Cause Of Death Research Articles

Abstract PO5-24-05: The Metabolic and Epigenetic Contributions of Fibroblast Growth Factor Receptor-Mediated Breast Cancer Progression

Abstract Despite recent improvements in treatment options, breast cancer remains the second leading cause of cancer-related deaths among women, with metastasis of the primary tumor accounting for most of these deaths. Signaling by fibroblast growth factor receptors (FGFRs) is active in 85% of breast cancers and results in enhanced proliferation, migration, invasion, and therapeutic resistance of tumor cells. A common feature of breast cancer is altered cholesterol metabolism including an increase in cholesterol stored intracellularly as cholesteryl esters (CEs). In breast cancer cells, high levels of CEs are associated with aggressive disease and CEs are essential for growth and migration of cancer cells. Furthermore, there is mounting evidence that modifications to metabolic pathways impact epigenetic processes including DNA methylation and histone post-translational modifications. These epigenetic changes support tumor progression and metastasis through oncogene activation and silencing of tumor suppressors. While there have been numerous studies focused on the role of metabolic and epigenetic changes in breast cancer, none have attempted to connect these altered pathways to upstream growth factor receptor pathways, such as the FGFR pathway, in cancer cells. We hypothesize that FGFR signaling promotes changes to cholesterol metabolism and epigenetic regulation which lead to breast cancer progression. To study the proposed roles of FGFR signaling, we utilized murine mammary cells of differing metastatic abilities with inducible, oncogenic FGFR1 signaling. We also included the FGFR-dependent murine mammary tumor lines 4T1 and 4T07 which demonstrate differing metastatic capabilities. Through gene expression studies, we found an FGFR-mediated increase in cholesterol metabolic processes including cholesterol storage, uptake, and synthesis. Along with this, we found an FGFR-mediated increase in CE content in our models. Interestingly, these changes were exclusive to our highly metastatic models. Additionally, we have identified FGFR-mediated changes in the expression of histone modifying enzymes in our cell lines. Many of the enzymes modified by FGFR have been previously reported to play a role in breast cancer metastasis. To further elucidate the role of enhanced cholesterol storage in breast cancer progression, we treated cells with pharmacological inhibitors of cholesterol storage. Using in vitro assays, we demonstrate that cell survival, migration, and invasion all decrease when cholesterol storage is inhibited. Again, we observe that our highly metastatic cell line models are more sensitive to this inhibition. Taken together, these data suggest a role for FGFR signaling in promoting breast cancer progression and metastasis. With further studies, this connection may inform the development of novel therapeutic strategies to combat therapeutic resistance in breast cancer. Citation Format: Jennifer Tuokkola, Lyndsay Reese, Kaylee Schwertfeger. The Metabolic and Epigenetic Contributions of Fibroblast Growth Factor Receptor-Mediated Breast Cancer Progression [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 PO5-24-05.

Abstract PO1-03-01: Barriers, facilitators, and challenges for the implementation of a hybrid multidisciplinary lifestyle intervention

Abstract Background. Breast cancer is the leading cause of cancer-related death and disability among young women in Mexico. The physical and psychological symptoms they experience affect their quality of life, physical functioning, and psychological well-being. To address this, the National Cancer Institute in Mexico City developed a program called "Joven & Fuerte" that provides services for young women with breast cancer. Due to the COVID-19 pandemic, the program has migrated to virtual attention and now offers hybrid attention to meet the needs of these patients. The research group developed the "Joven, Fuerte & Saludable" intervention, which is a hybrid (face-to-face and virtual) multidisciplinary lifestyle intervention that includes nutrition, rehabilitation, psychological support, mindfulness intervention, and lifestyle education for early disease young women undergoing oncology treatments. This study aims to evaluate the barriers and facilitators for implementing this lifestyle intervention. Methodology. The study involved young women with early breast cancer enrolled in the "Joven & Fuerte" program in 2022. They were invited to participate in a study to evaluate the barriers, facilitators, and challenges of a hybrid multidisciplinary lifestyle intervention during the first months since the diagnosis (3 months). The intervention included face-to-face consultations for anthropometric and biochemical assessments, interdisciplinary team evaluations, and virtual support through WhatsApp and Zoom. Educational materials such as printed or digital healthy lifestyle guides and educational videos were available on a private Facebook and YouTube group. Follow-up sessions were conducted via phone, video, or on-site visits. To evaluate lifestyle habits and quality of life status, distress, anxiety, and depression validated questionnaires were used. The CFIR and RE-AIM questionnaires were used to identify the barriers and facilitators among the program staff and patients while adopting the intervention. Results. The study found that patients were satisfied with the intervention and educational materials, but there were some barriers for implementation. One of the main barriers was the patients' geographical location, as 62.5% of patients were foreign and lived far from the hospital. Additionally, patients only sometimes used the educational materials due to forgetfulness, lack of time, not having internet access, or low digital literacy. Patients also had difficulty recognizing the impact of a "healthy lifestyle" and prioritized other consultations before the program schedule. Institutional barriers included a lack of human resources, which led to a loss in follow-up and patient motivation due to waiting-list periods. Undergraduate and postgraduate training students were introduced to support the multidisciplinary team in overcoming this challenge. Despite these obstacles, patients reported feeling supported by the multidisciplinary team and experienced benefits such as reduced stress and anxiety and better management of treatment side effects upon completing program activities. An important institutional success was achieved by reducing service waiting times from three months to just 1-2 weeks for all services. Conclusions. Cultural behavior and emotional distress at diagnosis and during the first 3 months of intervention are the major challenges for patients. A hybrid educational intervention seems convenient to make follow-up more practical and accessible. Patients feel motivated because they are in touch with their clinicians and receive fast resolutions to their concerns. Many talented and enthusiastic human resources are needed to implement these interventions, but it is possible for a Latin American public hospital, considering the essential benefits for the patients. Citation Format: Daniela Martinez-Palacios, Marlid Cruz-Ramos, Fernanda Sarahi Fajardo-Espinoza, Yanira Elvira Rodriguez-Fonseca, Alicia Gonzalez-Perez, Aline Barranco-Cortés, Dana Aline Pérez-Camargo, Alejandro Mohar, Cynthia Mayté Villarreal Garza. Barriers, facilitators, and challenges for the implementation of a hybrid multidisciplinary lifestyle intervention [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 PO1-03-01.

