bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3157: Prediction of adverse drug reactions of anti-breast cancer drugs using machine learning
Authors: Seongmo Kang , Lee Suehyun , Shin Hyunah , Kim Hyun Uk
Published: June 2023

Chemotherapy is a representative treatment option for cancers, but one of the challenges during the course of cancer treatment is the possible occurrence of adverse drug reactions (ADRs) caused by an anticancer drug. For example, ADRs such as encephalopathy, radiation recall dermatitis, acute cardiogenic shock and febrile neutropenia have been reported for 5-fluorouracil, an anticancer drug used to treat several cancer types. These ADRs may be caused by a single drug or by interactions with other drugs. Unfortunately, it is extremely difficult to predict potential ADRs a priori because the occurrence of ADR depends on the patient’s genetics and health condition as well as a combination of drugs taken together. To address this problem, we use electric health record (EHR) data of breast cancer patients as a proof-of-concept demonstration to develop a machine learning model that predicts ADRs. For this, administrations of breast cancer patients, diagnostic records, and additional personal information (e.g., age and gender) were used as input data. To deal with high sparsity of EHR data, which has categorical information, factorization machine was applied. Factorization machine can effectively capture key information in an sparse environment. The model classifies whether a patient shows one of pre-defined ADRs as an output. The machine learning model developed in this study can be useful for predicting potential ADRs of various drugs by taking into account a patient’s health condition.

Citation Format: Kang Seongmo, Suehyun Lee, Hyunah Shin, Hyun Uk Kim. Prediction of adverse drug reactions of anti-breast cancer drugs using machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3157.
Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity
Authors: Elliott Sarah C. , Sharma Jayesh , Zhang-Velten Elizabeth R. , Elnwasany Abdallah , Vidal Chantal , Szweda Luke , Alluri Prasanna
Published: June 2023

Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production.

Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation.

Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity.

Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity.

Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.
Abstract 3628: RAC1 aberrations in head and neck cancer affect immune microenvironments
Authors: Chan Helen Hoi Yin , Liu Yuchen , Ngan Hoi Lam , Lui Vivian Wai Yan
Published: June 2023

RAC1 is a Rho GTPase well-identified as an oncogene overexpressed in various cancer types. RAC1 amplification or gain account for ~40% of head and neck squamous cell carcinoma (HNSCC) while mutation of RAC1 occurs at ~3% according to TCGA-HNSCC cohort. HNSCC patients with RAC1 aberrations, including RAC1 mutations and amplification or gain, are associated with poor overall and disease-free survival in HNSCC. Significantly higher tumor mutational burden is observed in RAC1-mutated group (p=0.0336) or in RAC1-amplified/gain group (p=0.0109) vs. wildtype patients in TCGA-HNSCC cohort. As increases in TMB are often associated with immune cell infiltration in cancers, we hypothesized that RAC1 aberrations impact the tumor immune microenvironment (TIME) of HNSCC, potentially contributing to disease progression.PD-L1 (CD274) is an important immunosuppressive immune checkpoint molecule expressed in tumor cells. Here, we first reported that ectopic overexpression of RAC1 p.P29S and p.A159V mutations in a human HNSCC cell line (PECAPJ41 clone D2, ATCC, USA) could cause upregulation of PD-L1 at both mRNA (by RNA-seq) and protein levels (by Western blotting), first demonstrating a direct effect of RAC1 mutations on potential HNSCC TIME modulation via PD-L1. Furthermore, by tumor immune estimation resources (TIMER) analysis, we found that RAC1-mutated tumors have significantly higher level of neutrophils immune infiltration of 38.63% (p=0.027) compared to the wildtype tumors. From the CIBERSORTx analysis, M2 Macrophages was significantly increased by 40.42% in RAC1-mutated tumors vs wildtype in the TCGA-HNSCC cohort (p=0.031). We also validated this finding by immunofluorescent staining of PD-L1 and M2 Macrophages in immunocompetent mouse HNSCC xenografts models expressing RAC1 p.P29S and p.A159V mutations as compared to controls.

Our in silico, in vitro and in vivo findings first uncover an important role of RAC1 aberrations in HNSCC TIME immunosuppression by regulating PD-L1 expression, neutrophil and M2 macrophages infiltrations. Clinical activities of PD-L1 inhibitors in RAC1-mutated HNSCC patients worth future investigations.

