Future Cancer Research Articles

Crosstalk Between Cancer-associated Fibroblasts and Myeloid Cells Shapes the Heterogeneous Microenvironment of Gastric Cancer.

Targeted therapies have improved the clinical outcomes of most patients with cancer. However, the heterogeneity of gastric cancer remains a major hurdle for precision treatment. Further investigations into tumor microenvironment heterogeneity are required to resolve these problems. In this study, bioinformatic analyses, including metabolism analysis, pathway enrichment, differentiation trajectory inference, regulatory network construction, and survival analysis, were applied to gain a comprehensive understanding of tumor microenvironment biology within gastric cancer using single-cell RNA-seq and public datasets and experiments were carried out to confirm the conclusions of these analyses. We profiled heterogeneous single-cell atlases and identified eight cell populations with differential expression patterns. We identified two cancer-associated fibroblasts (CAFs) subtypes, with particular emphasis on the role of inflammatory cancer-associated fibroblasts (iCAFs) in EMT and lipid metabolic crosstalk within the tumor microenvironment. Notably, we detected two differentiation states of iCAFs that existed in different tissues with discrepant expression of genes involved in immuno-inflammation or ECM remodeling. Moreover, investigation of tumor-infiltrating myeloid cells has revealed the functional diversity of myeloid cell lineages in gastric cancer. Of which a proliferative cell lineage named C1QC+MKI67+TAMs was recognized with high immunosuppressive capacities, suggesting it has immune suppression and cell proliferation functions in the tumor niche. Finally, we explored regulatory networks based on ligand-receptor pairs and found crucial pro-tumor crosstalk between CAFs and myeloid cells in the tumor microenvironment (TME). These findings provide insights for future cancer treatments and drug discovery.

Abstract C036: Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses

Abstract As a critical component of innate and adaptive immunity, macrophages play an important role in shaping the tumor microenvironment (TME), which affects tumor initiation, progression, and response to treatment. Tumor-associated macrophages can display anti-tumor or pro-tumor activity, a cell fate attributed to macrophage polarization that depends on metabolomic regulation. Targeting macrophage metabolism could be a promising approach for cancer treatment by converting a pro-tumor TME into an anti-tumor TME. To examine in vivo mechanisms behind glutamine metabolism on macrophages, we treated immunocompetent murine ovarian cancer models with a clinical-grade glutamine prodrug, JHU083, and performed single-cell RNA sequencing (scRNAseq). In addition to the significant anti-tumor efficacy of JHU083, we found that JHU083 specifically suppressed the M2-like tumor macrophages while sparing M1-like macrophages. To better understand the molecular mechanism of how JHU083 causes macrophage polarization shift, we cultured an M1-like macrophage cell line with DON (6-Diazo-5-oxo-L-norleucine), the active component of JHU083, and performed bulk RNA sequencing. Using bulk RNAseq and scRNAseq transcriptome analyses on M1-like macrophages, glutamine inhibitor treatment significantly enhanced MHC class II genes, including CD74, H2-Aa, H2-Eb1, H2-Ea, H2-Ab1, and TNF family genes including Tnfsf12, and Tnfrsf14 which may promote T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Moreover, DON-treated bone marrow-derived M1 macrophages promoted CD4+ T cell expansion. On the other hand, DON treatment significantly suppressed bone marrow-derived M2 macrophages. In conclusion, our findings suggest that glutamine metabolism reprogramming can promote anti-tumor functions in tumor macrophages. Therefore, targeting glutamine metabolism to regulate macrophage function and polarization can be a promising direction for future cancer therapy. Citation Format: Jiawei Fan, Sumeng Qi, Ie-Ming Shih, Tian-Li Wang. Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C036.

PinX1 plays multifaceted roles in human cancers: a review and perspectives.