A novel long non-coding RNA MIR4500HG003 promotes tumor metastasis through miR-483-3p-MMP9 axis in triple-negative breast cancer

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.

Abstract PO2-10-04: Clinicopathological Characteristics and Factors Associated With Screening and Late-Stage Diagnosis in Patients With Breast Cancer in Latin America: The LATINA Study (LACOG 0615/MO39485)

Abstract Background: Breast cancer (BC) is the most common malignancy and one of the leading causes of cancer death in women in Latin America (LATAM). However, the region lacks a unified multinational initiative to investigate BC and to further understand regional disparities. Methods: LATINA (LACOG 0615/MO39485) is the first multinational prospective cohort study designed to describe clinicopathological characteristics, treatment patterns, and outcomes of patients with BC in LATAM. Patients aged ≥18 years diagnosed with primary or recurrent BC in the 12 months preceding site activation were included. Data were collected at enrollment and every 6 months for up to 5 years. We present here the results for clinicopathological and demographic characteristics at BC diagnosis. Multivariable logistic regression was performed to investigate characteristics associated with later diagnosis (stage II/III vs. stage I) and detection method (symptomatic vs. screening). Causal mediation analysis was performed to investigate the detection method as a mediator of the effect of health care provision (public or private) on stage at diagnosis. Results: Between February 2020 and August 2022, 3276 patients from 31 research sites in 10 LATAM countries were included. Most patients in this cohort (72.1%, N=2362) were treated in the public health system. Regarding ethnicity, most patients (91.8%, N=3008) self-identified as Latinos and were White (47.3%, N=1549), American Indian (21.0%, N=689), and Black or Brown (16.6%, N=544). The median age at diagnosis was 54 years (range 23–95), 41.8% (N=1368) were < 50 years of age at BC diagnosis, and 54.1% (N=375) of the American Indian patients were ≤50 years of age. BC subtype distribution was: 43.2% (N=1336) luminal A, 14.3% (N=433) luminal B, 22.9% (N=709) human epidermal growth factor receptor 2-positive (HER2+), and 15.4% (N=477) triple negative. In patients older than 50 years old, most cases were detected with symptoms, particularly in the public health system (63.2%, N=836) vs. 50.5% (N=232) in the private health system, p< 0.0001). This was also the case in Black/Brown (61.6%, N=178) and American Indian patients (89.5%, N=281) vs. White patients (45.6%, N=413) (p< 0.0001). In the public system, 37.7% (N=890) and 31.7% (N=748) of cases were diagnosed at stage II and III vs. 37.6% (N=343) and 26.6% (N=243) of cases in the private system, respectively (p< 0.0001). Users of the public health system had a significantly higher risk of being diagnosed with symptoms vs. screening (adjusted odds ratio [aOR] 3.54, 95% CI 2.17–5.76). Causal mediation analysis showed that the detection method (screening vs. symptomatic) mediated 21.8% (95% CI 1.7%–41.9%, p=0.034) of the effect of health care provision (public or private) on stage at diagnosis. Self-identifying as Black (aOR 2.11, 95% CI 1.29–3.45), age < 40 years (aOR 1.97, 95% CI 1.20–3.23), public health care provision (aOR 2.18, 95% CI 1.32–3.59), and a diagnosis of HER2+ (aOR 1.74, 95% CI 1.20–2.52) or triple-negative BC (aOR 2.34, 95% CI 1.47–3.71) were associated with an increased risk of being diagnosed at a later stage. Conclusions: A significant proportion of new BC diagnoses in LATAM is observed in patients < 50 years of age. Reflecting the low screening coverage throughout the region, most patients detect the disease with symptoms. Stage III BC accounted for 30.3% of new cases, being more common among users of the public health system. Differences in the stage at diagnosis related to health care provision (public or private), ethnicity, and country underscore significant disparities that need to be addressed. Further analyses of these data will help identify factors associated with late diagnosis and support the development of regional corrective health policies. Citation Format: Gustavo Werutsky, Cynthia Villarreal-Garza, Henry Gómez, Juan Manuel Donaire, José Bines, Luis Henrique Fein, Maria Clara Horsburgh, Paula Cabrera-Galeana, Heloísa Resende, Rosa Vasallo Veras, Miriam Raimondo, Ricardo Elías Brugés Maya, Vidal Maria Del Rosario, Yeni Nerón, Ana Maria Donoso, Fernanda B. Damian, José D'Oliveira, Couto Filho, Maria Isabel Alonso, Victoria Costanzo, Tomás Reinert, Adriana Elizabeth Borello, Eduardo Cronenberger, Luis Fein, Marcela Urrego, Enrique Alanya, Jorge Luis Soriano García, Saúl Campos-Gomez, Eduardo A. Richardet, Hugo Castro-Salguero, Felipe Cruz, Diego Gómez, Angel Hernández, Carlos Alberto Farfan Tello, Ronald Rodríguez, Rafaela Jesus, Gustavo Gössling, Carlos Barrios. Clinicopathological Characteristics and Factors Associated With Screening and Late-Stage Diagnosis in Patients With Breast Cancer in Latin America: The LATINA Study (LACOG 0615/MO39485) [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 PO2-10-04.