Acknowledgement: This research is funded by the General Research Fund (Ref. No.:14168517) and the Research Impact Fund (Ref. No.: R4015-19) from the Research Grants Council in Hong Kong. VWYL is supported by Start-up Fund, Georgia Cancer Center, Medical College of Georgia at Augusta University.

Citation Format: Helen Hoi Yin Chan, Yuchen Liu, Hoi Lam Ngan, Vivian Wai Yan Lui. RAC1 aberrations in head and neck cancer affect immune microenvironments. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3628.
Abstract 3656: A multi-scale approach to quantitatively evaluate the SMAD signaling pathway
Authors: Heimsath Ernest , Arvidson Lisa , Prioli Reginaldo , Wood Antony
Published: June 2023

Angiogenesis and cell proliferation are fundamental biological processes whose pathologic states represent two hallmarks of cancer. Central to controlling both processes is the TGF-β/BMP signaling pathway, for which the SMAD proteins serve as major downstream effector molecules. Upon ligand-binding, TGF-β or BMP type I/II receptor heterotetramers phosphorylate receptor-regulated SMADs (R-SMADs). TGF-β-receptor binding leads to SMAD2/3 phosphorylation, whereas BMP-receptor binding induces phosphorylation of SMADs 1/5/8. Phosphorylated SMADs (pSMADs) then form a complex with the co-SMAD SMAD4 at which point they undergo nuclear translocation, where they function as transcriptional modulators of target genes. The magnitude of SMAD phosphorylation and functional output (e.g., stimulated angiogenesis or attenuated cell proliferation) depends on both the ligand concentration, as well as the duration of exposure. In this study, we quantitatively evaluate the phosphorylation states of R-SMADs, as well as their downstream biological effects at three different biological scales: 1) biochemical, 2) cellular, and 3) tissue/3D models. At the biochemical level, the temporal and dose-dependent phosphorylation of R-SMADs in response to growth factor stimulation can be quantified using a quantitative ELISA approach. Growth factor stimulation can be quantified at the cellular level by high content imaging of SMAD phosphorylation and nuclear translocation, while simultaneously monitoring cell proliferation rates. Lastly, high-resolution confocal imaging can be employed to observe developmental consequences of phospho-SMAD signaling using a HUVEC-based 3D angiogenesis model system.

For Research Use Only. Not for use in diagnostic procedures.

Citation Format: Ernest Heimsath, Lisa Arvidson, Reginaldo Prioli, Antony Wood. A multi-scale approach to quantitatively evaluate the SMAD signaling pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3656.
Abstract 4168: BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy
Authors: Liu Demi Xiaojuan , Lian Kaixia , Yan Xuefei , Lin Jie , Zheng Lei , Xiaoyu An Annie , Xu Xiaoxi , Bourre Ludovic , Wang Jingjing
Published: June 2023

Introduction: T cell immune response plays critical roles in cancer immunotherapy. CD3 complex, composed of CD3ε, CD3δ and CD3γ chains, is an essential component of TCR-CD3 complex mediating TCR signaling. Targeting CD3 complex has therefore become a popular strategy for manipulation of T cell function. Clinically relevant animal models for proper evaluation of human CD3 antibodies is in great demand in the field. Currently, adoptive transfer of human CD3+ T cells or transplantation of human hematopoietic stem/precursor cells to immunodeficient mice are usually employed. However, these mouse models are not fully immunocompetent. In this study we have evaluated in vitro CD3 EDG functionality and in vivo therapeutic efficacy, in BALB/c-hCD3EDG knock-in mouse in which all the three components of the CD3 complex — Cd3ε, Cd3δ, and Cd3γ— are replaced by their human counterparts, CD3E, CD3D, and CD3G.

Methods: A humanized CD3EDG mouse model (HuGEMM) on BALB/c background was generated by replacing the entire mouse CD3EDG with its human counterpart through ES cell-based gene targeting. The cell surface expression of CD3E and intracellular expression of CD3D and CD3G were confirmed by FACS. Naïve CD3+ T cells were isolated from the splenocytes of homozygous CD3EDG HuGEMM and activated by anti-hCD3 antibody. T cell proliferation was demonstrated by CFSE dilution assay. To validate the TCR functionality of humanized CD3EDG in vivo, we evaluated bispecific antibody anti-hCD3/hEpCAM5 in BALB/c-CD3EDG HuGEMM bearing CT26-hEpCAM5.

