapy recommended for incomplete resections or high-risk subtypes. Advanced surgical techniques and reconstruction allow for radical resections while preserving function. Incorporating genetic insights and better sarcoma classification can further optimize treatments.
Gender Differences in Kidney Failure incidence in Australia: a Registry study
Authors: Stallard Belinda C. , McDonald Stephen P.
Published: February 2025

Introduction
Previous studies have shown that there is a higher incidence of men initiating kidney replacement therapy (KRT) in comparison to women. However, the contribution of gender disparity may well differ among the different types of kidney disease, and over time. Utilising a nationwide Registry, we examined disease- and gender-specific trends in incident kidney failure required KRT.
Methods
Registry-based analysis of all incident patients commencing KRT in Australia using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. All patients who initiated dialysis in Australia from January 1971 to 31 December 2021 were included. Confidence intervals around rates were calculated and compared using Poisson distributions.
Results
During the study period a total of 31834 women and 47718 men were recorded in ANZDATA to have commenced KRT in Australia, a male to female ratio of 1.51 [1.49-1.53]. The male to female ratio increased over time from 1.05 [0.83-1.34] in 1971 to 1.78 [1.66-1.92] in 2021. There was a progressive increase in the male:female ratio with age; for those starting in 2017-21 this rose from 1.37 [95% CI 1.26-1.50] among 25-44 years olds to 4.38 [2.47-5.53] among those ≥85 years at KRT start.
Conclusions
Men had a significantly higher rate of starting KRT in Australia compared with women, and this difference is increasing over time. This disparity also varied between types of primary kidney disease but was higher among older age groups. It is still seen for causes (such as polycystic kidney disease) that have equal gender disease distribution, suggesting differences in propensity to commence KRT as well as differences in underlying disease processes.
Large scale population screening for BRCA1 and BRCA2 Ashkenazi founder mutations: perspectives of professionals providing oncogenetic consultations
Authors: Furman Yael , Gofin Yoel , Litz Philipsborn Shira , Hartmajer Shulamit , Sukenik-Halevy Rivka
Published: February 2025

Introduction: In March 2020, a nationwide population carrier screening for BRCA1/2 pathogenic variants among Ashkenazi Jewish women was initiated in Israel. We aimed to assess views regarding the program among professionals who provide oncogenetic counseling for detected carriers.
Methods: An online survey was distributed to clinical geneticists and genetic counselors.
Results: The participants’ impression was that most carriers did not comprehend the implications of a positive result when deciding to take the test. Some carriers, in retrospect, regretted taking it. Some had a known mutation carrier in the family, and some had a family history that justified a broader test (and so should not have been tested through the screening program). Eight survey participants (29%) reported they were initially against the screening program, but half of them are currently in favor of it. Most participants are unsatisfied with the way the screening is conducted and suggested various improvements. Emotional distress of carriers, as assessed by participants, was higher for those detected by the screening program, compared to those tested after oncogenetic counseling. No association was found between the age, profession and prior experience of participants and their responses.
Conclusions: While the general attitude towards the screening program is positive, most professionals feel the need to improve the current screening program by defining exclusion criteria, providing comprehensive pretest information and adding other BRCA1/2 founder mutations, as well as expanding the screening to include ethnicities other than Ashkenazi Jews.
Mothers of young children during the COVID-19 pandemic: Depressive symptoms and perceived stress
Authors: Woll-Weber Christian F.J. , Reck Corinna , Marx Anton K.G. , Küçükakyüz Su Mevsim , Müller Mitho , von Tettenborn Alexandra , Nonnenmacher Nora , Zietlow Anna-Lena
Published: February 2025

Objective: Due to the COVID-19 pandemic, psychosocial well-being of families and parents worldwide has been impaired. As part of a larger online survey, we analyzed maternal depressive symptoms and perceived stress.
Method: 666 mothers from Germany with young children (mostly aged 0–3 years) filled out the Edinburgh Postnatal Depression Scale (EPDS) and the Perceived Stress Scale (PSS) at two time points during the pandemic (T1: summer/fall 2020; T2: early spring 2021). We (1) calculated prevalence rates of a risk for depression and high perceived stress levels, (2) analyzed differences between time points via paired t-tests, and (3) examined the reciprocal relation between the two constructs via cross-lagged panel modeling.
Results: Considering cut-off values of the EPDS (≥ 10) and PSS (≥ 27), 33.8 % carried a risk for depression and 15.2% high levels of stress at T1, whereas, respectively, 55.1% and 26.0% did so at T2. Depressive symptom severity and perceived stress levels significantly differed between measurement points with higher values at T2 (p < .001). Our cross-lagged panel analysis revealed large correlations (p < .001) within as well as small to medium (i.e., [.21, .47]) auto-regressive (p < .001) and reciprocal (p < .001) predictions across time points between the severity of depressive symptoms and perceived stress.
Conclusions: This work demonstrates how severely mothers of infants were affected by depressive symptoms and perceived stress in a time of pandemic crisis. Psychosocial support should focus on screening and treating mothers as early as possible to mitigate the risk for subsequent depressive symptoms and perceived stress. Aiming attention at both depressive symptom reduction and stress relief most successfully promotes maternal well-being.
Relationships between cardio-ankle vascular index and peptides related to hypertensive disorders of pregnancy in patients with lower extremity arterial disease
Authors: Wakabayashi Ichiro , Sotoda Yoko
Published: February 2025