Abstract PO5-06-07: Unravelling the role of PKC-eta in modulating the Hippo Pathway: a novel therapeutic strategy for triple-negative breast cancer metastasis

Abstract Breast cancer (BC) is the leading cause of cancer-related deaths in women, with metastasis being the primary reason for BC mortality. Triple-Negative Breast Cancer (TNBC) is aggressive and highly metastatic, having fewer treatment options than other types of breast cancer. Protein kinase C eta (PKCη), an anti-apoptotic kinase of the novel PKC subfamily, is associated with poor prognosis in invasive BC patients. In this study, we show the role of PKCη in promoting cell migration and invasion, and we demonstrate that its expression is required to maintain the mesenchymal state during EMT. Furthermore, we show that PKCη activates YAP/TAZ, tumor aggressiveness, and metastasis using in vitro and in vivo models. PKCη promotes metastasis in TNBC cells, showing that the PKCƞ-YAP signaling axis mediates this. Data analysis of BC patients with a high metastatic invasive propensity and low survival BC revealed a positive correlation between the elevated expression levels of PKCη and the expression of YAP. Knockout of PKCη (PKCηKO) in the TNBC cells 4T1 and MDA-MB-231 markedly inhibited their invasion and migration capability. We further show that PKCη enhances cell survival and anoikis prevention ability, which have crucial roles in metastasis formation, allowing cancer cells to circulate and home to distant sites in the body. Further substantiated by in vivo experiments with 4T1 xenografts in NSG mice, demonstrating that 4T1 PKCηKO cells depicted reduced primary tumor size and a significant decrease in size and number of tumor metastases in the lungs, with fewer tumor nodules. MDA-MB-231 PKCηKO xenografts also expressed reduced metastasis in the distant brain, lung, and liver organs. Mechanistically, we show that PKCη regulates epithelial-to-mesenchymal transition (EMT) markers as knockout of PKCη in TNBC cell lines increased expression of E-cadherin, EpCAM, and slug, and decreased expression of vimentin and ZEB1. Further profiling of the Hippo-YAP axis showed that PKCη is a negative regulator of the Hippo pathway that leads to YAP stabilization and is associated with phosphorylation at Ser128, which allows YAP to translocate to the nucleus and contributes to metastasis of TNBC cells. Moreover, our data support direct interaction between PKCη and YAP1 in TNBC cells. Finally, we show that treatment of TNBC cells with uPEP2 (a uORF-encoded peptide of the PKCη transcript) downregulates the PKCη expression, activates the Hippo signaling pathway and promotes YAP degradation. Our findings highlight the importance of PKCη in TNBC metastasis and provide a new avenue for therapeutic intervention in this aggressive and lethal disease. In conclusion, our studies identify a novel role of PKCη as a negative regulator of the Hippo pathway and reveal its function in promoting EMT and metastasis by modulating YAP/TAZ activity in TNBC. Results suggest that PKCη may represent a therapeutic target for this highly lethal and metastatic TNBC. Citation Format: Liju Vijaya Steltar Belsamma, Amitha Muraleedharan, Divya Ram Jayaram, Kamran Waidha, Sankar Jagadeeshan, Rose Sinay, Ekaterina Eremenko, Omer Berner, Moshe Elkabets, Etta Livneh. Unravelling the role of PKC-eta in modulating the Hippo Pathway: a novel therapeutic strategy for triple-negative breast cancer metastasis [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 PO5-06-07.

Abstract PO3-26-10: Small molecule inhibitor of PELP1 exhibit cytotoxic effects on breast cancer cells by blocking ribosome biogenesis

Abstract Introduction: Breast cancer (BC) is the second-leading cause of cancer-related deaths in women. Despite responsive to endocrine therapy, a sizeable portion of estrogen receptor positive (ER+) BC goes on to develop therapy-resistant breast cancer (TR-BC). Furthermore, triple-negative breast cancer (TNBC) has a more aggressive clinical course with fewer targeted therapeutic options. The development of more effective therapies for TR-BC or TNBC represent an unmet need. Excessive ribosome biogenesis has recently been linked to BC progression, and resistance to therapy. Oncogene PELP1, which is required for ribosome biogenesis, is frequently dysregulated in BC and serves as a prognostic factor for poor BC survival and therapy resistance. We recently identified SMIP34 as a PELP1 small molecule inhibitor of its kind and it is effective against both TR-BC and TNBC. The objective of this study is to determine the mechanisms by which SMIP34 exhibit cytotoxic effects on BC cells. Methods: We have used multiple ER+, therapy resistant and TNBC models in cell viability, and apoptosis assays. Modelling studies were done based on Cryo-EM structure of the WDR18/PELP1 Rix1 complex (PDB code 7UWF). Biochemical assays include immune precipitation, reporter assays, GST pulldown, and Western Blotting. SMIP34 effect on protein synthesis was measured by using Western blot of puromycin treated total lysates for puromycinylated protein content. SMIP34 effect on protein synthesis assessed using Cayman’s Protein Synthesis Assay Kit. Ribosome biogenesis in SMIP34 treated cells was monitored using confocal microscopy using rpS6 antibody. Results: In in vitro cell based assays, SMIP34 was highly effective in reducing the cell viability, reducing colony formation and inducing apoptosis of ER+, endocrine therapy resistant, and TNBC model cells. PELP1 homodimer has recently been predicated to act as the core of the WDR18/PELP1 assembly. Our biochemical assay results suggest that SMIP34 binds to the same region involved in the PELP1 homodimerization and disrupts the formation of PELP1 homodimer and subsequently blocks the formation of WDR18/PELP1 Rix1 complex. Modeling studies predicted that altering the conformation of PELP1 aa 696-720 loop by SMIP34 binding may influence the conformation of the following C-terminal region, which may disturb the interaction of other PELP1 partners such as SENP3 and TEX10. Accordingly, the results from immunoprecipitation experiments demonstrated decreased association of Rix1 complex proteins WDR18, TEX10, and SENP3 with PELP1 under conditions of SMIP34 treatment. Further, Western blotting analysis confirmed that SMIP34 treatment decreased levels of PELP1 and its complex proteins, such as WDR18, TEX10, LAS1L, and SENP3. SMIP34 significantly reduced ribosomal biogenesis in a dose dependent manner. Additionally, puromycin labelling experiments confirmed a dose dependent decrease in new protein synthesis upon SMIP34 administration. Data from the DepMap database analysis revealed that PELP1 is required for cancer cell survival. Additionally, analysis of TCGA breast cancer datasets revealed that PELP1 expression is positively correlated with WDR18, TEX10, LAS1L, and SENP3. In in vivo xenograft assays and ex vivo explant assays using tumor tissue, SMIP34 strongly inhibited the growth of ER+, endocrine treatment resistant, and TNBC model cells. Conclusion: These findings provide solid evidence that the Rix1 complex, which is required for ribosomes production, is disturbed by SMIP34 binding to PELP1. SMIP34 represents a new therapeutic for the treatment of both ER+ and TNBC breast cancer. Supported by VA grant 1 I01 BX004545-01A1. Citation Format: Xue Yang, Khaled Mohamed Nassar, Uday Pratap, Rahul Gopalam, Behnam Ebrahimi, Durga Meenakshi Panneerdoss, Xiaonan Li, Yaxia Yuan, Daohong Zhou, Gangadhara R. Sareddy, Rajeshwar R. Tekmal, Manjeet Rao, Suryavathi Viswanadhapalli, Ratna Vadlamudi. Small molecule inhibitor of PELP1 exhibit cytotoxic effects on breast cancer cells by blocking ribosome biogenesis [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 PO3-26-10.

