bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism
Authors: Roca Suarez Armando Andres , Plissonnier Marie-Laure , Grand Xavier , Michelet Maud , Giraud Guillaume , Saez-Palma Maria , Dubois Anaëlle , Heintz Sarah , Diederichs Audrey , Van Renne Nicolaas , Vanwolleghem Thomas , Daffis Stephane , Li Li , Kolhatkar Nikita , Hsu Yao-Chun , Wallin Jeffrey J , Lau Audrey H , Fletcher Simon P , Rivoire Michel , Levrero Massimo , Testoni Barbara , Zoulim Fabien 
Published: May 2024

ObjectiveAchieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment.DesignWe identifiedTLR8-expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN’s indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN’s effect were validated using transcriptomic data from HBV-infected patients.ResultsHepaticTLR8expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg,S100A12) and downregulated genes associated with the KC identity (eg,SPIC). Treatment of hepatocytes with SLGN-CM downregulatedNTCPand impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition.ConclusionOur transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.
Interpreting results, impacts and implications from WHO FCTC tobacco control investment cases in 21 low-income and middle-income countries
Authors: Mann Nathan , Spencer Garrison , Hutchinson Brian , Ngongo Carrie , Tarlton Dudley , Webb Douglas , Grafton Daniel , Nugent Rachel 
Published: May 2024

BackgroundTobacco control investment cases analyse the health and socioeconomic costs of tobacco use and the benefits that can be achieved from implementing measures outlined in the WHO Framework Convention on Tobacco Control (WHO FCTC). They are intended to provide policy-makers and other stakeholders with country-level evidence that is relevant, useful and responsive to national priorities and policy context.MethodsThis paper synthesises findings from investment cases conducted in Armenia, Cabo Verde, Cambodia, Chad, Colombia, Costa Rica, El Salvador, Eswatini, Georgia, Ghana, Jordan, Laos, Madagascar, Myanmar, Nepal, Samoa, Sierra Leone, Sri Lanka, Suriname, Tunisia and Zambia. We examine annual socioeconomic costs associated with tobacco use, focusing on smoking-related healthcare expenditures, the value of lives lost due to tobacco-related mortality and workplace productivity losses due to smoking. We explore potential benefits associated with WHO FCTC tobacco demand-reduction measures.ResultsTobacco use results in average annual socioeconomic losses of US$95 million, US$610 million and US$1.6 billion among the low-income (n=3), lower-middle-income (n=12) and upper-middle-income countries (n=6) included in this analysis, respectively. These losses are equal to 1.1%, 1.8% and 2.9% of average annual national gross domestic product, respectively. Implementation and enforcement of WHO FCTC tobacco demand-reduction measures would lead to reduced tobacco use, fewer tobacco-related deaths and reduced socioeconomic losses.ConclusionsWHO FCTC tobacco control measures would provide a positive return on investment in every country analysed.
Drops of volatile binary mixtures on brush-covered substrates
Authors: Diekmann Jan , Thiele Uwe 
Published: May 2024

AbstractWe introduce a mesoscopic hydrodynamic model for drops of binary mixtures of volatile partially wetting liquids on brush-covered substrates, i.e., we model the coupled dynamics of spreading, evaporation, imbibition, diffusion and partial demixing of the two volatile components across the three phases—brush, drop and gas. The formulation of the model as gradient dynamics on an underlying free energy functional allows us to systematically account for cross-couplings between the six scalar fields needed to describe the dynamics of both components within each of the three phases. The energy accounts for concentration- and brush state-dependent capillarity and wettability, miscibility of the two components within drop and brush, and entropy in the gas. Finally, the usage of the model is illustrated by employing numerical time simulations to study the dynamics of a sessile drop.
Intra-plate Jal Az-Zor strike-slip faulting deciphering the enigma of local earthquakes in Kuwait
Authors: Al-Helal Anwar B. , Al-Mahmoud Mohammed J. 
Published: May 2024