Pin2/TRF1 interacting protein X1 (PinX1), a telomerase inhibitor, is located at human chromosome 8p23. This region is important for telomere length maintenance and chromosome stability, both of which are essential for regulating human ageing and associated diseases. We investigated the research progress of PinX1 in human cancers. In cancers, the expression levels of PinX1 mRNA and protein vary according to cancer cell types, and PinX1 plays a critical role in the regulation of cancer development and progression. Additionally, a review of the literature indicates that PinX1 is involved in mitosis and affects the sensitivity of cancer cells to radiation-induced DNA damage. Therefore, PinX1 has therapeutic potential for cancer, and understanding the function of PinX1 in the regulation of cancers is crucial for improving treatment. In this review, we discuss the expression level of PinX1 in a variety of cancers and how it affects the implicated pathways. Additionally, we outline the function of PinX1 in cancer cells and provide a theoretical basis for PinX1-related cancer therapy. PinX1 has promising prospects in future cancer therapeutics. This review may provide theoretical support for researchers in this field.

De novo strategy of organic semiconducting polymer brushes for NIR-II light-triggered carbon monoxide release to boost deep-tissue cancer phototheranostics.

The integration of photoacoustic imaging (PAI) and photothermal therapy (PTT) within the second near-infrared (NIR-II) window, offering a combination of high-resolution imaging and precise non-invasive thermal ablation, presents an attractive opportunity for cancer treatment. Despite the significant promise, the development of this noninvasive phototheranostic nanomedicines encounters challenges that stem from tumor thermotolerance and limited therapeutic efficacy. In this contribution, we designed an amphiphilic semiconducting polymer brush (SPB) featuring a thermosensitive carbon monoxide (CO) donor (TDF-CO) for NIR-II PAI-assisted gas-augmented deep-tissue tumor PTT. TDF-CO nanoparticles (NPs) exhibited a powerful photothermal conversion efficiency (43.1%) and the capacity to trigger CO release after NIR-II photoirradiation. Notably, the liberated CO not only acts on mitochondria, leading to mitochondrial dysfunction and promoting cellular apoptosis but also hinders the overexpression of heat shock proteins (HSPs), enhancing the tumor's thermosensitivity to PTT. This dual action accelerates cellular thermal ablation, achieving a gas-augmented synergistic therapeutic effect in cancer treatment. Intravenous administration of TDF-CO NPs in 4T1 tumor-bearing mice demonstrated bright PAI signals and remarkable tumor ablation under 1064nm laser irradiation, underscoring the potential of CO-mediated photothermal/gas synergistic therapy. We envision this tailor-made multifunctional NIR-II light-triggered SPB provides a feasible approach to amplify the performance of PTT for advancing future cancer phototheranostics.

Using bioinformatics and artificial intelligence to map the cyclin-dependent kinase 4/6 inhibitor biomarker landscape in breast cancer.

A cyclin-dependent kinase 4/6 (CDK4/6) inhibitor combined with endocrine therapy is the standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. However, not all patients respond to the treatment, resistance often occurs and efficacy outcomes from early breast cancer trials have been mixed. To identify biomarkers associated with CDK4/6 inhibitor response or resistance, we combined bioinformatic-database analyses, artificial intelligence-assisted literature review, and manual literature review (Embase and OVID Medline; search window: January 2012-October 2022) to compile data to comprehensively describe the CDK4/6 inhibitor biomarker landscape. Based on these results, and validation by external experts, we identified 15 biomarkers of clinical importance (AR , AURKA, ERBB2, ESR1, CCNE1, CDKN1A/B, CDK2, CDK6, CDK7, CDK9, FGFR1/2, MYC, PIK3CA/AKT, RB1 and STAT3) that could guide future breast cancer research.

Abstract 4138519: A Scoping Review Exploring Cardiovascular Risk and Health Metrics and Cancer Prediction