Optimization of Phloretin-loaded Nanospanlastics for Targeting of FAS/SREBP1c/AMPK/ OB-Rb Signaling Pathway in HFD-induced Obesity.

Obese patients are at increased risk for CVD, which is the main cause of premature death and has been a major cause of disability and ill health in recent years. PTN, a natural dihydrochalcone flavonoid, has a variety of pharmacological characteristics. This article aimed to prepare PTN-NSLs to evaluate their anti-obesity activity. Morphology, Particle size, zeta potential, UV-vis, entrapment efficiency, FT-IR spectra, and an in vitro release study of PTN-NSLs were described. PTN-NSLs were also tested for their anti-obesity properties in obese rats. The LD50 of PTN-NSLs was calculated, as was the 1/20 LD50 prepared for the treatment of obese rats. Also, the level of glycemic, oxidative stress and inflammatory biomarkers were estimated in the obese rat's model. The synthesized PTN-NSLs were uniform, spherically shaped, and well dispersed with no aggregation noted, with a size range of 114.06 ± 8.35 nm. The measured zeta potential value of PTN-NSLs was -32.50.8 mv. Also, the UV spectra of PTN and PTN-NSLs have strong absorption at 225 and 285 nm. Also, the LD50 of PTN-NSLs was found to be 2750 mg/kg.b.w. Moreover, administrating obese rats with PTN-NSLs resulted in improved glycemic features as well as GSH, SOD, GPx, GR, IL10, TBARs, and IL-6 levels, as well as attenuated FAS, SREBP1c, AMPK, ACO, CPT1, and OB-Rb gene expression. Administration of PTN-NSLs significantly attenuated the levels of glycemic, oxidative stress, and inflammatory biomarkers. The biochemical and PCR findings are aided by histological investigations. Also, the present findings imply that PTN-NSLs might be a promising pharmacological tool for the treatment of obesity-related diseases.

Abstract PO1-25-01: LMTK3 promotes macrophage M2 polarisation and suppresses monocyte infiltration in breast cancer by altering the proteomic cargo of exosomes

Abstract Background: Breast cancer (BC) is a leading cause of cancer death and despite numerous treatment advancements, metastatic BC is incurable. Extracellular vesicles (EVs) are lipid-delimited particles released from cells which contain bioactive protein and nucleic acid cargo. Numerous studies have shown their importance in facilitating communication between cancer cells and the tumour microenvironment, implicating them as mediators of many aspects of carcinogenesis. EV-mediated communication between BC and the innate immune system plays a crucial role in BC progression, metastasis and the maintenance of an immunosuppressive microenvironment. LMTK3 overexpression in BC promotes therapy resistance, disease progression and invasion and metastasis, leading to a poorer prognosis in patients. Analysis of deconvoluted TCGA data indicated that LMTK3 overexpression also correlates with exclusion of M1 macrophages from the tumour microenvironment. This study aimed to explore the role of LMTK3 in EV-mediated communication between BC and immune cells. Methods EVs were collected from conditioned media of wild-type and LMTK3-overexpressing BC cells through differential ultracentrifugation, then characterised by transmission electron microscopy, nanoparticle tracking analysis, quantitative mass spectrometry and Western blotting. Monocytes were treated with EVs and proteomic and phosphoproteomic changes were analysed. 3D coculture models of BC and immune cells were used to assess monocyte and macrophage infiltration, polarisation and anti-cancer activity. Immunofluorescence and flow cytometry was used to assess macrophage polarisation. Bioinformatic analysis of TCGA datasets validated the findings in a clinical setting and the data was also validated in vivo, using syngeneic immunocompetent mouse models. Results LMTK3 overexpression in BC cells promotes the upregulation of a subpopulation of large (80-150nm) CD81+ EVs which are significantly enriched in oncogenic and immunoregulatory proteins, including LDHB, ARHGEF15, PSAT1 and HIC2. EVs from LMTK3-overexpressing but not control BC cells strongly reduce the ability of monocytes to infiltrate BC tumour spheroids and migrate through Matrigel. Proteomics analysis of the monocytes showed an enrichment in M2 polarisation proteins and a downregulation of proteins essential for migration, including S100A8, KLF13 and TRPC3. LMTK3 overexpression in BC also promotes M2 polarisation and exclusion of M1 macrophages in vivo. Summary LMTK3 overexpression in BC correlates with poor prognosis and reduced overall survival. We hypothesise that this is, in part, due to monocyte M2 polarisation and exclusion of M1 macrophages from the TME, mediated by LMTK3-dependent alterations in EV cargo, contributing to tumour immune evasion. Citation Format: Mark Samuels, William Jones, Charlotte Turner, Georgios Giamas. LMTK3 promotes macrophage M2 polarisation and suppresses monocyte infiltration in breast cancer by altering the proteomic cargo of exosomes [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 PO1-25-01.

