bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2398: The tobacco cembranoid β-cembrenediol as promising prostate cancer recurrence suppressor lead
Authors: Mudhish Ethar A. , Siddique Abu Bakar , Abdelwahed Khaldoun S. , King Judy A. , Sayed Khalid A. El 
Published: June 2022

Abstract
Prostate cancer (PC) is the second leading cause of men death in the US, annually killing &gt;34,000 men. Despite progress in early PC diagnosis and treatment, many patients have locally and distant disease recurrence. Therapeutic androgens deprivation have limited curative potential and associated with severe side effects and rapid resistance development justifying the dire need for discovery of novel recurrence inhibitors. (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (β-CBT) and its 4-epi-analog (α-CBT) are the precursors to key flavor ingredients in leaves of most Nicotiana species. Nearly 40-60% of β- and α-CBT are purposely degraded during the commercial tobacco fermentation. Earlier, we reported the lack of β-CBT cytotoxicity below 50 µM while at 50 nM it reversed the calcitonin-stimulated decrease in transepithelial resistance and increased paracellular permeability in PC-3M PC cells. β-CBT also proven to stimulate tight junction formation between PC-3M cells, producing a tighter intercellular barrier. β-CBT 10-50 nM potently inhibited the calcitonin-stimulated PC-3M cells invasion in Matrigel assay. This study demonstrates the in vitro β-CBT anti-migratory (wound-healing assay) and anti-clonogenicity (colony-formation assay) activities against five PC cell lines, including the metastatic castration-recurrent human prostate cancer (mCRPC) CWR-R1ca. Meanwhile, β-CBT potently suppressed the in vivo locoregional and distant recurrences after the primary tumor surgical excision of the tumor formed by engrafting the human metastatic prostate PC-3M-Luc cells at the suprascupular region in male nude mice model. β-CBT treatments prevented organ and significantly suppressed bone metastasis and lacked any major toxicity over the 60-day study course. Therefore, β-CBT emerges as an effective promising PC recurrence and metastasis suppressive lead appropriate for near future use as a prospective nutraceutical.
Citation Format: Ethar A. Mudhish, Abu Bakar Siddique, Khaldoun S. Abdelwahed, Judy A. King, Khalid A. El Sayed. The tobacco cembranoid β-cembrenediol as promising prostate cancer recurrence suppressor lead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2398.
Abstract 2446: Low dose dimethyl sulfoxide (DMSO) downregulates the expression of androgen receptor (AR) and AR-variant 7 (AR-v7) in castration resistant prostate cancer (CRPC) cells
Authors: Khurana Namrata , Kim Hogyoung , Khan Talal , Kahhal Shohreh , Bukvic Amar , Abdel-Mageed Asim B. , Sikka Suresh C. , Mondal Debasis 
Published: June 2022

Abstract
The highly aggressive prostate cancer (PC) cells utilize androgen receptor (AR) signaling to facilitate their growth and metastasis. Despite androgen deprivation therapy (ADT), recurrence of castration-resistant prostate cancer (CRPC) often occur due to constitutive AR signaling via both full-length AR (AR-FL) and AR splice variants, primarily AR-V7. Therefore, safe strategies to suppress both AR-FL & AR-V7 expression in CRPC cells will be of significant benefit. Several plant-derived organosulfur compounds, e.g. sulforaphane and diallyl-trisulfide, can potently suppress AR expression in CRPC cells, but are yet to be clinically approved. We investigated whether dimethyl sulfoxide (DMSO) an approved organosulfur compound often used as a solvent for pharmaceutical agents, can similarly suppress AR levels in the CRPC cell lines, C4-2B and 22Rv1. Exposure to low dose DMSO (0.1-1%) was not cytotoxic to these CRPC cells, and less than 20% cytotoxicity was seen with 2.5% DMSO even at 96 h post-exposure. Interestingly however, DMSO dose-dependently suppressed AR-FL in C4-2B cells and both AR-FL and AR-V7 in 22Rv1 cells within 24 h post-exposure. Exposure to DMSO also downregulated the expression of hetero-nuclear ribonucleoprotein H1 (hnRNPH1), which is known to regulate AR expression and splicing. Although DMSO exposure showed a dose- and time-dependent effect on reactive oxygen species (ROS) production by PC cells, the AR-suppressive effect of DMSO was not altered by the antioxidant n-acetyl cysteine (NAC). Furthermore, although DMSO did not affect cell viability at these clinically-achievable concentrations, a significant (p&lt;0.01) decrease in the migratory ability of both CRPC cell lines was clearly evident. Our novel findings indicate that safe doses of DMSO may be used to decrease AR expression and metastatic ability in CRPC cells.
Citation Format: Namrata Khurana, Hogyoung Kim, Talal Khan, Shohreh Kahhal, Amar Bukvic, Asim B. Abdel-Mageed, Suresh C. Sikka, Debasis Mondal. Low dose dimethyl sulfoxide (DMSO) downregulates the expression of androgen receptor (AR) and AR-variant 7 (AR-v7) in castration resistant prostate cancer (CRPC) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2446.
Abstract 2448: Mmp-2 facilitates prostate cancer entry into and exit from dormancy
Authors: Nasr Mostafa 
Published: June 2022

