bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1111: The status of Government-funded radiotherapy centres in Nigeria
Authors: Aruah Simeon C. , Chidebe Runcie C. , Orjiakor Tochukwu C. , Uba Fatima , Shagaya Uchechukwu , Ugwanyi Charles , Umar Aisha A. , Ige Taofeeq , Asogwa Obinna C. , Ahmadu Oiza T. , Ali-Gombe Musa , Adewumi Alabi , Okwor Vitalis C. , Jimoh Mutiu A. , Bello Basheer , Eriba Lucy O. , Ahmed Yusuf A. , Bisalla Awwal , Itanyi Ukamaka , Balogun Ramatallah A. , Alabi Suleiman , Pistenmaa David , Norman Coleman C. , Manjit Dosanjh 
Published: June 2023

Abstract
PURPOSE: Access to radiotherapy (RT) is now one of the stark examples of global cancer inequities. Over 800,000 new cancer cases require potentially curative or palliative RT services in Africa, arguably less than 15% of these patients currently have access to this important service. For a population of over 200 million, Nigeria requires a minimum of 280 RT machines for the increasing number of cancer cases. Painfully the country has only 8 government-funded radiotherapy machines. This study aimed to evaluate the status of the eight (8) Government-funded RT centres in Nigeria regarding RT equipment, workforce and infrastructure to quantify their ability to deliver effective RT to their patients.
METHODS: A survey addressing ten (10) critical areas was used to assess the eight (8) Government-funded RT centres in Nigeria.
RESULTS: Unfortunately, 6 of the 8 centres (75%) surveyed have not treated patients with RT over the last 2 years because they do not have functioning teletherapy machines. Only 2 RT centres have the capability of treating patients using advanced RT techniques. There is no PET-CT scan in any of the Government-funded RTcentres. The workforce capacity and infrastructure across the 8 centres are limited. All of the centres lack residency training programmes for medical physicists and radiation therapy technologists (RTTs) resulting in very few well-trained staff.
CONCLUSION: As the Nigeria government plans for the new National Cancer Control Plan, there is an urgent need to scale up access to radiotherapy by upgrading the RT equipment, workforce and infrastructure to meet the current needs of Nigerian cancer patients. While the shortfall is apparent from a variety of radiotherapy-capacity data bases, this detailed analysis provides essential information for an implementation plan involving solutions from within Nigeria and with global partners.
Citation Format: Simeon C. Aruah, Runcie C. Chidebe, Tochukwu C. Orjiakor, Fatima Uba, Uchechukwu Shagaya, Charles Ugwanyi, Aisha A. Umar, Taofeeq Ige, Obinna C. Asogwa, Oiza T. Ahmadu, Musa Ali-Gombe, Alabi Adewumi, Vitalis C. Okwor, Mutiu A. Jimoh, Basheer Bello, Lucy O. Eriba, Yusuf A. Ahmed, Awwal Bisalla, Ukamaka Itanyi, Ramatallah A. Balogun, Suleiman Alabi, David Pistenmaa, Coleman C. Norman, Dosanjh Manjit. The status of Government-funded radiotherapy centres in Nigeria [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 1111.
Abstract 1151: CD6 isoforms improve CAR T cell fitness
Authors: Morris Jessica S. , Gad Ahmed Z. , Godret-Miertschin Lea M. , Fleischmann Ryan , Salsman Vita , Joseph Sujith K. , Ahmed Nabil 
Published: June 2023