Results: The expression of human CD3E, CD3D and CD3G were confirmed by flow cytometry. hEpCAM5 antigen expression was confirmed in CT26 cell line in vitro and tumor in vivo by flow cytometry. The TCR functionality was detected by in vitro T cell activation assays using anti-hCD3 antibody. In vivo efficacy was demonstrated using a bispecific antibody that simultaneously binds to human CD3 and human tumor associated antigen EpCAM5 in human CD3 EDG knock-in mice engrafted with CT26-hEpCAM5 tumor. The therapeutic efficacy of the bispecific antibody showed 32% tumor growth inhibition compared to control treatment. No significant body weight loss was recorded in any of the animals.

Conclusion: This study showed the successful establishment of humanized CD3 knock-in BALB/c mouse models providing a full immunocompetent model for human CD3-targeted tumor immunotherapies evaluation.

Citation Format: Demi Xiaojuan Liu, Kaixia Lian, Xuefei Yan, Jie Lin, Lei Zheng, Annie Xiaoyu An, Xiaoxi Xu, Ludovic Bourre, Jingjing Wang. BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4168.
Abstract 5254: Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202
Authors: Vaishampayan Prajakta , Jandova Jana , Ai Yuchen (Ella) , Kirschnerova Viktoria , Curiel-Lewandrowski Clara , Wondrak Georg T. , Dickinson Sally E.
Published: June 2023

Immune evasion is a molecular hallmark of cancer, and overexpression of the immune checkpoint protein PD-L1 (CD274) has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). Notably, while baseline levels of PD-L1 in normal human epidermis are low, acute solar-simulated light (SSL) exposure increases the expression of this protein in epidermal keratinocytes, an effect which can be replicated in cultured keratinocytes and in mouse models. While current immunotherapies targeting the PD-1/PD-L1 axis using monoclonal antibodies are providing therapeutic benefits in many cancers including cSCC, small molecule inhibitors are also being developed to target PD-L1 which may be amenable for topical formulation and therefore early intervention with reduced systemic exposure. We have recently tested one such molecule, BMS-202, in vitro and in vivo. BMS-202 application to keratinocytes in culture inhibits UV-induced PD-L1 RNA and protein expression. Notably, exposure to this inhibitor also reduced UV-induced stress signaling as measured by AP-1 luciferase assay in cultured keratinocytes. Topical application of BMS-202 to immunocompetent SKH-1 mouse skin resulted in significant inhibition of SSL-induced epidermal PD-L1 as determined by immunoblot analysis. NanoString nCounter Pathway™ transcriptomic analysis of full-thickness SKH-1 mouse skin shows strong inhibition of SSL-induced inflammatory responses, chemokine activity, innate immune response and NF-κB activation in BMS-202 treated samples compared to SSL-only controls. Our results indicate that early intervention against PD-L1 expression/activity could be a viable target for skin cancer photochemoprevention. Topical application of small molecule PD-L1 inhibitors such as BMS-202 may provide novel treatment options for populations at high risk for cSCC.

Citation Format: Prajakta Vaishampayan, Jana Jandova, Yuchen (Ella) Ai, Viktoria Kirschnerova, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson. Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5254.
Abstract 5298: Multiplex immunoassay characterization of 48 cytokines, chemokines, and growth factors in colorectal cancer
Authors: Lie Wen-Rong , Steiner Harold , Williams Sasha , Banerjee Munmun , Saporita Anthony , Gilliam Brooke , Xiao Qiang
Published: June 2023

Cytokines, chemokines, and growth factors are critical mediators of immune system function capable of signaling through autocrine, paracrine, and endocrine mechanisms. Their pleiotropic immunomodulatory properties allow these biomolecules to react to diverse stimuli and regulate the immune response. We developed a novel immunoassay, using Luminex xMAP technology, for the simultaneous measurement of 48 cytokines, chemokines, and growth factors in serum, plasma, and cell culture supernatant. Many of these proteins have been proposed as biomarkers of colorectal cancer (CRC) and as key regulators of the tumor microenvironment (TME). While this complex milieu can support antitumor immunity, CRC is frequently characterized by chronic inflammation driving disease progression, with the TME serving as a potent reservoir from which the cytokines, chemokines, and growth factors exert their influence. The MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel B (HCYTB-60K) assays were performed in 96-well plates and run on the Luminex LX200™ instrument. Data was acquired via xPONENT v. 4.3 software. Data analysis was performed for all immunoassays using the Belysa Immunoassay Curve Fitting Software. Commercially available serum samples obtained from colorectal cancer patients and healthy controls were evaluated for cytokine, chemokine, and growth factor expression. Of the 48 analytes tested, statistically significant increases in BAFF, sFas, SCF, and MPIF-1 were observed in colorectal cancer serum. In contrast, IL-20 and ENA-78 decreased relative to healthy controls. While the immunoassay was verified for measurement of serum and plasma samples, additional sample types may be of interest to cancer researchers. Therefore, we evaluated the ability of the 48-plex immunoassay to measure these biomarkers in CSF, urine, milk, tumor samples and exosomal isolates, establishing a profile for these proteins in each sample type. Altogether, this study uses a novel multiplex immunoassay to characterize the immunological profile of colorectal cancer serum, focusing on 48 cytokines, chemokines, and growth factors. Additionally, alternative sample types were evaluated to establish the utility of this technology for applications beyond serum, plasma, and cell culture supernatant.