Abstract
Prostate cancer (PC) patients often relapse with skeletal metastases years after remission. This is attributed to the dormancy program acquired by disseminated tumor cells (DTCs) in the bone microenvironment. Understanding the molecular mechanisms driving dormancy & reawakening (D&R) can reveal novel therapeutic opportunities. Matrix metalloproteinases (MMPs) are involved in each step of the metastatic cascade. Recent studies have shown upregulation of MMP-2 expression in D&R. To determine whether MMP-2 plays a causal role, we initially developed a model representing dormancy in PC cell lines using basal growth conditions and high seeding density. The generated dormant cells (D-Cs) formed clusters and had negative expression of Ki-67 (98% of cells, p = 0.007), Low ERK/P38 activity ratio (p = 0.002), and higher percentage of G0/G1 arrested cells (p = 0.0004). The clusters can remain dormant and viable even after long-term culture (&gt;28 days). We observed that D-Cs can reawaken in-vitro by re-introducing serum-containing media. Next, we assessed MMP-2 expression in D-Cs and reawakened cells. We found MMP-2 expressed during entry into dormancy but highly upregulated during reawakening. Using a siRNA approach, we found that MMP-2 silencing prevented entry into dormancy by significantly inhibiting cluster formation and survival. To determine the role of MMP-2 in reawakening, we used a pharmacological approach due to the temporal nature of MMP-2 silencing by siRNA. Using a highly selective bisphosphonate-based MMP-2 inhibitor (ML115), we found that blocking MMP-2 activity prevented the reawakening of prostate cancer cells without impacting cell viability at 1µM as assessed by caspase-3 cleavage via immunoblotting. In conclusion, we developed an in-vitro PC-specific model for dormancy & reawakening. We found MMP-2 to be key for controlling entry and exit from dormancy in-vitro. We are currently elucidating the mechanisms through which MMP-2 mediates these effects. We also posit that our selective bone-targeting MMP-2 inhibitor may be effective in blocking the reawakening of dormant cells in-vivo.
Citation Format: Mostafa Nasr. Mmp-2 facilitates prostate cancer entry into and exit from dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2448.
Abstract 2535: Omental preadipocytes support ovarian cancer tumorigenesis by mediating genes important for extracellular matrix reorganization
Authors: Waters Jennifer A. , Robinson Mikella , Gilbert Samuel F. , Urbano Ixchel , House Carrie D. 
Published: June 2022