Introduction: Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality. Since they share risk factors, it is plausible that CVD risk scores and cardiovascular health (CVH) metrics could also be used to predict cancer. Research Question: What is the relationship between established CVD risk scores and CVH metrics and the incidence of cancer? Methods: A librarian searched four databases (Embase, PubMed, Scopus, Web of Science: Core) in February 2024 without language restriction. Using Covidence, two reviewers independently screened the titles, abstracts, and full texts of the retrieved articles based on the inclusion criteria (prospective observational studies, adults aged ≥18 years, reported incidence of any type of cancer as an outcome, and used at least one CVD risk score or CVH metric as an exposure). A third reviewer resolved conflicts. The characteristics of the studies retained after screening and the summary estimates of the associations were extracted using Excel. Results: Of the 4,165 records screened, 13 studies (reporting 14 CVD or CVH metrics) were included. The heterogeneity in the scales (comparison group) precluded a meta-analysis. Four studies evaluated CVD risk scores (Atherosclerotic Cardiovascular Disease [ASCVD], Framingham Risk Score, Systematic Coronary Risk Evaluation), and 10 reported CVH metrics (American Heart Association [AHA] Life’s Simple 7, AHA Life’s Essential 8). Sample size ranged from 1,880 to 342,226, with median follow-up from 8.1 to 29.6 years. Most of the studies included more women than men (61.5%) and mean age ranged from 44.8 to 72 years. The majority of studies included all cancer types (71.4%), including breast, lung, colorectal, and prostate cancer subtypes, and the total number of cancer events ranged from 387 to 11,643. Studies utilizing CVD risk scores consistently reported that individuals with a higher CVD risk, developed any type of cancer, with hazard ratios (HRs) ranging from 1.02 to 3.71, and studies employing CVH metrics generally indicated an ideal CVH is associated with a lower cancer risk, with HRs ranging from 0.49 to 0.95. Conclusion: Despite heterogeneity in CVD risk metrics and cancer subtypes, most studies reported that higher CVD risk scores or worse CVH metrics may increase future cancer risk. More rigorous studies are needed focusing on specific CVD risk metrics and cancer types of cancer to produce evidence suitable for a meta-analysis.

EPCO-16. METHOD TO MODEL AND CORRECT NOISE IN SINGLE-NUCLEI RNA-SEQUENCING DATA FROM POST-MORTEM BRAIN

Abstract Post-mortem brain samples are crucial for neuropathological research. For brain cancers, they provide insights about disease progression, microenvironmental factors, and treatment resistance. In some brain diseases, brain tissue may only be available post-mortem. Establishing a reference atlas of healthy brain also requires post-mortem donations. Beyond logistical and ethical challenges of post-mortem samples, there are also post-mortem factors that mask biological signal. In this study, we specifically aim to model post-mortem gene expression changes in single-nuclei RNA-sequencing (snRNA-seq) data. We analyze a public snRNA-seq dataset of pediatric high-grade glioma (pHGG) that has matched samples at initial resection and autopsy. We find a clear gene signature, composed of mitochondrial genes, stress-related genes, and metabolism-related genes, that is upregulated post-mortem. This signature also appears in post-mortem snRNA-seq data from other brain diseases and healthy donors. We classify it as “post-mortem noise”. We model the post-mortem noise as a combination of technical and biological artifact. The technical artifact is correlated with the percentage of mitochondrial reads and is a general measure of sample quality. The biological artifact is correlated with post-mortem interval and represents gene expression changes due to post-mortem stress. We apply our model to the pHGG data by regressing out the technical and biological artifact. Removing the post-mortem noise results in an improvement in malignant versus normal cell prediction, cell type classification, and the uncovering of pathways related to glioma progression. We confidently identify several normal cell types and predict their interactions with cancer cells, highlighting the utility of wider possible margins post-mortem. Therefore, after removing post-mortem noise, we analyze glioma progression at an unparalleled timepoint and characterize late-stage changes in the tumor microenvironment. In conclusion, we develop a method that models post-mortem noise in snRNA-seq brain data. Our method can be broadly applied to future brain cancer studies using post-mortem tissue.

Causal relationship between gout and liver cancer: A Mendelian randomization and transcriptome analysis.