Citation Format: Wen-Rong Lie, Harold Steiner, Sasha Williams, Munmun Banerjee, Anthony Saporita, Brooke Gilliam, Qiang Xiao. Multiplex immunoassay characterization of 48 cytokines, chemokines, and growth factors in colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5298.
Abstract 5303: Upregulation of the polycomb group protein SCML2 contributes to aggressive prostate cancer
Authors: Boston Ava M. , Dwead Abdulrahman M. , Al-Mathkour Marwah M. , Khazaw Kezhan , Cinar Bekir
Published: June 2023

Advanced prostate cancer (PC) is the leading cause of death in the US because there is no effective treatment due to the poorly understood disease mechanism. Sex comb on midleg-like-2 (SCML2) is a member of Polycomb repressive complex 1 and regulates homeotic gene expression during development. Using proteomic approaches, we have identified SCML2 as a binding partner of the YAP1 protein complexes isolated from PC cell lines. Both SCML2 and YAP1 regulate basic cellular biology, including stem cell maintenance and carcinogenesis; however, whether SCML2 and YAP1 cooperate to contribute to the aggressive PC in humans remains unknown. We showed that AR-positive cell lines express high levels of SCML2 with a significant increase in castration-resistant PC cells compared to its castration-sensitive cell counter, suggesting a possible role of SCML2 in PC progression. We also showed that androgens regulated the protein-protein interaction between SCML2 and YAP1, as evaluated by proximity ligation assay. In addition, the GST-pulldown assay revealed that SCML2 interacted with the WW/SH3 domain of YAP1, where AR also binds. Besides, our RNAi-aided gene silencing experiment demonstrated that YAP1 and SCML2 might be functionally antagonistic. Moreover, gene silencing and growth assays showed that SCML2 might act as a growth suppressor in castration-sensitive PC cells while acting as a growth mediator or survival factor in castration-resistant PC cells. Furthermore, our analysis of the cancer genome atlas PC data set has indicated that amplification of SCML2 is associated with reduced progression-free survival. These observations suggest that SCML2 and YAP1 interaction is biologically functional, and the degree of their interaction may play a critical role in PC progression downstream of dysregulated androgen/AR signaling.

Citation Format: Ava M. Boston, Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Kezhan Khazaw, Bekir Cinar. Upregulation of the polycomb group protein SCML2 contributes to aggressive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5303.
Abstract 5503: Targeting CDK12-mediated DNA damage response to overcome cisplatin resistance in human urothelial carcinoma
Authors: Chow Po-Ming , Dong Jun-Ren , Shi Chung-Sheng , Huang Kuo-How
Published: June 2023

Urothelial carcinoma (UC) accounts for more than 90% of bladder cancer. According to the 2019 Surveillance, Epidemiology and End Results (SEER) Program database, the 5-year survival rates of regional and metastatic bladder cancer are 36.3% and 4.6%, respectively. Patients who received radical cystectomy suffer from a high recurrence rate of up to 30%. As for metastatic UC, only half of the patients respond to standard platinum-based chemotherapy, with 20% of 5-year overall survival. CDK12 shows transcription regulatory effects via regulating RNA polymerase II CTD phosphorylation. In our research, we used CDK12 selective inhibitor SR-4835 to treat the UC cell lines including T24, BFTC905, RT4, and cisplatin-resistant T24/R. MTT assay result has demonstrated the cytotoxicity of SR-4835 against UC cells. Using q-RT-PCR and immunoblotting, we have confirmed the reduction of ATM mRNA and protein expression after the treatment of SR-4835. The expression of DNA damage marker gamma-H2AX was also elevated. Flow cytometry data indicated an increase in apoptotic population after treatment. According to these findings, we presume SR-4835 can lead to a DNA damage-induced apoptosis process. Furthermore, we also observed the inhibition of AKT pathway, which is related to cell survival and proliferation. Due to the effects of DNA-repair inhibition, we aim to combine SR-4835 to enhance the anti-cancer effects of cisplatin. The results of UC mice xenograft have confirmed that SR-4835 and cisplatin display a synergistic effect against UC tumor growth in vivo. We will further dissect the mechanisms of the in vitro synergistic effects between SR-4835 and cisplatin using immunoblotting, RNA-sequencing, comet assay, and various functional assays. Conclusively, our study aims to explore the role of CDK12 in urothelial carcinoma and the therapeutic effects of SR-4835, especially its potential to overcome cisplatin resistance and manage metastatic disease.