Abstract
Kuwait National Seismic Network (KNSN) data show the clustering of earthquakes in northern and southern clusters. Spatial correlation between these clusters and oil fields led previous studies to declare that oil production/injection triggered earthquakes, but some suggested the possibility of tectonic causes.
This study addresses the genuine objective of uncovering the origin of Kuwait earthquakes by analysing relationships between earthquake spatial and temporal patterns, oil production/injection, structural and tectonic setting, and subsurface fluid pressures.
A kinematic model of the Jal Az-Zor dextral-slip fault was presented as a decipherer to the earthquake's origin. The northern and southern clusters represent leading quadrants, where increased mean stress causes earthquakes. Dibdibah Trough and Kuwait Bay represent trailing quadrants with decreased mean stress and a lack of earthquakes. The small percentage of earthquakes falling outside clusters are caused by the concentration of regional compressive stresses related to Arabian Plate motion on pre-existing faults. Triggering earthquakes by oil field operations requires 10% pressure increase above the original pressures, which never occurs in Kuwait oil fields.
The results of this study emphasize the significance of understanding fault kinematics to assess earthquake hazards and the need to focus on engineering requirements for developments in the leading quadrants areas.
Abstract ED03-01: Breaking the Obesity-Breast Cancer Link: Comparing Diet, Drug and Surgical Approaches
Authors: Hursting S. 
Published: May 2024

Abstract
The prevalence of obesity, an established risk and progression factor for at least 15 types of cancer (including breast cancer), continues to rise in the US and many other countries. Lifestyle approaches to weight loss have proven challenging for most people to maintain, and bariatric surgery, while effective, is expensive and has numerous adverse effects. The recent availability of highly effective incretin therapies for weight loss raises several key questions that we will address, including: i) do these agents drive weight loss in obese female mice?; ii) do they reverse obesity-induced metabolic dysregulation?; iii) can they reverse obesity-driven cancer?; iv) how heterogeneous is the response to these agents? We will report our study of the effects of extended (13 weeks) tirzepatide (TZP, a dual GLP1R/GIPR agonist) treatment in obese female mice on weight loss, metabolic hormones, and mammary tumor growth. We found that—similar to reports in the literature using male mice—obese female mice lost &gt;20% body weight by 4 weeks of TZP treatment. Moreover, TZP-induced weight loss was maintained through 13 weeks of treatment by progressively escalating the dose up to 40 nmol/kg. Congruent with reports in male rodents and humans, we found the majority of weight loss in female mice was attributed to loss of adipose tissue, rather than lean mass. The effects of TZP on body weight and composition were associated with reversal of obesity-induced changes in glycemic control and circulating levels of metabolic hormones, particularly leptin, insulin, and IGF-1. TZP also significantly reversed the protumor effects of obesity in our murine E0771 orthotopic transplant model of TNBC.Furthermore, daily 30% calorie restriction, which we previously reported has strong weight loss-inducing, metabolic reprogramming and anticancer effects in multiple mouse models of breast and other cancers, reversed body weight, adiposity, and TNBC tumor growth and altered metabolic hormones to a greater extent than all groups studied, including the never-obese control mice and TZP-treated mice.
Citation Format: S. Hursting. Breaking the Obesity-Breast Cancer Link: Comparing Diet, Drug and Surgical Approaches [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED03-01.
Abstract ED03-02: Mechanisms for the effects of incretin and dual-incretin to produce substantial weight loss
Authors: Seeley R. 
Published: May 2024

Abstract
We are in the midst of a revolution when it comes to treating individuals with obesity. "Incretin" and "Dual-Incretin" drugs now can produce weight loss that was only possible via bariatric surgery just five years ago. Key questions remain concerning just how these drugs exert these powerful effects and how those effects compare to weight loss induced by bariatric surgery. Evidence points toward these drugs not just being "anorexic" agents that reduce food intake but rather lowering the "set-point" for body weight/body fat. The presentation will focus on how weight is regulated and how that system interacts with these newest classes of drugs.
Citation Format: R. Seeley. Mechanisms for the effects of incretin and dual-incretin to produce substantial weight loss [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED03-02.
Abstract ED10-01: PI3K past, present, and future
Authors: Vasan N. 
Published: May 2024

Abstract
The PI3K pathway has long remained a fertile ground for drug discovery in cancer, including in estrogen receptor positive metastatic breast cancer. It has also remained a pathway difficult to drug effectively due to on target toxicities. New strategies to overcome these toxicities have manifested in novel drug types and management strategies for patients. Here I discuss the PI3K pathway in signaling and oncogenesis, current therapies inhibiting PI3K, mechanisms limiting efficacy, and increasing the PI3K therapeutic window with a focus on mutant selective PI3K inhibitors. Finally, I will expound on the translational future of the PI3K field, highlighting advances in biomarker discovery, tumor correlative analysis, and patient advocacy.
Citation Format: N. Vasan. PI3K past, present, and future [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED10-01.
Abstract PO1-02-01: T Cell Receptor Sequencing to Monitor Pelareorep-Induced Expansion of Tumor Infiltrating Lymphocytes
Authors: Trauger Richard , Loghmani Houra , Coffey Matt , Salvador Fernando , Gavilá Joaquín , Manso Luis , Pascual Tomás , Prat Aleix , Heineman Thomas 
Published: May 2024