Abstract PS18-03: The Association between Food Deserts, Food Swamps, and Postmenopausal Breast Cancer Mortality in the United States

Abstract Purpose: Breast cancer (BRCA), the 4th leading cause of cancer death in the United States (U.S.), is one of 13 obesity-related cancers. Healthy food consumption is a protective factor shown to decrease obesity risk and postmenopausal BRCA mortality, respectively. However, residing in geographical areas with no access to healthy food options (food deserts) or unhealthy food options (food swamps) reduces access to healthy foods and has been severely understudied. We examined the relationship between residing in food swamps and deserts with postmenopausal BRCA mortality. Methods: We conducted an ecological analysis utilizing 2010 – 2020 Center for Disease Control and Prevention postmenopausal BRCA mortality data (restricted to 45+ years old) and aggregated 2012 – 2020 data from the U.S. Department of Agriculture Food Environment Atlas data. Food swamp score (FS) was calculated as the ratio of fast-food and convenience stores to grocery stores and farmer’s markets. Food desert score (FD) was calculated as the proportion of residents living more than one mile (urban) or 10 miles (rural) from a grocery store and household income ≤ 200% of the federal poverty threshold. We categorized FD and FS to low, moderate, or high; higher scores indicated counties with poorer healthy food resources. Multilevel generalized mixed effects models were used to estimate the mentioned association. Results: 2,280 counties/county equivalents with high postmenopausal BRCA mortality rates had higher percentage of non-Hispanic (NH)-Black population (5.80 vs. 2.08), poverty rates (17.2 vs. 14.2), and high food swamp scored areas (39.0 vs. 24.5) versus counties/county equivalents with low postmenopausal BRCA mortality rates (p-value < 0.0001). After adjusting for age, percentage of NH-Blacks per county, and poverty rate, we found 42% increased odds of having high postmenopausal BRCA mortality rates among U.S. counties/county equivalents with high food swamp scores (adjusted odds ratio [AOR] = 1.42; 95% CI: 1.14 – 1.78). Conclusions: Sampled U.S. counties with the poorest food swamp environment had significantly increased odds of postmenopausal BRCA mortality. We suggest that local policymakers and community stakeholders should employ sustainable approaches at combating obesity and BRCA by increasing healthier accessible food sources (e.g. creating more walkable neighborhoods and community gardens). Citation Format: Malcolm Bevel, Meng-Han Tsai, April Parham, Sydney Andrzejak, Samantha Jones, Justin Moore. The Association between Food Deserts, Food Swamps, and Postmenopausal Breast Cancer Mortality in the United States [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 PS18-03.

Abstract PO5-10-06: A Pilot Study for Clinical Research Nurse Navigation at an Urban NCI-Designated Comprehensive Cancer Center

Abstract Background: Breast cancer is now the leading cause of cancer death for non-Hispanic Black women in Georgia with non-Hispanic Black women 40% more likely to die of breast cancer compared to White women. Inadequate representation of patients in clinical trials may contribute to health care inequity, though prior work has also shown disparate outcomes on similar clinical trials at Emory, suggesting differences in tumor biology may also be contributing to the disparity. Improving diversity in trial participation is imperative to better understand these differences, particularly with newer molecularly targeted therapies. We aimed to utilize Clinical Trials Nurse Navigation to increase clinical trial enrollment at an urban NCI-designated comprehensive care center in Atlanta, Georgia. Methods: A prospective pilot study was conducted investigating the role of a Clinical Research Nurse as a dedicated Clinical Trials Nurse Navigator to identify, pre-screen, and refer potential patients to both breast and next generation sequencing (NGS)-driven basket clinical trials at the Winship Cancer Institute at Emory University. The role also included centralizing all molecular data from patients with stage IV breast cancer into a database as a tool to refer patients to NGS-driven clinical trials. This role expands upon the Institute’s current research nursing scope to better meet the needs of our diverse patient population. Our catchment area is 35% non-Hispanic Black or African American. The nurse prescreened patients with stage IV breast cancer from breast oncology clinic templates and the breast NGS database to match them with clinical trials, with a particular emphasis on patients with stage IV triple negative breast cancer. The study began in January 2022 and is currently ongoing. Results: Since study initiation in January 2022, there has been a 27% increase in breast cancer clinical trial enrollment over a 12-month period. Over the last 6 months from January 2023, this has increased even further with 57 patients enrolled onto breast cancer clinical trials compared to a total enrollment of 70 patients onto breast cancer clinical trials in 2022 (Table 1). Of these patients, 11% enrolled in NGS-driven clinical trials in 2022 to present compared to 0% in 2021. Twenty-two (31.4%) non-Hispanic Black women enrolled onto breast cancer clinical trials in 2022 with another 21 (36.8%) non-Hispanic Black women enrolled thus far in 2023 (Table 1). Conclusion: Disparities in clinical trial enrollment may contribute to racial inequities in breast cancer outcomes. Implementation of clinical research nurse navigation has successfully improved clinical trial enrollment and diversity in clinical trial enrollment at our urban cancer center. Through increasing clinical trial prescreening, centralizing an NGS database, and dedicated nurse support to allow patients to navigate onto clinical trials, we achieved a 21% improvement in clinical trial enrollment from 2021 to 2022 and are on track to increase enrollment by 200% by the end of 2023. Clinical trials nurse navigators serve as an essential link between clinical trial patients and their providers, and should strongly be considered a key component of all clinical trials programs. Table 1 Breast Working Group Patient Enrollment by Race and Ethnicity, 2019-2023 Citation Format: Lizzie Huckaby, Maisey Ratcliffe, Madison Canning, Demetria Smith-Graziani, Kevin Kalinsky, Manali Bhave. A Pilot Study for Clinical Research Nurse Navigation at an Urban NCI-Designated Comprehensive Cancer Center [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 PO5-10-06.