Gout is an inflammatory arthritis resulting from urate crystal deposition, now recognized as part of metabolic syndrome. Hyperuricemia, a hallmark of gout, is associated with various health complications, including liver cancer. Observational studies indicate a link between gout and increased cancer incidence. However, the causal relationship between gout and hepatocellular carcinoma remains uncertain. This study utilizes Mendelian randomization (MR) to explore this connection, minimizing confounding factors commonly present in observational studies. Genome-wide association study data for gout and liver cancer were sourced from the UK Biobank. We selected single nucleotide polymorphisms that are strongly associated with gout and liver cancer as instrumental variables for the analysis. We conducted 2-sample MR analysis using multiple MR methods (MR-Egger, weighted median, inverse variance weighting, and weighted mode) to evaluate causality. Co-localization and transcriptomic analyses were employed to identify target genes and assess their expression in hepatocellular carcinoma tissues. The 2-sample MR analysis indicated a significant causal relationship between gout and heightened liver cancer risk (P_IVW = .014). Co-localization analysis identified phosphatidylethanolamine N-methyltransferase (PEMT) as a crucial gene associated with gout (pH4 = 0.990). Transcriptomic data showed that PEMT expression was significantly higher in normal liver tissues compared to malignant samples (P < .001), and higher PEMT levels correlated with improved survival outcomes (P = .045). Immunohistochemical analysis revealed lower PEMT expression in hepatocellular carcinoma from patients with concurrent gout compared to those without (P < .05). The results indicate that gout increases the risk of hepatocellular carcinoma, with PEMT potentially playing a key role. Although this study focused on European populations, indicating a need for further research in diverse groups, the results emphasize the potential for liver cancer screening in newly diagnosed gout patients. Understanding the relationship between these conditions may inform future clinical practices and cancer prevention strategies.

Fabrication of a natural nanocomposite from Syzygium cumini and squid bone waste decorated with Cu-Nps for simultaneous use in the triple method of photodynamic/photothermal/chemotherapy.

This work reports a new nano platform made from natural materials. For this purpose, calcium carbonate nanoparticles derived from Persian Gulf squid bones as a drug carrier, Syzygium cumini (dye extracted from the fruit of the Persian Gulf trees) as a photosensitizer, and Doxorubicin as a chemotherapy drug have been used. In addition, copper nanoparticles were added to the above composition to increase the efficiency of photothermal treatment. For phototherapy, samples were irradiated by an 808 nm laser (1 W). The results show that nanocomposites play an influential role in the reactive oxygen species process, and an increase of 21 degrees in temperature during 15 minutes of laser radiation is effective in photodynamic/photothermal therapy. The drug loading capacity of the nanocomposite was calculated as 49%. This new nanocomposite for simultaneous photodynamic/photothermal/chemotherapy holds great promise for future cancer treatment due to its excellent potential in treatment and reduced systemic toxicity.&#xD.

Chitosan-coated nanoemulsion for intranasal administration increases temozolomide mucosal permeation, cellular uptake, and In vitro cytotoxicity in glioblastoma multiforme cells

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of brain cancer in adults. Temozolomide (TMZ) is the chemotherapeutic agent used to treat primary central nervous system tumors. However, TMZ's clinical effectiveness faces several challenges due to its physical-chemical properties and biological features of GBM, such as the blood-brain barrier (BBB). Mucoadhesive nanosystems such as those coated with chitosan represent a promising alternative for optimizing the delivery of therapeutic agents to the central nervous system, as they possess ideal characteristics that enhance their interaction with the intranasal mucosa. We aimed to develop a chitosan-coated nanoemulsion containing temozolomide (CS-NE-TMZ) for nose-to-brain delivery and characterize its physical-chemical and in vitro biological properties. CS-NE-TMZ were obtained by emulsification followed by sonication. The optimized CS-NE-TMZ presented droplet size of 123,4 ± 2,3 nm, polydispersity index of 0.273 ± 0.028, zeta potential of +21,5 ± 0,81 mV, entrapment efficiency of 100 ± 1,91 % and drug loading of 2 ± 0,007 %. An in vitro release study of CS-NE-TMZ showed sustained release for up to 24 h following the Korsmeyer-Peppas model with Fickian diffusion. CS-NE-TMZ demonstrated significantly enhanced ex vivo mucosal permeation, compared to free TMZ, and showed enhanced in vitro cellular uptake, selectively increasing cytotoxicity in U-87MG glioma cells but not in healthy L929 fibroblasts, reinforcing the potential of mucoadhesive nanoemulsions as effective intranasal drug delivery systems for future brain cancer therapies.