Citation Format: Po-Ming Chow, Jun-Ren Dong, Chung-Sheng Shi, Kuo-How Huang. Targeting CDK12-mediated DNA damage response to overcome cisplatin resistance in human urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5503.
Abstract 6352: Combination treatment with recombinant murine IL-12 and anti-PD-1 antibody enhanced anti-tumor efficacy through the activation of cytotoxic T cell response
Authors: Yang Yeng-Jey , Tsou Pei-Yi , Chou Shiuh-Dih , Lee Meng-Na , Chen San-Chi
Published: June 2023

Introduction: Immune checkpoint inhibitors (ICIs) are widely used in cancer therapy. Among them, anti-PD-1 antibodies are the most used and have been approved by FDA for the treatment of many types of cancer (1). In our previous studies, combination of anti-PD-1 antibody with IL-12 demonstrated significant synergistic effect on tumor growth inhibition. The elevation of IFN-γ mRNA expression suggested the potential roles of CD8 T cells and NK cells in this process. In this study, we used two syngeneic mice tumor models to investigate the mechanisms of synergistic effect by the combination of IL-12 and anti-PD-1 antibody.

Methods: We used syngeneic mice tumor models with mice cancer cell lines CT-26 and MC-38. The mice inoculated with tumor cells and were treated until tumors grew to 100 mm3. The mice were divided into three groups to receive the treatment, including rmIL-12 alone, anti-PD1-antibody alone, and the combination of rmIL-12 and anti-PD1-antibody (BIW x 3 weeks). At the end of the study, the mice were sacrificed and tumor resection and splenectomy were performed. The tumor infiltrating lymphocyte subpopulations within the tumor microenvironment were analyzed by flow cytometry and gene expression profile by RNA Seq.

Results: The combination of rmIL-12 and anti-PD-1 antibody significantly inhibited tumor growth compared to the treatment with rmIL-12 and anti-PD-1 antibody alone. The combination group demonstrated more CD8+ T cell in the tumor microenvironment via flow cytometry. In addition, RNA Seq showed the combination group increased CD8+ T cells, NK cells, and Th1 populations. The levels of cytotoxicity related genes (IFN-γ, Granzyme B, Perforin) were also higher in combination group.

Conclusion: Combination of rmIL-12 and anti-PD-1 antibody increased immune cells infiltration in the tumor microenvironment and enhanced anti-tumor response suggesting the potential of this combination for cancer treatment.

Citation:(1). Watson, G.A. et al. (2020) “Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?,” British Journal of Clinical Pharmacology, 86(9), pp. 1753-1768. https://doi.org/10.1111/bcp.14355.

Citation Format: Yeng-Jey Yang, Pei-Yi Tsou, Shiuh-Dih Chou, Meng-Na Lee, San-Chi Chen. Combination treatment with recombinant murine IL-12 and anti-PD-1 antibody enhanced anti-tumor efficacy through the activation of cytotoxic T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6352.
Abstract 6452: A plasma metabolomic signature of healthy lifestyles and risk of colorectal cancer in the UK Biobank
Authors: Yuan Fangcheng , Yu Danxia , Wen Wanqing , Zheng Wei
Published: June 2023

Background: Lifestyle factors contribute to the etiology of colorectal cancer (CRC). We aimed to derive a metabolomic signature of adherence to healthy lifestyles and examine its association with CRC risk.

Methods: In the analysis, we included 98,898 UK Biobank participants with 168 metabolomic biomarkers measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. A healthy lifestyle score (HLS) was derived from 8 lifestyle factors according to the American Cancer Society (ACS) guidelines. We applied elastic net regularized regressions to identify a metabolomic signature from 130 biomarkers. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of metabolomic signature with CRC risk after adjusting for known confounders.