Abstract
The ability of chimeric antigen receptor (CAR) T cells to initiate and sustain an effective immune response entails a delicate balance between T-cell activation and deactivation and is key for complete tumor elimination. CD6 is a co-receptor that fine-tunes T cell receptor signal strength through a unique dual function intracellular domain. CD6 is alternatively spliced, creating isoforms that lack distinct regions which interact with activating or inhibitory adapter proteins, thereby delivering inhibitory or activating signals, respectively. We hypothesized that CAR T cell fitness, namely their ability to sustain their effector function, can be achieved by using alternatively spliced CD6 isoforms which lack exons responsible for inhibitory signaling. First, we discovered that overexpression of the canonical full-length CD6 molecule, isoform CD6A, resulted in marginal improvement of CAR T cell function, while its deletion using CRISPR/Cas9 depressed the antitumor CAR T cell functionality. This supported a net stimulatory role for CD6 in CAR T cell function. To study their effect on cellular fitness, we then synthesized and overexpressed known alternatively spliced cytoplasmic isoforms CD6B, CD6C, CD6D, CD6E, and CD6F on CAR T cells and, noted a significant tendency towards preserving the CAR T cell naïve and central memory compartments, upon tumor encounter. Overexpression of isoform CD6F, which lacks exon 9, and to a lesser extent isoforms CD6C and CD6E enhanced the short- and long-term cytotoxicity of HER2 and CD19 targeting CAR T cells when compared to CAR T cells alone or CAR T cells overexpressing, CD6A. Despite exhibiting a lower proliferation index, and lower CAR CD3ζ phosphorylation at rest, CD6F CAR T cells secreted significantly higher concentrations of the Th1 cytokine, IFN-γ, and mediated more sustained in vitro cytotoxicity long-term, with more complete elimination of large tumor cell loads. Lastly, in an orthotopic model of human glioblastoma, the adoptive transfer of CD6F HER2 CAR T cells induced a more significant but also more sustained anti-glioma effect that translated into a significant survival advantage for experimental animals. Our data support that the overexpression of the alternatively spliced CD6 isoforms improves CAR T cell fitness resulting in superior antitumor activity both in vitro and in vivo.
Citation Format: Jessica S. Morris, Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, Nabil Ahmed. CD6 isoforms improve CAR T cell fitness [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 1151.
Abstract 1176: Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD
Authors: Elzein Arijh , Gorelick Alexander N. , de Bruijn Ino , Taylor Barry S. , Hanrahan Aphrothiti J. , Solit David B. 
Published: June 2023

Abstract
The majority of somatic variants identified by tumor genomic profiling are low frequency alterations of unknown biologic and clinical significance. To facilitate the systematic identification of likely oncogenic versus benign somatic mutations, there has been a growing interest in harnessing additional computationally amenable metrics such as sequence paralogy. Here, we developed a novel paralogy-directed computational methodology called Enriched Paralogy to identify Occult Cancer Hotspots (EPOCH), which calculates the significance of mutational recurrence at aligned positions in evolutionarily related genes to prioritize likely oncogenic mutations for in depth functional characterization. We validated the utility of EPOCH using sequencing data from a cohort of 52,676 tumor/normal pairs, with a focus on identifying likely oncogenic mutations in the well characterized PIK3CA (p110α) class 1a PI3K isoform and the lesser characterized PIK3CD (p110δ) isoform. p110δ mutants nominated as likely oncogenic by EPOCH induced AKT pathway activation, enhanced anchorage-independent colony formation, and demonstrated allele-specific dependencies on p85 regulatory protein binding. The potency of PI3K inhibitors against p110δ mutants was at best equal to or less than wildtype p110δ. In sum, we present the novel algorithm EPOCH that integrates paralogy to extend the utility of current recurrence-based precision oncology predictions and to automate the functional interpretation of less common mutations. Our work identifies novel oncogenic and targetable p110δ mutants and supports the inclusion of PIK3CD in targeted sequencing panels despite the relative rarity of mutations in this gene. The therapeutic studies herein also provide the rationale for the development and clinical testing of isoform- or mutant-specific p110δ inhibitors for patients with rare, yet druggable, oncogenic p110δ mutations.
Citation Format: Arijh Elzein, Alexander N. Gorelick, Ino de Bruijn, Barry S. Taylor, Aphrothiti J. Hanrahan, David B. Solit. Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD [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 1176.
Abstract 1240: mSin1 regulates epithelial-mesenchymal transition
Authors: Huang Shile , Luo Yan , Liu Lei , Cheng Bing 
Published: June 2023

Abstract
The mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2. Extensive studies have focused on mTORC1 in the regulation of cell growth, autophagy, and metabolism. However, the role of mTORC2 is poorly understood. mTORC2 has been found to control cell migration, but the underlying mechanism remains to be determined. Here we show that mammalian stress-activated protein kinase interacting protein 1 (mSin1), a unique component of mTORC2, plays an important role in cell migration. Knockout of mSin1 reduced the migration of mouse embryo fibroblasts (MEFs). Similarly, knockdown of mSin1 also inhibited the migration of tumor cells (Rh30 and HeLa). Furthermore, we observed that mSin1 is crucial for the epithelial-mesenchymal transition (EMT). Knockout or knockdown of mSin1 promoted the mesenchymal-epithelial transition (MET), a transition from multipolar or spindle shape to apico-basal polar shape. In addition, depletion of mSin1 increased the cellular protein level of E-cadherin (an MET marker) and decreased the cellular protein levels of N-cadherin and Twist (EMT markers). The results suggest that mSin1 positively regulates cell migration at least partly by promoting induction of EMT. Our findings support that mSin1 is crucial for mTORC2-mediated cell migration. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA)
Citation Format: Shile Huang, Yan Luo, Lei Liu, Bing Cheng. mSin1 regulates epithelial-mesenchymal transition [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 1240.
Abstract 1326: Perineural invasion and bone metastases in prostate cancer - is there a link
Authors: Sigorski Dawid , Galli Susana , Hong Sung Hyeok , Iżycka-Świeszewska Ewa , Kitlinska Joanna B. 
Published: June 2023