Global Disparities of Cancer and Its Projected Burden in 2050

Cancer prevention and care efforts have been challenged by the COVID-19 pandemic and armed conflicts, resulting in a decline in the global Human Development Index (HDI), particularly in low- and middle-income countries. These challenges and subsequent shifts in health care priorities underscore the need to continuously monitor cancer outcome disparities and statistics globally to ensure delivery of equitable and optimal cancer prevention and care in uncertain times. To measure the global burden of 36 cancers in 2022 by sex, age, and geographic location and to project future trends by 2050. This cross-sectional study used population-based data from 2022 in 185 countries and territories were obtained from the Global Cancer Observatory database. Data extraction and analysis were carried out in April 2024. Counts, rates, prevalence, mortality to incidence ratios (MIRs), and demography-based projections were used to characterize current and future cancer burden. This population-based study included 36 cancer types from 185 countries and territories. By 2050, 35.3 million cancer cases worldwide are expected, a 76.6% increase from the 2022 estimate of 20 million. Similarly, 18.5 million cancer deaths are projected by 2050, an 89.7% increase from the 2022 estimate of 9.7 million. Cancer cases and deaths are projected to nearly triple in low-HDI countries by 2050, compared to a moderate increase in very high-HDI countries (142.1% vs 41.7% for cancer cases and 146.1% vs 56.8% for cancer deaths). Males had a higher incidence and greater number of deaths in 2022 than females, with this disparity projected to widen by up to 16.0% in 2050. In 2022, the MIR for all cancers was 46.6%, with higher MIRs observed for pancreatic cancer (89.4%), among males (51.7%), among those aged 75 years or older (64.3%), in low-HDI countries (69.9%), and in the African region (67.2%). In this cross-sectional study based on data from 2022, cancer disparities were evident across HDI, geographic regions, age, and sex, with further widening projected by 2050. These findings suggest that strengthening access to and quality of health care, including universal health insurance coverage, is key to providing evidence-based cancer prevention, diagnostics, and care.

Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer

ABSTRACT Human aldehyde dehydrogenases (ALDHs) are a group of 19 isoforms often overexpressed in cancer stem cells (CSCs). These enzymes play critical roles in CSC protection, maintenance, cancer progression, therapeutic resistance, and poor prognosis. Thus, targeting ALDH isoforms offers potential for innovative cancer treatments. Flavonoids, known for their ability to affect multiple cancer-related pathways, have shown anticancer activity by downregulating specific ALDH isoforms. This study aimed to evaluate 830 flavonoids from the PubChem database against five ALDH isoforms (ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH3A1) using computational methods to identify potent inhibitors. Extra precision (XP) Glide docking and MM-GBSA free binding energy calculations identified several flavonoids with high binding affinities. MD simulation highlighted flavonoids 1, 2, 18, 27, and 42 as potential specific inhibitors for each isoform, respectively. Flavonoid 10 showed high binding affinities for ALDH1A2, ALDH1A3, and ALDH3A1, emerging as a potential multi-ALDH inhibitor. ADMET property evaluation indicated that the promising hits have acceptable drug-like profiles, but further optimization is needed to enhance their therapeutic efficacy and reduce toxicity, making them more effective ALDH inhibitors for future cancer treatment.

Reactive oxygen species augmented polydopamine-chlorin e6 nanosystem for enhanced chemo/photothermal/photodynamic therapy: A synergistic trimodal combination approach in vitro & in vivo

Amalgamation of near-infrared laser phototherapies with chemotherapy in multi-modal synergistic therapy holds great promise for future precision cancer nanomedicine due to its minimal invasiveness, reduced adverse reactions, and high anticancer efficacy. Herein, CuO nanoparticles were functionalized with photosensitizer molecule, chlorin e6 (Ce6) and coated with polydopamine (PDA) to achieve a drug delivery system (CuO@Ce6-PDA) with photothermal/photodynamic therapy (PTT/PDT). Subsequently, chemical drug PTX was loaded for chemotherapy, and folic acid (FA) serving as cancer-targeting exterior material. Prepared FA@CuO@Ce6-PDA/PTX nanoparticles were nano-sized with favorable biocompatibility, colloidal stability, optimal surface charge, effective PTX loading, and controllable PTX release. In vitro studies on 4 T1 cells showed that FA@CuO@Ce6-PDA/PTX had noteworthy synergistic therapeutic antitumour effects featuring chemo/PTT/PDT with IC50 of 50 μg/mL lower than that FA@CuO@Ce6-PDA/PTX without NIR laser irradiation (225 μg/mL). Additionally, FA@CuO@Ce6-PDA/PTX produced intracellular high reactive oxygen species (ROS) in presence of 660 nm laser, altering mitochondrial membrane potential and promoting tumour cell death. In vivo results indicate nanoplatform could accumulate in tumour spots enabling thermal imaging capabilities and exhibit synergistic therapeutic effect if irradiated with NIR laser (808 and 660 nm), evident from in vitro antitumour assay. Therefore, in vitro finding postulates FA@CuO@Ce6-PDA/PTX could be an intriguing nanoplatform for Chemo/PTT/PDT-based combination therapy.