Abstract PO5-09-10: Inflammatory Breast Cancer Patient Profile in a Population of Puerto Rican Women

Abstract Background: Breast cancer (BC) is the most frequently diagnosed cancer type, as well as the leading cause of cancer death among women in Puerto Rico (PR). Moreover, inflammatory breast cancer (IBC) is a highly aggressive BC subtype. The current study aimed to describe the patient profile and the clinicopathological characteristics of IBC tumors in Hispanic women living in Puerto Rico. Methods: This is a retrospective, population-based study using the Puerto Rico Central Cancer Registry (PRCCR) database and the Health Insurance Linkage Database (PRCCR-HILD) to identify and describe the patient profile of Puerto Rican women diagnosed with IBC from 2008 to 2018. Variables such as age at diagnosis, staging variables, tumor receptor subtypes, treatment received, and overall survival (OS) were studied. Statistical analysis methods were employed to describe the population, estimate survival curves and examine the risk of dying. Results: We identified a total of 51 patients. The mean age at diagnosis of IBC in the current study was 59 years old, which is older than the mean age at diagnosis of IBC for women in the mainland US, but younger than the mean age of women that are diagnosed with BC in PR (63 years old). A total of 62.8% of patients had no metastases at diagnosis and 64.7% were diagnosed with stage III disease. Most tumors presented with ER+/PR+/Her2- (21.6%), or a triple-negative (ER-/PR-/Her2-, 15.7%) tumor concordance. The OS during the 12 months post-diagnosis was 66%, whereas at 36 months, OS decreased to 39%. The triple-negative subtype had the worst survival at 36 months (36%). Women with stage IV disease and those with ER-/PR- tumor subtype had a higher risk of dying. Conclusions: This is the first research to describe the patient profile and characteristics of women diagnosed with IBC in Puerto Rico. Our results suggest that the Puerto Rican IBC patient population presents unique characteristics. This research increases awareness about this lethal disease in PR. Citation Format: Luz Arroyo-Cruz, Michelle Martinez-Montemayor. Inflammatory Breast Cancer Patient Profile in a Population of Puerto Rican Women [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 PO5-09-10.

Abstract PO2-18-08: Identification of novel genetic/therapeutic vulnerabilities in breast cancer

Abstract Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide. Triple negative breast cancer (TNBC) is an aggressive subtype that is defined by the lack of expression of estrogen and progesterone receptors in the absence of HER2 amplification or overexpression. TNBC represents 15-20% of all breast cancers and occurs more frequently in young premenopausal women. TNBC often ends with a poor clinical outcome due to high histological grade, rapid recurrence in many patients combined with few treatment options. These realities highlight the urgent need to identify novel therapeutics vulnerabilities that can be leveraged to improve TNBC patient outcomes. Methods: We utilized the publicly available DepMap and Kaplan Meier datasets to identify essential genes that were unique to TNBC cells and whose expression levels were associated with worse patient outcomes. siRNA based approaches were used to confirm the relevance of top hits in mediating cancer cell phenotypes including viability, cell-cycle profiles and induction of apoptosis among others. A novel drug currently being developed was identified for the top hit in these studies and was subsequently employed in multiple in vitro approaches to characterize the mechanisms of action in TNBC as well as initial efficacy studies using clinically relevant ex vivo patient derived models. Results: Using the DepMap database, we interrogated genome-wide sgRNA knockout screens conducted in over 40 breast cancer cell lines to identify specific genes whose expression was required for cell viability in TNBC cells, but not other breast cancer cell lines. This endeavor identified 6 genes (CTPS1, HUS1, PRKRA, RAD1, RAD9A and RHOA) that were preferentially essential in TNBC cells. Further profiling of these genes revealed that CTPS1 expression is higher in cancer relative to normal tissue and that its expression is further upregulated in chemotherapy- and PARPi-resistant models. Knockdown of CTPS1 in TNBC cells was shown to decrease cell proliferation and viability with no effects observed in estrogen receptor+ cell lines. Using a first-in-class, highly selective and orally bioavailable CTPS1 inhibitor (STP938) developed by Step-Pharma, we identified IC50s in the low nM range for many TNBC cell lines, including cell models that are resistant to existing standard-of-care therapies. Inhibition of CTPS1 was shown to arrest cells in S phase. Conclusions: Our studies have identified CTPS1 as an essential gene in TNBC. CTPS1 encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphosphate), an essential step in the biosynthesis of nucleic acids. These findings are timely in light of the recent and ongoing development of the first-in-class CTPS1 inhibitor, STP938, for which first-in-human studies are underway for refractory B- and T-cell lymphomas. Based on our initial studies using this drug, we provide pre-clinical evidence of its efficacy in multiple models of primary and advanced TNBC. Efforts are currently underway to move this work toward a clinical trial for TNBC patients. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Russell, Esther Rodman, Philip Beer, John Hawse. Identification of novel genetic/therapeutic vulnerabilities in breast cancer [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 PO2-18-08.