Results: During a median follow-up time of 8.2 years, 818 incident primary CRC cases were identified after participants were enrolled for more than two years. We observed a strong partial correlation between the metabolomic signature and HLS (r = 0.34), as well as waist-to-hip ratio, sedentary time, red and processed meat intake, and tobacco smoking aspects of the HLS (r = 0.14-0.33). A higher HLS was characterized by a signature of increased levels of linoleic acid, total cholines, and polyunsaturated fatty acids and decreased levels of omega-6 fatty acids, phospholipids in intermediate-density lipoprotein, and phosphatidylcholines. The metabolomic signature showed a significantly inverse association with CRC risk (HR = 0.84; 95% CI = 0.80-0.89 per standard deviation increment). The significantly inverse associations were observed irrespective of sex, educational attainment, and CRC subsite. Stronger associations were seen among participants aged between 50 and 60 years at study enrollment, and those diagnosed with CRC at 60 years old or later.

Conclusion: We identified a metabolomic signature characterizing adherence to the ACS guidelines and showed that the signature was inversely associated with CRC risk.

Citation Format: Fangcheng Yuan, Danxia Yu, Wanqing Wen, Wei Zheng. A plasma metabolomic signature of healthy lifestyles and risk of colorectal cancer in the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6452.
Abstract 6464: Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies
Authors: Lee Eunkyung , Li David , Park Yongho , Rodriguez-Fuguet Alice , Wang Xiaochuan , Zhang Wen Cai
Published: June 2023

Objectives: Recent preclinical studies suggested potential anticancer effects of antidepressant (AD) use in multiple cancers, but the effect on lung cancer in human studies remains unclear. This meta-analysis examined the effect of AD use on lung cancer incidence and mortality.

Methods: Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by June 2022. We conducted a meta-analysis using a random effects model to estimate pooled risk ratio (RR) and 95% confidence interval (CI) for comparing those with AD use and non-use. Heterogeneity was examined using Cochran’s Q test and inconsistency I2 statistics. The methodological quality of selected studies was assessed using the Newcastle-Ottawa Scale for observational studies.

Results: The meta-analysis, including 11 publications involving 1913172 participants, showed that AD use significantly increased lung cancer risk by 11% (RR= 1.11; 95% CI= 1.01, 1.22; I2= 74.3%; n= 6); however, all-cause mortality was not affected by AD use (RR= 1.05; 95% CI= 0.68, 1.58; I2= 90.1%; n= 4) while lung cancer-specific mortality could be reduced by 32% from onse study. Subgroup analysis showed that serotonin and norepinephrine reuptake inhibitors (SNRIs) were associated with an increased lung cancer risk (RR= 1.38; 95% CI= 1.07, 1.78), but selective serotonin reuptake inhibitors (RR= 1.05; 95% CI=0.91, 1.21) and tricyclic antidepressants (RR= 1.09; 95% CI=0.95, 1.26) were not. In addition, variations in the definition of AD use could be the source of heterogeneity of observed effects. The quality of selected studies was good (n= 5) to fair (n= 6).

Conclusions: Evidence suggests that AD use was associated with an elevated risk of lung cancer but not with all-cause mortality. More research is needed to precisely estimate the effect of AD use on lung cancer-specific mortality. (Funding: University of Central Florida Center for Behavioral Health Research and Training; Registration: PROSPERO; registration number: CRD42022350719)

Citation Format: Eunkyung Lee, David Li, Yongho Park, Alice Rodriguez-Fuguet, Xiaochuan Wang, Wen Cai Zhang. Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6464.
Abstract 6621: Simulating the distortion of clonal fractions in ctDNA due to spatially heterogenous selection
Authors: Rachman Thomas W. , Carja Oana , Schwartz Russell
Published: June 2023

Time-series circulating tumor DNA (ctDNA) sequencing has the potential to reveal emerging variants in the tissue in real time, and there is now substantial evidence that it can detect tumor growth and treatment-resistant mutations long before growth is visible. However, the reliability of ctDNA for profiling the primary tumor may be compromised by spatial heterogeneity in the tumor genetics, for example due to selective effects of differential drug penetration, immune infiltration, and oxygenation. We explore the influence of spatial factors on tumor genetics through a lattice-based branching process model of solid tumor evolution and ctDNA shedding with the goal of understanding where spatially variable selection pressure could lead to a significant difference between the clonal fractions in the blood and the tissue. The lattice model divides space into regions with different growth rates which result in different rates of driver mutation accumulation. The effects of regional differences in selection cause different apoptosis rates to correlate with the location of expanding driver clones. Using these rates to simulate ctDNA shedding, our model found that clones fit enough to invade a hostile region are temporarily amplified in the blood compared to their tissue frequency by as much as 300% for a limited window of time before the population expands further and the clonal fraction in the blood returns to close agreement with tissue. The results suggest evolutionary contexts in which liquid biopsy might provide highly biased estimates of tumor state, but also shows how this effect might be exploited to provide more sensitive detection of clonal expansion with implications for blood-based detection of recurrence and metastasis.