Abstract
Ovarian cancer is the most lethal gynecological malignancy in the United States, with a known predilection for metastasizing to the omentum, a sheet of fatty tissue that encloses the abdomen. While it has been shown that ovarian cancer cells invade towards mature adipocytes in vitro, the contribution of stromal cells that reside in the omentum is not well understood. We hypothesize that preadipocytes, the precursor cells that give rise to omental adipocytes, are important mediators of cancer progression in the omental tumor microenvironment as they have a pro-inflammatory secretome that is distinct from that of mature adipocytes. To evaluate this hypothesis, we tested whether preadipocyte secreted factors altered tumorgenicity of ovarian cancer cells using colony formation and cell viability in vitro and a limiting dilution in vivo in a subcutaneous mouse model. The mouse studies showed that low dilutions of cancer cells require preadipocytes for engraftment and tumor formation. A transplantation assay showed that cancer cells require the presence of preadipocytes for sustained tumor formation capacity. In vitro co-culture assays revealed that preadipocytes secrete factors that increase clonogenicity and extend cell viability in serum-free conditions. To identify signaling pathways induced by preadipocytes we co-cultured cancer cells with either primary human omental preadipocytes or differentiated mature adipocytes derived from the same female donor and performed RNA sequencing and gene set enrichment analysis (GSEA). We identified differentially expressed genes in cancer cells that were unique to preadipocyte co-culture, including DCN, MMP2, COL6A2 and COL12A1, genes involved in extracellular matrix organization. The most significantly upregulated gene was insulin-like growth factor binding protein 5 (IGFBP5), which has functions in insulin-like growth factor signaling and ECM interactions. Ongoing studies using CRISPR edited cancer cells suggest IGFBP5 mediates the enhanced tumorigenesis of cancer cells in the presence of preadipocytes. Our findings highlight the role of preadipocytes in the ovarian tumor microenvironment and implicate IGFBP5 as a preadipocyte-mediated gene. Future studies will determine if there is a link between the upregulation of IGFBP5 and modulation of extracellular matrix proteins that promote cancer progression. Understanding these processes will enable the design of more effective therapies for treating ovarian cancer.
Citation Format: Jennifer A. Waters, Mikella Robinson, Samuel F. Gilbert, Ixchel Urbano, Carrie D. House. Omental preadipocytes support ovarian cancer tumorigenesis by mediating genes important for extracellular matrix reorganization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2535.
Abstract 2555: Immunophenotyping early stage lung adenocarcinomas (LUAD) by histologic subtype
Authors: Xi Zhanhao , Pfefferkorn Roxana , Burks Eric , Beane Jennifer , Mazzilli Sarah 
Published: June 2022

Abstract
The immune microenvironment is thought to influence Lung Adenocarcinoma (LUAD) subtype formation, disease progression, and thus patient outcome. Despite recent advancements in screening, immunotherapy, and targeted therapy, the biology of aggressive LUAD is still poorly understood, and in-depth characterization associated with LUAD histologic subtypes and progression are needed. In this study, we sought to measure the immune environment associated with different LUAD subtypes using Imaging Mass Cytometry (IMC). IMC has emerged as a powerful new tool that enables the multiplex imaging of more than 50 markers simultaneously, quantify multiple protein expressions at a single cell level, and preserve tissue spatial information. We stained a tissue microarray of early stage LUAD patient samples, representing different LUAD subtypes, with a panel of 21 antibodies. These antibodies are designed to phenotype immune cell subsets, as well as using Ki67 to stain for highly proliferative epithelial cells. This will allow us to better understand how different immune cells are interacting with each other, as well as how they interact with highly proliferating epithelial cells. The resulting ablated samples generate images containing antibody intensity and coordinates, which we then perform cell segmentation to generate single cell data. The marker expression is then quantified, and single cell data analyzed using HistoCAT. Cell neighborhood interactions are analyzed based on spatial relationships, and similarly interacting cells are grouped into phenoclusters. Our results suggest that a Ki67 high phenocluster within solid LUAD subtypes have fewer macrophages (CD68, CD163) and T cell populations (CD8, CD4, FOXP3), however, are enriched for plasma B cells (CD20) and immune suppressive populations (PD1, PDL1). In contrast, a Ki67 high cluster within lepidic subtypes are enriched for of macrophage (CD68) and T cell populations (CD8, CD4, FOXP3). Using IMC, we have begun to identify immune subset shifts in LUAD. This early analysis of LUAD using IMC begins to shed light on the immune regulation that may indicate progression and/or guide intervention approaches.
Citation Format: Zhanhao Xi, Roxana Pfefferkorn, Eric Burks, Jennifer Beane, Sarah Mazzilli. Immunophenotyping early stage lung adenocarcinomas (LUAD) by histologic subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2555.
Abstract 2556: The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin
Authors: Sulsenti Roberta , Frossi Barbara , Cancila Valeria , Enriquez Claudia , Ferri Renata , Sangaletti Sabina , Tripodo Claudio , Pucillo Carlo Emilio , Colombo Mario Paolo , Jachetti Elena 
Published: June 2022