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [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 PO1-06-10.

Identifying causes and associated factors of stillbirths using autopsy of the fetus and placenta.

The study aimed to evaluate the causes of death and associated factors in cases of stillbirth, using post-mortem examination and applying a rigorous, evidence-based holistic approach. Our retrospective observational study included cases of autopsy following stillbirth that occurred at our tertiary medical center during a period of 8 years. Detailed up-to-date criteria that incorporate clinical reports, medical history, prenatal imaging, and histopathological findings were used to evaluate the cause of death and associated factors. After applying our proposed methodology, 138 cases of stillbirth were classified into eight categories based on the causes of death. A definitive cause of death was observed in 100 (72%) cases, while 38 (28%) cases were considered unexplained. The leading cause of death was placental lesions (n = 39, 28%) with maternal vascular malperfusion (MVM) lesions being the most common (54%). Ascending infection was the second most common cause of fetal death (n = 24, 17%) and was often seen in the setting of preterm labor and cervical insufficiency. The largest category of cause of death was attributed to placental pathology. Using rigorous detailed up-to-date criteria that incorporate pathological and clinical factors may help in objectively classifying the cause of death.

Proarrhythmic drugs, drug levels, and polypharmacy in victims of sudden arrhythmic death syndrome: An autopsy-based study from Denmark

BackgroundSudden arrhythmic death syndrome (SADS), characterized by an unknown or inconclusive cause of death at autopsy, together with a negative or non-lethal toxicology screening, is the most common cause of sudden cardiac death (SCD) in victims under the age of 35. The complete causality of SADS remains unclear, with drugs being a potential risk factor. ObjectiveTo describe the toxicological profiles of SADS victims, focusing on proarrhythmic drugs, drug levels, and polypharmacy. MethodsAll deaths in Denmark from 2000–2019 aged 1–35 years and 2007–2019 aged 36–49 years were examined through death certificates, national registries, and autopsy reports with toxicology screenings. We investigated all sudden unexpected death victims with an autopsy performed, and where cause of death was unknown or inconclusive, including negative or non-lethal drug findings (SADS). ResultsWe identified 477 SADS victims; 313 (66%) had a positive toxicology screening (adjudicated non-lethal), with an average of 2.8 drugs/case. More than half of the SADS victims with a positive toxicology screening had QT-prolonging or brugadogenic drugs present. Polypharmacy was present in 66%, psychotropic polypharmacy in 37%, and QT-prolonging polypharmacy in 22%, with the most frequent overall and QT-prolonging drug combination being an antipsychotic and a psychoanaleptic drug. QT-prolonging drugs were more often present at suprapharmacological levels than non-QT-prolonging drugs. ConclusionA majority of the SADS population had a positive toxicology, with a notably large proportion having proarrhythmic drugs and polypharmacy. This highlights the need for future focus on drugs as a risk factor for SADS.

Neonatal mortality during the war in Tigray: a cross-sectional community-based study

Neonatal mortality is among the key national and international indicators of health services. The global Sustainable Development Goal target for neonatal mortality is fewer than 12 deaths per 1000 livebirths, by 2030. Neonatal mortality estimates in the 2019 Ethiopian Demographic Health Survey found 25·7 deaths per 1000 livebirths. Subnational surveys specific to Tigray, Ethiopia, reported a neonatal mortality lifetime prevalence of 7·13 deaths. Another government report from the Tigray region estimated a neonatal mortality rate of ten deaths per 1000 livebirths in 2020. Despite the numerous interventions in Ethiopia's Tigray region to achieve the Sustainable Development Goals, the war has disrupted most health services, but the effect on neonatal mortality is unknown. Thus, this study aimed to investigate the magnitude and causes of neonatal mortality during the war in Tigray. A cross-sectional community-based study was conducted in Tigray to evaluate neonatal mortality that occurred from Nov 4, 2020, to May 30, 2022. Among the 31 districts, 121 tabias were selected using computer-generated random sampling, and 189 087 households were visited. We adopted a validated WHO 2022 verbal autopsy tool, and data were collected using an interviewer-administrated Open Data Kit. In the absence of the mother, other respondents to the verbal autopsy interview were household members aged 18 years and older who provided care during the final illness that led to death. 29 761 livebirths were recorded during the screening of 189 087 households. Verbal autopsy was administered for 1158 households with neonatal deaths. 317 neonates were stillborn, and 841 neonatal deaths were recorded with the WHO 2022 verbal autopsy tool from Nov 4, 2020, to May 30, 2022, in 31 districts. The neonatal mortality rate was 28·2 deaths per 1000 livebirths. 476 (57%) of the 841 neonatal deaths occurred at home and 296 (35%) in health facilities. A high rate of neonatal deaths was reported in rural districts (80% [673 of 841]) compared with urban districts (20% [168 of 841]), and 663 (79%) deaths occurred during the early neonatal period, in the first week of life (0-6 days). The leading causes of neonatal death were asphyxia (35% [291 of 834]), prematurity (30% [247 of 834]), and infection (12% [104 of 834]). Asphyxia (37% [246 of 663]) and infection (28% [50 of 178]) were the leading causes of death for early and late neonatal period deaths, respectively. Neonatal mortality in Tigray is high due to preventable causes. An urgent response is needed to prevent the high number of neonatal deaths associated with the depleted health resources and services resulting from the war, and to achieve the Sustainable Development Goal on neonatal mortality. UNICEF and United Nations Fund for Population Activities. For the Tigrigna translation of the abstract see Supplementary Materials section.