Abstract
Bone metastases are the most common secondary lesions in prostate cancer (PCa) patients. Typically, initial bone metastases develop in the lower part of the spine and pelvis. While this metastatic pattern is not consistent with the random nature of the arterial osseous dissemination, previous reports suggested the role of the retrograde venous spread in this phenomenon. However, clinical data also indicate a positive association between the degree of perineural invasion (PNI) and bone metastases in PCa patients. Yet, the mechanism linking these two means of dissemination remains unknown. To identify the processes involved in the initial PCa dissemination we used the PC3-ML cell line, which was previously shown to trigger bone metastases, in the orthotopic xenograft model. To this end, the cells were injected into the prostates of male SCID/Bg mice and tumor development and progression was followed by magnetic resonance imaging (MRI) and histopathology. MRI indicated local invasion of the primary tumor, which later resulted in the formation of multiple secondary lesions along the lower spine. However, histopathological analysis revealed that these lesions were initiated in the soft tissues surrounding the vertebral column, while the subsequent invasion of the vertebra was the secondary event. The staining for neuronal markers, neurofilament (NF), tyrosine hydroxylase (TH) and neuropeptide Y (NPY), revealed that PCa cells created multicellular clusters spreading longitudinally along the small nerve fibers, particularly in the paraspinal muscle compartment. The staining for the endothelial cell marker, CD31, detected small vessels present within PCa clusters. However, no evident encapsulation of the PCa cells within blood vessels consistent with the retrograde venous spread was observed. Altogether, these results suggest PNI as the main route of the initial local dissemination of the PCa cells toward the bone, which then triggers bone invasion and subsequent hematogenous spread to distant bones. Further mechanistic studies are required to confirm this hypothesis.
Citation Format: Dawid Sigorski, Susana Galli, Sung Hyeok Hong, Ewa Iżycka-Świeszewska, Joanna B. Kitlinska. Perineural invasion and bone metastases in prostate cancer - is there a link [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 1326.
Abstract 1339: Targeting specific extracellular matrix proteins to reactivate T cell trafficking in triple-negative breast cancer
Authors: Gauthier Valentine , Tyler Elly , Liu Ying , Sharp Tyson V. , Pearce Oliver MT 
Published: June 2023

Abstract
It is now widely recognised that the tumour microenvironment (TME) is playing a crucial role in promoting tumour immune evasion by modulating the local immune infiltration. A growing body of evidence highlights the crucial role of the tumour extracellular matrix (ECM) in limiting trafficking of newly activated T cells in solid cancers, thus restricting their access to tumour and preventing the success of cancer immunotherapies. Accordingly, we are investigating whether targeting specific tumour ECM components may enhance T cell infiltration in triple-negative breast cancer (TNBC). Matrisome profiling of patient-derived fibroblasts and patient tumour tissues allowed us to identify two matrix proteins overexpressed in tumours and associated with T cell signatures, the matrix proteoglycan, versican (VCAN) and the glycoprotein, fibronectin (FN1). As there are currently no specific inhibitors of matrix proteins, we have modelled their loss-of-function using the clustered, regularly interspaced, short palindromic repeats-associated nuclease Cas9 (CRISPR-Cas9) technology with the goal of engineering cell-editable matrisomes which are enriched, reduced, or absent for specific matrix proteins. First, we constituted a panel of human and murine mammary fibroblast and TNBC cancer cell lines, which we have introduced with an inducible Cas9 protein expression. We measured VCAN and FN1 expression in the panel which showed distinct VCAN levels. Therefore, depending on VCAN basal levels, we have generated cell lines with VCAN overexpression, transient knockdown or stable knockout. Proteomic matrisome profiling of transient VCAN knockdown cells revealed that reducing VCAN may impact ECM abundance by decreasing VCAN direct binding partners. Finally, we used the edited cells to build 2D and 3D in vitro TME models to evaluate the impact of modulating VCAN expression on chimeric antigen receptor (CAR) T cell cytotoxicity and location. In parallel, we built in vivo mouse models of TNBC with controlled ECM deposition. Specifically, we have targeted mVcan and mFn1 in tumours and investigated the impact of their removal on tumour growth and immune cell infiltration. Overall, this work aims to identify immunomodulating features of the ECM which could be targeted to boost response to immunotherapies in solid cancers.
Citation Format: Valentine Gauthier, Elly Tyler, Ying Liu, Tyson V. Sharp, Oliver MT Pearce. Targeting specific extracellular matrix proteins to reactivate T cell trafficking in triple-negative breast 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 1339.
Abstract 1381: Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells
Authors: He Jianping , Abikoye Abigail M. , McLaughlin Brett P. , Middleton Ryan S. , Sheldon Ryan , Jones Russell G. , Schafer Zachary T. 
Published: June 2023