Abstract
Background: Tumor infiltrating lymphocytes (TILs) represent a major immunological tumor control mechanism that is associated with better prognosis in breast cancer. We have previously reported the effect of pelareorep (pela), an intravenously delivered, non-engineered oncolytic reovirus, on a composite measurement of TILs and tumor cellularity (CelTIL) from the AWARE-1 window-of-opportunity study in patients with early breast cancer (eBC). These results showed treatment increased in CelTIL scores especially in the atezolizumab group. To confirm and extend these findings we applied T cell receptor sequencing of matched tumor tissue and whole blood pre and post-treatment from the AWARE-1 study to further explore the effects of pela therapy on TILs. Methods: Newly diagnosed HR+/HER2- eBC patients were enrolled into two cohorts: Cohort 1: pela + letrozole (n=10); and Cohort 2: pela + letrozole + atezolizumab (n=10). Pela was administered on days 1, 2 and 8, 9, and atezolizumab was given on day 3. Tumor biopsies (FFPE samples) collected pre-treatment (~D-23) and on day ~21 when tumors were surgically removed. T cell fraction analysis and T cell receptor sequencing were performed by Adaptive Biotechnology (Seattle, Washington) Immunoseq protocol. Results: As was shown for the CelTIL scores, an increase in the tumor T cell fraction, a direct measurement of TILs, was observed at 1-month post-treatment in both cohorts with a mean percent increase of 21% for Cohort 1 and 67% for Cohort 2. Through TCR-sequencing of tumor tissue, we identified TIL clones and tracked their differential abundance in tumor tissue and blood post-treatment. The results of this analysis at Day 21 showed a mean post-treatment expansion of 10 tumor specific clones in the blood for Cohort 1, and a mean post-treatment increase of 40 tumor specific clones for Cohort 2. Conclusions: These results confirm the previously reported CelTIL results from AWARE-1 on pela-induced increases in TILs and demonstrate the expansion of these clones in both tumor and blood as a consequence of pela therapy for HR+/HER2- breast cancer.
Citation Format: Richard Trauger, Houra Loghmani, Matt Coffey, Fernando Salvador, Joaquín Gavilá, Luis Manso, Tomás Pascual, Aleix Prat, Thomas Heineman. T Cell Receptor Sequencing to Monitor Pelareorep-Induced Expansion of Tumor Infiltrating Lymphocytes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-01.
Abstract PO1-04-07: Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical breast cancer models
Authors: Willis Kelsi , Hein Renee , Snead Katie , Thurman Robert , Kulukian Anita 
Published: May 2024

Abstract
Disitamab vedotin (DV, RC48-ADC) is an antibody-drug conjugate (ADC) that targets cancers expressing HER2. DV consists of an anti-HER2 monoclonal antibody, disitamab, conjugated with the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a cleavable vedotin linker. DV has multimodal antitumor mechanisms of action that include direct cytotoxicity of HER2-expressing cancer cells and bystander effect-based cytotoxicity of neighboring cells, both of which are mediated by the intracellular release of MMAE. Released MMAE can also induce immunogenic cell death, which promotes immune cell recruitment to the tumor. In addition, DV stimulates Fc-gamma receptor mediated antibody-dependent cellular cytotoxicity, which can lead to target cell death. DV also inhibits HER2-activated downstream signaling pathways, further blocking cell growth, survival, and proliferation. Previously, we showed the cytotoxic activity of DV against a panel of breast cancer cell lines with varying levels of HER2 expression, including the HER2-low range. Here, we sought to further characterize the preclinical antitumor activity of DV in patient-derived 3D models and patient-derived xenographs (PDX). In cultured breast cancer cells, DV was more potent and internalized to a greater magnitude than the HER2-directed ADCs trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). In patient-derived 3D models, DV had superior activity compared to T-DXd. We further explored whether dual HER2 targeting with DV in combination with the HER2-selective oral TKI tucatinib improved the antitumor outcomes. In PDX models with varying HER2 IHC levels and models refractory to T-DXd, DV as a monotherapy and in combination with tucatinib showed significant tumor growth inhibition. This result is consistent with previous in vitro results that showed increased cytotoxicity of the combination of DV and tucatinib in cell lines with a wide range of HER2 expression, which may be mechanistically attributed to elevated HER2 cell surface levels upon treatment with tucatinib. Overall, these findings provide scientific rationale to explore DV in HER2-positive and HER2-low breast cancer patients as a monotherapy or in combination with tucatinib.
Citation Format: Kelsi Willis, Renee Hein, Katie Snead, Robert Thurman, Anita Kulukian. Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical breast cancer models [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-07.
Abstract PO1-07-07: Radiomics features for distinguishing true recurrence versus new primary tumor following breast-conserving treatment
Authors: Qu Feilin , Su Guan-Hua , Li Jin-Hui , You Chao , Shao Zhi-Ming 
Published: May 2024