High mitochondrial DNA levels accelerate lung adenocarcinoma progression.

Lung adenocarcinoma is a common aggressive cancer and a leading cause of mortality worldwide. Here, we report an important in vivo role for mitochondrial DNA (mtDNA) copy number during lung adenocarcinoma progression in the mouse. We found that lung tumors induced by KRASG12D expression have increased mtDNA levels and enhanced mitochondrial respiration. To experimentally assess a possible causative role in tumor progression, we induced lung cancer in transgenic mice with a general increase in mtDNA copy number and found that they developed a larger tumor burden, whereas mtDNA depletion in tumor cells reduced tumor growth. Immune cell populations in the lung and cytokine levels in plasma were not affected by increased mtDNA levels. Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.

E2F1-induced autocrine IL-6 inflammatory loop mediates cancer-immune crosstalk that predicts T cell phenotype switching and therapeutic responsiveness.

Melanoma is a metastatic, drug-refractory cancer with the ability to evade immunosurveillance. Cancer immune evasion involves interaction between tumor intrinsic properties and the microenvironment. The transcription factor E2F1 is a key driver of tumor evolution and metastasis. To explore E2F1's role in immune regulation in presence of aggressive melanoma cells, we established a coculture system and utilized transcriptome and cytokine arrays combined with bioinformatics and structural modeling. We identified an E2F1-dependent gene regulatory network with IL6 as a central hub. E2F1-induced IL-6 secretion unleashes an autocrine inflammatory feedback loop driving invasiveness and epithelial-to-mesenchymal transition. IL-6-activated STAT3 physically interacts with E2F1 and cooperatively enhances IL-6 expression by binding to an E2F1-STAT3-responsive promoter element. The E2F1-STAT3/IL-6 axis strongly modulates the immune niche and generates a crosstalk with CD4+ cells resulting in transcriptional changes of immunoregulatory genes in melanoma and immune cells that is indicative of an inflammatory and immunosuppressive environment. Clinical data from TCGA demonstrated that elevated E2F1, STAT3, and IL-6 correlate with infiltration of Th2, while simultaneously blocking Th1 in primary and metastatic melanomas. Strikingly, E2F1 depletion reduces the secretion of typical type-2 cytokines thereby launching a Th2-to-Th1 phenotype shift towards an antitumor immune response. The impact of activated E2F1-STAT3/IL-6 axis on melanoma-immune cell communication and its prognostic/therapeutic value was validated by mathematical modeling. This study addresses important molecular aspects of the tumor-associated microenvironment in modulating immune responses, and will contribute significantly to the improvement of future cancer therapies.

Development, Content Validity and Usability of a Self-Assessment Instrument for the Lifestyle of Breast Cancer Survivors in Brazil.