Abstract
Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de novo NEPC can rarely occur in treatment-naïve patients. Treatment-related and de-novo NEPC have different genomic alterations but share a common transcriptional profile. Investigating the tumor microenvironment, we recently found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favoring its growth, whereas are excluded by de-novo NEPC both in patients and in the transgenic TRAMP spontaneous mouse model. TRAMP mice backcrossed with MCs-deficient KitWsh mice showed increased frequency of de-novo NEPC. The frequency of de-novo NEPC similarly raised also in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting KitWsh-TRAMP mice with wild type, but not with OPN-deficient, MCs lowered the frequency of NEPC to that of untreated TRAMP mice. We found that MCs stain positive for OPN in tumor sections and in vitro cultures, but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signaling downstream toll-like receptors (TLRs). In vitro, wild type, but not OPN-/- or MyD88-/-, MCs inhibited the proliferation of NEPC cells. Also, in silico analyses showed that genes related to inflammatory response and TLRs signaling are down regulated in human and murine NEPC.Our data suggest that TLRs/MyD88/iOPN-mediated pathways induce MCs to release factor(s) able to restrain NEPC. Further studies are required to molecularly dissect this novel function of MCs, to identify actionable targets against NEPC.
Citation Format: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti. The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2556.
Abstract 2581: IL-15 expressing MSCs for NK cell-mediatedcancer immunotherapy
Authors: Sehgal Drishti , Shanas No'ad , Prabha Swayam 
Published: June 2022

Abstract
Mesenchymal stem cells (MSCs) offer the possibility of achieving highly selective, tumor-targeted drug delivery because of their ability to home to malignant tissues. IL-15 is currently in clinical trial either alone or as an adjuvant for certain types of metastatic solid tumors. Systemic administration of IL-15 is associated with severe toxicities including hemodynamic imbalance, lymphopenia, and other cytokine-related complications. We hypothesized that tumor targeted delivery of IL-15 using MSCs can  improve efficacy and reduce toxicity  associated with IL-15.  MSCs were engineered to express IL-15 using a lentiviral system (pLenti-C-Myc-DDK-P2A-Puro vector; Invitrogen) tagged with C-terminal MYC/DDK tag for easy detection and purification with anti-DDK antibody. We achieved stable transfection of IL-15 in MSCs (5.7 ng/106 MSCs in 24 hrs; ELISA). Bioactivity of secreted IL-15 was confirmed by splenocyte proliferation assay. We then tested the anticancer activity of IL-15 secreting MSCs in a syngeneic LL/2 lung cancer model. Animals treated with IL-15 secreting MSCs demonstrated significant inhibition of tumor growth and prolonged survival compared to mice treated with IL-15 alone. It was further demonstrated that IL-15 expressing MSCs enhance tumor infiltration of various immune cells. These studies demonstrate the potential of developing novel MSC-based immunotherapy constructs with reduced toxicity.
Citation Format: Drishti Sehgal, No'ad Shanas, Swayam Prabha. IL-15 expressing MSCs for NK cell-mediatedcancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2581.
Abstract 2601: Concomitant treatment of ovarian cell lines with Tumor Treating Fields (TTFields) and PARP inhibitors
Authors: Martinez-Conde Antonia , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: June 2022