Introduction: Cardio-ankle vascular index (CAVI), a blood pressure-independent measure of heart-ankle pulse wave velocity, is a relatively new indicator of arterial stiffness. The absolute value of the difference in right CAVI and left CAVI (diff-CAVI) has been proposed as a new indicator of leg ischemia in patients with lower extremity arterial disease (LEAD). The aim of this study was to elucidate the relationships between diff-CAVI and peptides related to hypertensive disorders of pregnancy (HDP), which have been proposed as biomarkers for leg ischemia in patients with LEAD.
Methods: The subjects were 165 outpatients with LEAD who had already received medication therapy for LEAD. The relationships between diff-CAVI and serum levels of the seven HDP-related peptides, which were measured by mass-spectrometry, were investigated.
Results: HDP-related peptides with m/z 2091 (P-2091) and m/z 2378 (P-2378) showed significant positive correlations with diff-CAVI, and odds ratios (ORs) for large diff-CAVI (≥ 1.05) of the 3rd vs. 1st tertile groups of P-2091 (OR: 3.71 [1.24~11.15]) and P-2378 (OR: 4.46 [1.39~14.30]) were significantly higher (p < 0.01) than the reference level. The associations of P-2091 and P-2378 with diff-CAVI were shown to be independent of age, gender, habit of smoking, history of diabetes, BMI and blood pressure in multivariable analyses. The other peptides with m/z 2081, 2127, 2209, 2858 and 3156 did not show significant associations with diff-CAVI.
Conclusion: P-2091 and P-2378 were associated with diff-CAVI and are thought to be useful indicators of leg ischemia in patients with LEAD.
Muscular Injury is a Risk Factor for Post-Entire Circumferential Esophageal Endoscopic Submucosal Dissection Stricture
Authors: Azuma Daisuke , Hirasawa Kingo , Atsusaka Reo , Ozeki Yuichiro , Sawada Atsushi , Nshio Masafumi , Kobayashi Ryosuke , Sato Chiko , Maeda Shin
Published: February 2025

Introduction: Endoscopic submucosal dissection (ESD) has become a widely adopted treatment for early esophageal cancer. However, extensive mucosal defects resulting from ESD pose a significant risk of post-procedural strictures. Despite efforts to prevent strictures through various means, including steroid administration, they remain a challenge, significantly impacting patients' quality of life and healthcare costs. Thus, identifying risk factors for refractory strictures following entire circumferential esophageal ESD (EC-E-ESD) is imperative.
Methods: Between July 2013 and September 2023, 49 patients who underwent EC-E-ESD were retrospectively analyzed. Patients were classified based on the presence of refractory or non-refractory strictures. A refractory stricture was defined as requiring six or more endoscopic balloon dilation (EBD) procedures before stricture improvement. Clinicopathological features and outcomes were examined using multivariate logistic regression analysis.
Results: Refractory strictures were observed in 51% of patients. A comparison showed that the refractory group had a significantly higher percentage of muscular injury (52% vs. 8%, p=0.002) and mucosal defect length ≥50 mm (68% vs. 37%, p=0.047) than the non-refractory group. Multivariate analysis showed that muscular injury (odds ratio 16.2; 95% confidence interval: 2.04–129.1) was an independent risk factor for refractory strictures after EC-E-ESD.
Conclusions: Muscular injury during EC-E-ESD is a risk factor for refractory strictures. Strategies to prevent injury, such as meticulous dissection techniques, and effective steroid administration, may mitigate this risk. However, current prophylactic measures are inadequate, highlighting the need for further research into preventive strategies.
Impact on global health status, quality-sexual life and chronic fatigue state of risk-reducing salpingo-oophorectomy in women who are BRCA1/2 mutation carriers: experience from a third level italian center.
Authors: Della Corte Luigi , Palumbo Mario , Ascione Mario , D'Angelo Giuseppe , La Verde Marco , Ferrari Federico , Morra Ilaria , Bifulco Giuseppe
Published: February 2025