Breast cancer is the most common cancer among women globally, and it negatively impacts diet and quality of life, increasing the risk of recurrence. Adhering to World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) lifestyle guidelines, such as healthy eating habits and nutritional status, can help in primary and secondary cancer prevention. However, no questionnaire was found for self-assessment of these guidelines for the Brazilian population. The aim of this study is to carry out content validity, pilot, and usability testing of the self-administered digital instrument "PrevCancer" assessing adherence to the WCRF/AICR recommendations in Brazilian female breast cancer survivors. We conducted a psychometric study that involved the development of an instrument based on WCRF/AICR recommendations. Assessment of content validity involved the Content Validity Index (CVI) based on expert assessments (n = 7). The pilot study involved the System Usability Scale (SUS) after applying the developed instrument (n = 65) and anthropometric assessment for convergent validity by female participants (n = 55). The final usability test consisted of evaluating the satisfaction with the instrument of women with breast cancer (n = 14). The "PrevCancer" instrument demonstrated good content (CVI = 1.0) as well as good usability and acceptability in the pilot study (mean SUS score = 88.1). The convergent validity stage demonstrated positive associations between the PrevCancer parameters and anthropometric parameters (p < 0.001). In the final usability study (mean SUS score = 90.3), participants' receptivity to the instrument was excellent. The PrevCancer instrument had valid content and great usability by the target population, proving to be a useful tool for future cancer research.

Effect of Hypoxia on Siglec-7 and Siglec-9 Receptors and Sialoglycan Ligands and Impact of Their Targeting on NK Cell Cytotoxicity

Background/Objectives: Tumor microenvironmental hypoxia is an established hallmark of solid tumors. It significantly contributes to tumor aggressiveness and therapy resistance and has been reported to affect the balance of activating/inhibitory surface receptors’ expression and activity on NK cells. In the current study, we investigated the impact of hypoxia on the surface expression of Siglec-7 and Siglec-9 (Sig-7/9) and their ligands in NK cells and tumor target cells. The functional consequence of Siglec blockage using nanoparticles specifically designed to target and block Sig-7/9 receptors on NK cell cytotoxicity was elucidated. Methods: CD56⁺ CD3− NK cells were isolated from PBMCs along with an NK-92 clone and used as effector cells, while MCF-7 and K562 served as target cells. All cells were incubated under normoxic or hypoxic conditions for 24 h. To assess Siglec-7 and Siglec-9 receptor expression, U937, NK-92, and primary NK cells were stained with PE-labeled antibodies against CD328 Siglec-7/9. Interactions between Siglec-7/9 and their sialylated ligands, along with their functional impact on NK cell activity, were evaluated using polymeric nanoparticles coated with a sialic acid mimetic. Immunological synapse formation and live-cell imaging were performed with a ZEISS LSM 800 with Airyscan at 10x magnification for 24 h. Results: Our data indicate that hypoxia had no effect on the expression of Siglec-7/9 receptors by NK cells. In contrast, hypoxic stress resulted in an increase in Siglec-7 sialoglycan ligand expression by a sub-population of NK target cells. Using polymeric nanoparticles coated with a sialic acid mimetic that binds both Siglec-7 and -9 (Sig-7/9 NP), we demonstrated that incubation of these nanoparticles with NK cells resulted in increased immunological synapse formation, granzyme B accumulation, and killing of NK target cells. These studies indicate that hypoxic stress may have an impact on NK cell-based therapies and highlight the need to consider the hypoxic microenvironment for tumor-specific glycosylation. Conclusions: Our findings point to the role of Siglec–sialylated glycan interactions in hypoxic stress-induced NK cell dysfunction and recommend the potential integration of the manipulation of this axis through the targeting of Siglecs in future cancer immunotherapy strategies.

Significance of Image Reconstruction Parameters for Future Lung Cancer Risk Prediction Using Low-Dose Chest Computed Tomography and the Open-Access Sybil Algorithm.