Abstract
Background Despite modern surgical and irradiation techniques, ipsilateral breast tumor recurrence (IBTR) accounts for 5-15% of all cancer recurrences in women treated with breast conservative treatment. Historically, the methods to define true recurrence (TR) and new primary tumor (NP) for IBTR mainly rely on clinical and pathological criteria, limiting the accuracy of the discerption and causing misclassification. This study aimed to develop a preoperative, noninvasive model for distinguishing IBTR by integrating clinicopathological review with paired dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) at diagnosis and following in-breast recurrence. MethodsWe retrospectively extracted radiomics features from MRI to develop a radiomic cohort of IBTR (n =46), among which all patients underwent paired preoperative DCE-MRI. This radiomic cohort was divided into a training cohort (n =27) and a validation cohort (n =19) with stratified random sampling. Classification of IBTR as TR or NP on the basis of tumor location, histologic subtype, estrogen receptor, and HER2 status was set as the gold standard. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression were utilized to perform radiomics feature selection and model training, respectively. The clinical utility of the model was determined via decision curve analysis (DCA). Results We selected three radiomics features (first-order feature Kurtosis from the first postcontrast phase on IBTR DCE-MRI, GLCM feature Imc2 from the first postcontrast phase on IBTR DCE-MRI, and the delta feature Correlation from the precontrast phase of the change between IBTR and primary tumor DCE-MRI) to develop an IBTR-classification predicting radiomic model, which performed well in the validation cohort (AUC 0.867, 95% confidence interval (CI) 0.694-1). Further investigation for sensitivity (73.3%) and specificity (100%) verified a favorable concordance between the radiomic classification and the conventional standard, with a diagnostic accuracy of 79%. Conclusions: Our study demonstrated the feasibility of the radiomics model in predicting IBTR classification and provided preoperative information about the nature of “recurrence”. This might have important implications in surgical approaches and multidisciplinary care for IBTR. Further efforts are needed to improve the reproducibility of radiomics features and models in multiple centers.
Citation Format: Feilin Qu, Guan-Hua Su, Jin-Hui Li, Chao You, Zhi-Ming Shao. Radiomics features for distinguishing true recurrence versus new primary tumor following breast-conserving treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-07-07.
Abstract PO1-08-01: Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations
Authors: Al-Bader Salha , Habish Hind , Sulaiman Reem Al , Al-Mulla Hajer , Ghazouani Hafedh 
Published: May 2024

Abstract
PURPOSE: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast & ovarian cancers in Qatar and worldwide which is caused by pathogenic variants in the BRCA1& BRCA2 genes. The aim of this retrospective study is to describe a common recurrent founder pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype-phenotype correlations. METHODS: Medical records of Qatari patients (affected & unaffected) with personal and/or family history of breast & ovarian cancers who carry pathogenic/likely pathogenic mutations in the BRCA1 & BRCA2 genes were reviewed between 2013- 2020. Epidemiological information and clinical data were reviewed including age, gender, ethnic background, personal history of cancer, tumour characteristics and family history. We used frequencies and proportions to describe the data and used Kaplan-Meier curves and log-rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp LP. Result: Our result confirms the presence of a common recurrent pathogenic variant in BRCA1 gene [(c.4787 C&gt;A) (p. Ser 1596*)] among Qatari patients who belong to 8 consanguineous large families followed by BRCA1[ c.4065_4068delTCAA]. BRCA1 c.4787 variant is highly associated with early onset breast cancer specifically Invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. In addition, the c.4787 C&gt;A was found to be highly penetrant in families for young onset breast cancer. Conclusion: We showed that BRCA1 c.4787 C&gt;A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aide to improve patient’s survival & guide early personalized treatment and prevention.
Citation Format: Salha Al-Bader, Hind Habish, Reem Al Sulaiman, Hajer Al-Mulla, Hafedh Ghazouani. Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-01.