Abstract
Background: PARP inhibitors (PARPi) are an effective treatment option for ovarian cancer patients harboring deleterious BRCA mutations. While such mutations prevail in one third of ovarian cancer patients, most of the other patients gain little survival benefit by the use of PARPi. Tumor Treating Fields (TTFields) are alternating electric fields with antimitotic effects on cancerous cells, also shown to induce a state of BRCAness in several types of cancer cell lines. The current study aimed to explore the potential of combining TTFields with PARP inhibition for the treatment of ovarian cancer in vitro.
Methods: Ovarian carcinoma cells A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 deep deletion) were treated with TTFields using the inovitro system. Treatment was applied for 72 h at an intensity of 1.2 V/cm RMS and frequency of 200 kHz. The efficacy of concomitant application of TTFields with the PARP inhibitors niraparib and olaparib was examined via measurements of cell survival, colony forming ability, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction.
Results: A2780 or OVCAR3 cells treated with TTFields displayed about 50% reduction in cell counts. Co-application of TTFields with PARPi enhanced the cytotoxic effect compared to that demonstrated by TTFields or PARPi alone. Concomitant application also resulted in reduced clonogenicity, enhanced overall effect, and increased apoptosis.
Conclusions: The results suggest potential benefits for TTFields concomitant with PARP inhibiting agents for treatment of ovarian cancer.
Citation Format: Antonia Martinez-Conde, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Concomitant treatment of ovarian cell lines with Tumor Treating Fields (TTFields) and PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2601.
Abstract 2634: Vasoactive intestinal polypeptide (VIP) regulates ZEB1 expression in cancer
Authors: Rao Ishani H. , Dhamsania Rohan , Waller Edmund K. , Chandrasekaran Sanjay 
Published: June 2022

Abstract
Background: In cancer immunology, VIP is a neuropeptide with pleiotropic effects that include inhibiting T cell activation, increasing Treg frequency, and augmenting the myeloid-derived suppressor cells function. VIP expression by cancer may represent a paracrine immune-checkpoint pathway while simultaneously having autocrine effects on cancer growth. We used an in silico model to identify genes whose over-expression in cancer was correlated with VIP expression and confirmed the role of VIP receptor (VIPR) signaling in vitro using VIPR inhibitors.
Methods: The TCGA PanCan dataset (UCSC Xena) was used to compare mRNA expression data of VIP versus 760 genes involved in 48 cancer related pathways. Associations by cancer histology and germ layer were calculated. A Pearson’s Coefficient cutoff of R &gt; [0.3] defined a significant gene association. VIP and target gene expression were confirmed and quantified by western blot analysis in cancer cell lines and VIPR signaling was inhibited using ANT008, a novel VIPR inhibitor.
Results: Significant associations were observed between VIP expression and 10 genes (Table 1). Strong associations (R &gt; [0.4]) were observed in cancers derived from ectodermal and mesodermal germ layers. The strongest gene association was for VIP and ZEB1 in stomach adenocarcinoma (STAD, R = 0.7643). In vitro experiments using Jurkat T cells confirmed expression of VIP and ZEB1 proteins. Treatment with the VIPR inhibitor ANT008 (10μM) reduced VIP and ZEB1 protein expression by 50%. A similar fold increase in ZEB1 expression was observed with exogenous VIP. PCR studies are currently underway.
Conclusions: The results demonstrate autocrine signaling between VIP expression and cancer associated gene pathways. ZEB1 is a known EMT (epithelial mesenchymal transition) regulator, and our in vitro studies novelly link VIP to EMT and demonstrate that this pathway is therapeutically targetable using a VIPR inhibitor. Further studies in the pertinent tumor histologies are warranted.
Table 1. Genes All Samples Ectoderm (All) Mesoderm (All) Endoderm (All) MAPK3 0.3120 0.3537 0.2252 0.3380 ZEB1 0.3621 0.4341 0.4901 0.3348 NOS2 0.3611 0.3186 0.4849 0.3428 TEK 0.3113 0.3336 0.5131 0.2600 PTCH1 0.3031 0.4040 -0.0061 0.2879 EI4G1 -0.3216 -0.4268 -0.3779 -0.2064 GMPS -0.3074 -0.4698 -0.3005 -0.0928 CDK2 -0.3186 -0.4687 -0.2345 -0.0563 RUVBL1 -0.3135 -0.3270 -0.4716 -0.1886 TIMELESS -0.3036 -0.4284 -0.3717 -0.1505
Citation Format: Ishani H. Rao, Rohan Dhamsania, Edmund K. Waller, Sanjay Chandrasekaran. Vasoactive intestinal polypeptide (VIP) regulates ZEB1 expression in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2634.