Sybil is a validated publicly available deep learning-based algorithm that can accurately predict lung cancer risk from a single low-dose computed tomography (LDCT) scan. We aimed to study the effect of image reconstruction parameters and CT scanner manufacturer on Sybil's performance. Using LDCTs of a subset of the National Lung Screening Trial participants, which we previously used for internal validation of the Sybil algorithm (test set), we ran the Sybil algorithm on LDCT series pairs matched on kilovoltage peak, milliampere-seconds, reconstruction interval, reconstruction diameter, and either reconstruction filter or axial slice thickness. We also evaluated the cumulative effect of these parameters by combining the best- and the worst-performing parameters. A subanalysis compared Sybil's performance by CT manufacturer. We considered any LDCT positive if future lung cancer was subsequently confirmed by biopsy or surgical resection. The areas under the curve (AUCs) for each series pair were compared using DeLong's test. There was no difference in Sybil's performance between 1049 pairs of standard versus bone reconstruction filter (AUC at 1 year 0.84 [95% confidence interval (CI): 0.70-0.99] vs 0.86 [95% CI: 0.75-0.98], P = 0.87) and 1961 pairs of standard versus lung reconstruction filter (AUC at 1 year 0.98 [95% CI: 0.97-0.99] vs 0.98 [95% CI: 0.96-0.99], P = 0.81). Similarly, there was no difference in 1288 pairs comparing 2-mm versus 5-mm axial slice thickness (AUC at 1 year 0.98 [95% CI: 0.94-1.00] vs 0.99 [95% CI: 0.97-0.99], P = 0.68). The best-case scenario combining a lung reconstruction filter with 2-mm slice thickness compared with the worst-case scenario combining a bone reconstruction filter with 2.5-mm slice thickness uncovered a significantly different performance at years 2-4 (P = 0.03). Subanalysis showed no significant difference in performance between Siemens and Toshiba scanners. Sybil's predictive performance for future lung cancer risk is robust across different reconstruction filters and axial slice thicknesses, demonstrating its versatility in various imaging settings. Combining favorable reconstruction parameters can significantly enhance predictive ability at years 2-4. The absence of significant differences between Siemens and Toshiba scanners further supports Sybil's versatility.

Patient preferences regarding the cervix, ovaries, and fallopian tubes at the time of hysterectomy: a qualitative study

ABSTRACT Our objective is to understand patients’ preexisting values, beliefs, and preferences regarding removal or preservation of the cervix, ovaries, and fallopian tubes at the time of hysterectomy for benign indications. We performed semi-structured interviews from August 2021 to March 2022 with patients referred for hysterectomy. Participants were recruited according to pre-specified diversity axes. The interview guide was informed by literature review, expert stakeholders, and pilot testing. pers. comm. occurred prior to scheduled consultation. Responses were analyzed for themes, with thematic saturation reached. Age of participants (n = 13) ranged from 24 to 60 years. Identified themes included knowledge, decision-making, treatment goals, short- and long-term consequences, fertility, identity, and lack of concern. Many participants expressed lacking necessary knowledge of the risks and benefits of removing the cervix and adnexa. Treatment goals included symptom relief and definitive treatment. Long-term consequences included concerns about menopause and future cancer. Many patients expressed some degree of lack of knowledge, desire to remove most or all pelvic structures, or no attachment to their reproductive organs. Many patients expressed decision-making based on the effects of organ removal on long-term consequences and the relief of current symptoms, rather than immediate surgical risk. This information can help to inform patient-centered surgical counseling.

Exploring Neighborhood-Level Environmental Justice to Tackle County-Level Disparities in Breast Cancer Outcomes

Breast cancer is a disease in which cells, originating from the breast epithelium, grow out of control and form tumors. The progression of breast cancer can vary, and its severity is often categorized by stages ranging from early, localized forms to more advanced stages involving widespread dissemination. Breast cancer cases can be hereditary or non-hereditary; Hereditary cases are caused by a penetrant gene mutation: one that is pathogenic and has the potential to promote the development of cancer whereas non-hereditary cases can be caused by a variety of day-to-day exposures affected by socioeconomic disparities and health literacy rates. Despite scientific and technological advancements, researchers and health officials still do not know enough about the disease and breast cancer incidence rates in the United States have steadily increased. This literature review aims to synthesize the relationship between breast cancer health outcomes and environmental justice, health literacy, and socioeconomic disparities. This relationship was first examined from a county-level in the state of Florida. We first examined three Florida counties with varying socioeconomic profiles (Broward, Miami-Dade, and Palm Beach) and then examined neighborhoods within the county of Miami-Dade (selected because it has the highest breast cancer rates out of all Florida counties). This examination revealed higher incidences of breast cancer in Latinx and African American communities with high environmental exposures and lower socioeconomic statuses. The identification of specific neighborhoods primarily affected by environmental exposures and low socioeconomic statuses emphasizes the need for neighborhood level modeling to inform future breast cancer research and intervention strategies.