Objective: BRCA 1 and 2 mutation carriers are invited to follow intensive clinical and instrumental surveillance programs or are offered prophylactic ovarian surgery. These recommendations impact many aspects of their lives. The primary objective of this study was to assess the overall quality of life (HRQoL) before and after prophylactic bilateral salpingo-oophorectomy (BSO). Secondary objectives were investigating sexual health (SH) and fatigue severity state (FSS).
Design: This was a single-center, retrospective observational, study.
Setting: Women who underwent surgical treatment of bilateral salpingo-oophorectomy between 2018 and 2024 at “DAI Materno Infantile” of Azienda Ospedaliera Universitaria “Federico II” of Naples were included.
Methods: These patients were tracked down to undergo specific questionnaires, such as “Global Health Status and Quality of Life Scale (QOL) (EORTC QLQ-C30)”, “EORTC Sexual Health Questionnaire (QLQ-SH22), and “Fatigue Severity Scale (FSS)”, to evaluate their psychological, sexual and general physical condition impact before the surgery, 3 and 6 months later.
Results: The overall mean QoL score was 88.3±29.8 (mean + standard deviation), and this score worsened when the surgery was performed at 3 months (p <.0001) with a score of 51.7±30.7 with a mean difference (MD) of 36.6 points; instead, when we evaluated at 6 months, the overall mean QoL score was 73.1±24.3 with an MD of 21.4 points. FSS reported a score of 2.7±1.15 vs 4.2±1.59 (p<.0001) vs 3.5±1.43 (p<.0001), respectively, before and 3-6 months after surgery. EORTC QLQ-SH22 before and after treatment showed statistically significant changes in sexual satisfaction (p<.0001).
Conclusion: BSO may impact the quality of life regardless of the hormonal status of patients related to age or menopause, both about the functional evaluation and the psychological and emotional assessment report. The physical change related to the surgical procedure is associated with a mental shift that affects both the physical and sexual energy of our patients in the first 3 months postoperatively, with a slight improvement of these data at 6 months.
Interpretation of change in novel digital measures: a statistical review and tutorial
Authors: Trigg Andrew , Ratitch Bohdana , Kruesmann Frank , Majumder Madhurima , Parfionovas Andrejus , Krahn Ulrike
Published: February 2025

Background
Novel clinical measures assessed by a digital health technology tool require thresholds to interpret change over time, such as the minimal clinically important difference (MCID). Establishing such thresholds is a key component of clinical validation, facilitating understanding of relevant treatment effects.

Summary
Many of the approaches to derive interpretative thresholds for patient-reported outcomes can be applied to digital clinical measures. We present theoretical background to the use of interpretative thresholds, including the distinction between thresholds based on perceived importance versus measurement error, and thresholds for group- versus individual-level interpretations. We then review methods to estimate such thresholds, including anchor-based approaches. We illustrate the methods using data on cough frequency counts as measured by a wearable device in a clinical trial.

Key Messages
This paper provides an overview of statistical methodologies to estimate thresholds for the interpretation of change.
Sazonalidade em índices de preços : o caso do IPC-FIPE
Authors: Fava Vera Lucia , Rizzieri Juarez A. B.
Published: February 2025

Este artigo aborda a questao do ajustamento sazonal de índices de preços, assunto frequentemente discutido mas sobre o qual não existe consenso. Estuda-se o caso concreto do IPC-Fipe, índice largamente usado como indexador. O período considerado estende-se de janeiro de 1980 a dezembro de 1994. Utilizando duas metodologias alternativas método X-11 e Modelos Estruturais de Séries de Tempo foram identificados onze itens do IPC-Fipe com comportamento sazonal. Quando se agrupam os efeitos sazonais desses itens, observa-se que eles se compensam, não transferindo, dessa forma, nenhum padrão de sazonalidade para o índice geral. Por esse resultado, o ajustamento sazonal do IPC-Fipe não é necessário.
Correlação poupança-investimento: o que é possível dizer sobre o modelo de correção de erros a partir dos dados brasileiros
Authors: Rocha Fabiana
Published: February 2025

The purpose of this paper is to determine if the error correction model is superior to the other time series tests (cointegration between saving and investment and stationarity of the current account) which focused the long run relationship in evaluating the degree of capital mobility, as suggested by Jansen (1996). Besides it seeks to determine which kind of bias results from the estimates of the short run correlation, with variables in levels or first differences. Using Brazilian data for the period 1960-1996 as example all the tests point in the same direction, that is, capital mobility. The same result was previously found for the Brazilian economy using different methodologies. When the short run relationship is estimated, the regression in levels implies a high bias while the regression in differences implies no bias.