Citation Format: Thomas W. Rachman, Oana Carja, Russell Schwartz. Simulating the distortion of clonal fractions in ctDNA due to spatially heterogenous selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6621.
Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: June 2023

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM.

Significance:

Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.
Karakteristik Klinis Pasien Laserasi Kelopak Mata Akibat Trauma di Pusat Mata Nasional Rumah Sakit Mata Cicendo
Authors: Riza Afdal , Kartiwa Raden Angga
Published: June 2023

Introduction : Trauma of eyelids due to sharp object, blunt object, road traffic accidents etc. are the major causes resulting in injuries to eyelids. A good identification and prompt treatment can improve the outcome of palpebral laceration. 
Purpose : To describe clinical characteristics of eyelids laceration due to trauma without involvement of lacrimal system and other orbital
Methods : A retrospective descriptive cross sectional  study was conducted. Data is taken from medical records of patients diagnosed as eyelid laceration from January 2016 to November 2020. Age, gender, laterality, first reference, place, onset, cause, site of trauma, depth, outcome, complication and System for Peri-Ocular Trauma (SPOT) classification was reviewed.
Results : This study comprised of total 157 patients. Most of them were males 119 (75.80%) with median of age 24. The main mechanism of injury was direct trauma 88 (56.05%). The location where the injury occured was road side accidents 81 (51.59%). Superior eyelid was the most affected 96 (61.15%). Subcutaneus tissue as wound base 68 (43.31%) and affected to margin of eyelid 36 (22.92%). Hypertropic scar was the most complication found in 40 (25.47%). The most common SPOT  type injury were  Type IA.
Conclusion : Eyelids laceration due to trauma is common in male productive age, mainly affecting superior palpebra, mostly because of road side accidents. Hypertropic scar was most complication beside traumatic ptosis, lagophthalmos and lid margin notching. The SPOT classification can simplify a recording of palpebral injuries.
Karakteritik Pasien Dan Kategori Gangguan Penglihatan Pra Operasi Dan Pasca Operasi Katarak Berbasis Komunitas Pusat Mata Nasional Rumah Sakit Mata Cicendo
Authors: Hayyi Indri Nurul , Syumarti
Published: June 2023

Introduction : The main causes of blindness in the world are cataract. Community-based cataract surgery plays an important role in reducing the burden of cataract blindness.
Objective : To describe patient’s characteristic and visual impairment before and after community-based cataract surgery.
Methods : This is a retrospective descriptive study with secondary data from community-based cataract surgery by the Community Ophthalmology Installation of National Eye Center Cicendo Eye Hospital from January 2019 to December 2020. Visual impairment is divided into four categories based on WHO classification. 
Result : There were 3890 patients included. Most of patients were aged 60 to 69 years in 1533 people (39,41%). The most common diagnosis was immature senile cataract in 1826 people (46,94%). Most of patients underwent unilateral cataract surgery using Manual Small Incision Cataract Surgery method and implantation of intraocular lens. The most common category of visual impairment in one eye before surgery was blind, in  3714 eyes (95,48%) and one day after surgery was poor outcome, in 2466 eyes (63,39%). The two-eye blindness before surgery were 1492 people (38,35%) and after surgery were 652 people (16,76%). Sight restoration rate was 26,8%.
Conclusion : Most of the patients were aged 60-69 years. The most common diagnosis is immature senile cataract. The category of one eye visual impairment before surgery was mostly blind, after surgery was moderate visual impairment. There number of blind patients was decrease from 38,35% before surgery to 16,76% after surgery.
Karakteristik Klinis Pasien Ptosis Yang Telah Dilakukan Operasi Di Pusat Mata Nasional Rumah Sakit Mata Cicendo
Authors: Madyaputra Faris Mufid , Kartiwa Raden Angga , Dahlan M Rinaldi , Boesoirie Shanti Fitrianti
Published: June 2023