Child, maternal, and adult mortality in rural Ethiopia in 2019: a cross-sectional mortality survey using electronic verbal autopsies

Ethiopia, with about 10% of Africa's population, has little direct information on causes of death, particularly in rural areas where 80% of Ethiopians live. In 2019-2020, we conducted electronic verbal autopsies (e-VA) to examine causes of death and quantify cause-specific mortality rates in rural Ethiopia. We examined deaths under 70 years in the three years prior to the survey dates (November 25, 2019-February 29, 2020) among 2% of East Gojjam Zone (Amhara Region) using registered deaths and adding random sampling in this cross-sectional study. Trained surveyors interviewed relatives of the deceased with central dual-physician assignment of causes as the main outcome. We documented details on age, sex and location of death, and derived overall rural death rates using 2007 Census data and the United Nations national estimates for 2019. To these, we applied our sample-weighted causes to derive cause-specific mortality rates. We calculated death risks for the leading causes for major age groups. We studied 3516 deaths: 55% male, 97% rural, and 68% occurring at home. At ages 5 and older, injuries were notable, accounting for over a third of deaths at 5-14 years, half of the deaths at ages 15-29 years, and a quarter of deaths at ages 30-69 years. Neonatal mortality was high, mostly from prematurity/low birthweight and infections. Among children under 5 (excluding neonates), infections caused nearly two-thirds of deaths. Most maternal deaths (84%) arose from direct causes. After injuries, especially suicide, assaults, and road traffic accidents, vascular disease (15%) and cancer (13%) were the leading causes among adults at 30-69 years. HIV/AIDS and tuberculosis deaths were also important causes among adults. Rural Ethiopia has a high burden of avoidable mortality, particularly injury, including suicide, assaults, and road traffic accidents. International Development Research Centre, and the Canadian Institutes of Health Research.

The impact of COVID-19 on deaths from dementia and Alzheimer’s disease in Chile: an analysis of panel data for 16 regions, 2017–2022

Although several studies have documented the detrimental impacts of global COVID-19 containment measures on individuals with Alzheimer's disease and dementia, a comprehensive analysis of mortality rates for these conditions within the Chilean population is notably lacking. This study aimed to analyze the impact of COVID-19 on mortality rates among individuals with dementia and Alzheimer's disease in Chile. A retrospective longitudinal cross-sectional study was conducted, considering mortality data for specific mental health conditions during the pre-pandemic and pandemic contexts of COVID-19 in Chile. Quantile regression techniques were employed to analyze the existence of differences between the two periods, while non-observable heterogeneity models for panel data methods were used to evaluate the effect of COVID-19 mortality on crude mortality rates. Statistically significant differences were observed in the number of deaths from dementia and Alzheimer's disease between the pre-pandemic and COVID-19 pandemic periods. Specifically, crude mortality rates decreased by 10% (-0.10 [95% CI:-0.16,-0.05]) during the pandemic period. Furthermore, the number of deaths from COVID-19 during the pandemic period has a very weak incidence of deaths from mental health conditions such as dementia and Alzheimer's. Specifically, a unit percentage increase in confirmed cases from COVID-19 would result in a 7% (-0.07 [95% CI:-0.13,-0.001]) decrease in the number of deaths from dementia and Alzheimer's. These findings are supported by the application of panel regression with one-way random effects models. The study findings indicate a reduction in mortality rates attributed to dementia and Alzheimer's disease during the COVID-19 pandemic in Chile. This decline could be attributed to the potential underreporting of mental illness as the cause of death during the pandemic period. Several studies have highlighted that approximately 30% of death certificates fail to document the presence of a dementia syndrome. Moreover, the cause of death recorded for individuals with mental health conditions may be influenced by the physician's familiarity with the patient or reflect the prevailing approach to managing end-stage dementia patients. This work received no funding.

Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis

Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear. This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis. Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo. Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tert‑butylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC. Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.

Green synthesis of Abutilon indicum (L) derived iron oxide (FeO) nanoparticles with excellent biological, anticancer and photocatalytic activities

Cancer is one of the most common causes of death all over the world. Although there are many treatments available none of them are without side-effect and most of them are very expensive. Similarly, Inflammation is one of another common medical worldwide but most of the therapies available are not environment and pocket friendly. Thus, the aim of our study was to synthesize environmentally friendly, cost-effective FeO NPs with significant anticancer, anti-inflammatory, antibacterial properties. The green synthesis of Iron Oxide Nanoparticles (FeO NPs) using plant extract is one of the environmentally friendly, cost-effective, and a secure alternative to physical or chemical synthesis methods. In the present study we used Abutilon indicum leaf extract to synthesize the Ai-FeO NPs and performed various experiments to confirm the therapeutic potential of green synthesized Ai-FeO nanoparticles. In this method, an aqueous plant leaf extract (A. indicum: Ai) was used as a reducing and stabilizing agent for the synthesis of FeO nanoparticles. The synthesized Ai-FeO NPs were characterized by the ultraviolet–visible (UV–Vis) absorbance of the surface at a resonance band 415 nm. Fourier transform infrared (FTIR) spectroscopy study confirmed the inherent bioactive functional groups as capping and stabilizing agents for Ai-FeO NPs. The X-ray powder diffraction (XRD) spectra revealed crystalline nature of the NPs. Further, the synthesized NPs have been isolated in highly stable, crystalline nature with spherical shape having size 10–95 nm. In addition, the green synthesized Ai-FeO-NPs demonstrated dose-dependent antimicrobial, antioxidant, anti-inflammatory, and anticancer properties. The findings of this study suggested that A. indicum leaf extract mediated FeO nanoparticles could be potentially used as a therapeutic agent for many human diseases and breast cancer.