Abstract
Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Ferroptosis is an iron dependent non-apoptotic cell death due to catastrophic accumulation of lipid peroxidation. While the mechanism that determines ferroptosis sensitivity has been extensively investigated in attached cells, how cells respond to ferroptosis under ECM detachment is largely unknown. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. While alterations in membrane lipid content are observed during ECM-detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM-detachment due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy towards ECM-detached cells.
Citation Format: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells [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 1381.
Abstract 1476: FOXM1 inhibition: A novel therapeutic approach for small cell lung cancer
Authors: Khan Md Arafat , Khan Parvez , Fatima Mahek , Rehman Asad Ur , Maurya Shailendra Kumar , Mohiuddin Sameer , Venkata Ramakanth Chirravuri , Cox Jesse L. , Kim Sung Hoon , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Ganti Apar K. , Batra Surinder K. , Nasser Mohd Wasim 
Published: June 2023

Abstract
Outcomes from small cell lung cancer (SCLC) are dismal. Most SCLC patients have distant metastasis at diagnosis and the 5-year survival of these patients is around 2.8%. Despite initial response to chemotherapy and immunotherapy, relapses are very common. No targeted therapy is available for SCLC. Thus, there is an urgent need to understand the acquisition of chemoresistance, and to identify novel targets and therapeutic strategies for this deadly disease. Recently, FOXM1 was identified as an essential component in SCLC tumor growth. Our aim is to develop FOXM1-targeted therapy to thwart SCLC progression and the development of chemoresistance. We have targeted FOXM1 using highly specific small molecule inhibitor FDI-6 and found that FOXM1 inhibition drastically reduces colony formation and cell migratory capabilities in multiple SCLC cell lines (SBC3, SBC5). Additionally, we observed that FOXM1 downregulation via FDI-6 reduced SCLC growth both as monotherapy and in combination with cisplatin. Based on these studies, we conclude that FOXM1 inhibition alone or in combination with cisplatin could be a unique therapeutic approach for SCLC.
Citation Format: Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Shailendra Kumar Maurya, Sameer Mohiuddin, Ramakanth Chirravuri Venkata, Jesse L. Cox, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Apar K. Ganti, Surinder K. Batra, Mohd Wasim Nasser. FOXM1 inhibition: A novel therapeutic approach for small cell lung 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 1476.
Abstract 1486: The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer cells
Authors: Yokoyama Yuhki , Yamamoto Hirofumi 
Published: June 2023

Abstract
Kruppel-like factor 5 (KLF5) belongs to zinc finger transcription factors and its expression is up-regulated in specific cancer types, such as gastrointestinal cancer and squamous carcinoma. It is reported that KLF5 is associated with the maintenance of stemness and essential for the integrity of intestinal epithelium and oncogenesis. Colon Cancer Associated Transcript 1 (CCAT1) is a long noncoding RNA that was initially found to be up-regulated in colorectal cancer (CRC), and studies have reported that high CCAT1 expression is associated with poor prognosis in CRC patients. In this study, we performed in vitro enChIP (engineered DNA-binding molecule-mediated chromatin immunoprecipitation)-sequencing to identify the KLF5 enhancer region which interacts with KLF5 promoter region. We successfully identified the KLF5 enhancer region in colorectal cancer cells and further found that KLF5 promoter region interacted with the transcription start site (TSS) region of CCAT1 gene, which is located at the different chromosome. Our results indicated that KLF5 protein participated in the core regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which contributes to construction of the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. We also found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples and that KLF5 regulated CCAT1 expression. In conclusion, our data propose the mechanistic insight that KLF5 protein constructs the core regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.
Citation Format: Yuhki Yokoyama, Hirofumi Yamamoto. The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer cells [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 1486.