Introduction Ptosis is a condition of abnormal upper eyelid position in the primary gaze resulting in a decrease palpebral fissure width. Comprehensive assessments including history taking, physical and thorough eye examination are essential to determine the diagnosis and to decide the most appropriate management of ptosis according to the underlying etiology. The surgical intervention used in ptosis patients is based on the result of the physical examination.
Purpose To describe the clinical characteristic of ptosis patient whom underwent surgical intervention at National Eye Center Cicendo Eye Hospital.
Methods A descriptive retrospective study was conducted from medical records of ptosis patient after surgical intervention at National Eye Center Cicendo Eye Hospital, from January 2018 to December 2020. 
Results A total of 91 patients were reviewed. The median age was 19 years old, gender dominated by women. Of these patients, 66 (72.5%) patients had congenital ptosis and unilateral in 80 (87.9%) cases. Results obtained severe ptosis was the highest in ptosis degree as for 72 (79.1%). In total, 58 (63.7%) patients having moderate levator function.  Levator resection repair technique was the method of choice in 51 (56%) patients.
Conclusion The most commonly found clinical characteristics in ptosis patients whom underwent surgical intervention was severe degree ptosis and congenital ptosis.
Diet and Food and Nutrition Insecurity and Cardiometabolic Disease
Authors: Brandt Eric J. , Mozaffarian Dariush , Leung Cindy W. , Berkowitz Seth A. , Murthy Venkatesh L.
Published: June 2023

Poor nutrition is the leading cause of poor health, health care spending, and lost productivity in the United States and globally, which acts through cardiometabolic diseases as precursors to cardiovascular disease, cancer, and other conditions. There is great interest in how the social determinants of health (the conditions in which people are born, live, work, develop, and age) impact cardiometabolic disease. Food insecurity is an example of a powerful social determinant of health that impacts health outcomes. Nutrition insecurity, a distinct but related concept to food insecurity, is a direct determinant of health. In this article, we provide an overview of how diet in early life relates to cardiometabolic disease and then continue to focus on the concepts of food insecurity and nutrition insecurity. In the discussions herein we make important distinctions between the concepts of food insecurity and nutrition insecurity and provide a review of their concepts, histories, measurement and assessment devices, trends and prevalence, and links to health and health disparities. The discussions here set the stage for future research and practice to directly address the negative consequences of food and nutrition insecurity.
Epigenetics of Early Cardiometabolic Disease: Mechanisms and Precision Medicine
Authors: Baccarelli Andrea A. , Ordovás José
Published: June 2023

Epigenetics has transformed our understanding of the molecular basis of complex diseases, including cardiovascular and metabolic disorders. This review offers a comprehensive overview of the current state of knowledge on epigenetic processes implicated in cardiovascular and metabolic diseases, highlighting the potential of DNA methylation as a precision medicine biomarker and examining the impact of social determinants of health, gut bacterial epigenomics, noncoding RNA, and epitranscriptomics on disease development and progression. We discuss challenges and barriers to advancing cardiometabolic epigenetics research, along with the opportunities for novel preventive strategies, targeted therapies, and personalized medicine approaches that may arise from a better understanding of epigenetic processes. Emerging technologies, such as single-cell sequencing and epigenetic editing, hold the potential to further enhance our ability to dissect the complex interplay between genetic, environmental, and lifestyle factors. To translate research findings into clinical practice, interdisciplinary collaborations, technical and ethical considerations, and accessibility of resources and knowledge are crucial. Ultimately, the field of epigenetics has the potential to revolutionize the way we approach cardiovascular and metabolic diseases, paving the way for precision medicine and personalized health care, and improving the lives of millions of individuals worldwide affected by these conditions.
How Not to Do UN Peacekeeping
Authors: de Coning Cedric
Published: June 2023

Looking back over the past seventy-five years of UN peacekeeping, the most enduring question has been: Is peacekeeping effective? Historically, most peacekeeping operations have been. However, peacekeeping is currently suffering from a significant trust deficit. One important factor that differentiates contemporary peacekeeping operations with a stabilization mandate from the historic record is the absence of a viable political or peace process. When security is not directed to serve a peace process, it produces a stabilization dilemma: the more effectively a peace operation protects and achieves stability, the less incentive there is for ruling political elites to find long-term political solutions. This dilemma generates several perverse effects, including prolonging the conflict, trapping operations in place with no exit options, increasing the resilience of armed groups, and embedding peacekeeping in the local political economy. The article identifies five factors that help prevent the stabilization dilemma and influence the effectiveness of peace operations.