tbuckley/cabot-search huggingface dataset:
Abstract 1265: Comparison of mortality- vs. stage-based endpoints in randomized trials of cancer screening: A systematic review with implications for multi-cancer screening trials
Authors: Xiaoshuang Feng, Hana Zahed, Justina Onwuka, Mattias Johansson, Ruth Etzioni, Matthew E. Callister, Hilary A. Robbins
Journal: Cancer Research (2024)

Abstract Background: Randomized controlled trials (RCTs) assessing the endpoint of late-stage cancer incidence, rather than the gold-standard of cancer-specific mortality, are proposed for evaluation of multi-cancer early detection tests. Methods: We conducted a systematic review to assess whether stage-based endpoints can provide a valid alternative for mortality-based endpoints (registration: PROSPERO CRD42023411132). We searched PubMed to identify RCTs of cancer screening interventions published in English before January 20, 2023. Inclusion required that RCTs report, by study arm, numbers of cancer-specific deaths and cancer cases distinguishable between stages I-II vs. III-IV. Data extraction was done by 2 separate reviewers and included the numbers of cancer cases, deaths, and participants by study arm. For each trial, we calculated the percentage reduction in the cumulative (a) late-stage cancer incidence and (b) cancer-specific mortality between the intervention and control arms. We compared these two endpoints based on Pearson correlation coefficients, fixed-effects meta-analysis, and binary statistical significance. Results: We analyzed 41 trials ranging in size from 2,500 to 409,000 participants. Correlation between the reduction in cancer-specific mortality vs. stage III-IV cancer was strong for lung (Pearson’s ρ=0.92, n=12), breast (ρ=0.70, n=6), and ‘other’ cancers (ρ=0.69, n=8) but weak for colorectal (ρ=0.39, n=11) and prostate cancers (ρ&amp;lt;0, n=4). The overall correlation by fixed-effects meta-analysis across cancer types was 0.71 (95%CI=0.47-0.86) (I2=0.55). In larger trials, there was a smaller deviation between the observed reduction in cancer-specific mortality and that predicted, by cancer type, based on the trial’s reduction in stage III-IV cancer (p=0.02). Of 12 trials demonstrating a statistically significant reduction in stage III-IV cancer incidence (p&amp;lt;0.05), 5 also showed reduced cancer-specific mortality (42%). Conclusions: In screening RCTs, reductions in late-stage cancer vs. cancer-specific mortality are correlated, but with important differences by cancer type. Screening interventions that reduce late-stage cancer incidence do not necessarily reduce cancer-specific mortality. Citation Format: Xiaoshuang Feng, Hana Zahed, Justina Onwuka, Mattias Johansson, Ruth Etzioni, Matthew E. Callister, Hilary A. Robbins. Comparison of mortality- vs. stage-based endpoints in randomized trials of cancer screening: A systematic review with implications for multi-cancer screening trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1265.
Abstract 1354: Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1
Authors: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J. Mancuso, Didem Ağaç Çobanoğlu, James P. Allison
Journal: Cancer Research (2024)

Abstract Distinct effects on T-cell differentiation arise from immune checkpoint inhibition targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1). However, the effect of these immunotherapies on the immunological memory response remains unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T-cell formation in mice revealed that anti-CTLA-4 generates a more effective memory antitumor response than anti-PD-1. Memory T-cells arising after anti-CTLA-4 treatment exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more TCF-1+ T-cells during priming, while anti-PD-1 leads to more TOX+ T-cells. Experiments using conditional TCF-1- or TOX-knockout mice highlight TCF-1 is essential for memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system. Citation Format: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J. Mancuso, Didem Ağaç Çobanoğlu, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1354.
Abstract 1555: Nuclear accumulation of cell surface programmed cell death ligand 1 promotes metastatic outgrowth in triple-negative breast cancer cells
Authors: Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Kenichi Yamamoto, Hitoshi Murata, Masakiyo Sakaguchi
Journal: Cancer Research (2024)

Abstract PD-L1 presented on the cancer cell surface is well known for its role in immune checkpoint regulation by interacting with PD-1 on immune cells. On the other hand, it has been reported that PD-L1 is localized in the cancer cells’ nuclei, where the nuclear PD-L1 (nPD-L1) is conducive to cancer outgrowth and motility. However, there has yet to be reported about the mechanistic insight into the event. In this study, we, therefore, aimed to clarify still unidentified points in the nPD-L1-mediated event. Our efforts revealed that the upregulation is induced by a functional suppression of nuclear protein X (tentative name), which we identified as a novel binding protein with nPD-L1 at its cytoplasmic tail. Their nuclear interaction also abolished an aggressive cancer proclivity, epithelial-mesenchymal transition (EMT). The mechanism is helpful to the complex nature of PD-L1 in plural cancer cell behaviors. Citation Format: Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Kenichi Yamamoto, Hitoshi Murata, Masakiyo Sakaguchi. Nuclear accumulation of cell surface programmed cell death ligand 1 promotes metastatic outgrowth in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1555.
Abstract 1552: Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from <i>SNHG1</i> upregulation
Authors: Chuanshu Huang, Tengda Li, Honglei Jin
Journal: Cancer Research (2024)

Abstract hosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive. In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary basal muscle invasive BC (BMIBC) accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN poly-ubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorage-independent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice.Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation. Citation Format: Chuanshu Huang, Tengda Li, Honglei Jin. Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1552.
Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis
Authors: Fieke W. Hoff, Rahul Banerjee, Adeel M. Khan, Georgia McCaughan, Bo Wang, Xiaoliang Wang, James Roose, Larry D. Anderson, Andrew J. Cowan, S. Vincent Rajkumar, Gurbakhash Kaur
Journal: Blood Cancer Journal (2024)

Abstract Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18–70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p &lt; 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.
Abstract 1561: Identification of tumor-associated macrophages promoting early-stage metastasis during peritoneal dissemination in gastric cancer
Authors: Wataru Kawase, Yukihiko Hiroshima, Itaru Hashimoto, Shizune Onuma, Mitsuhiro Furuta, Nozomu Machida, Takashi Oshima, Yohei Miyagi
Journal: Cancer Research (2024)

Abstract Peritoneal dissemination (PD) is the most frequent metastasis pattern in gastric cancer (GC) and is a significant predictor of poor prognosis. However, the mechanisms underlying PD formation remain unclear, and a PD-specific signature has not been identified. PD development is thought to be influenced by various changes occurring in GC tumor cells and immune cells present in the peritoneal cavity. We previously performed RNA-seq analysis of cell components in cytology-positive (CY1) gastric cancer ascites. The results suggested that tumor-associated macrophages (TAMs) infiltrate the abdominal cavity together with GC tumor cells and might be involved in PD development. In this study, we aimed to identify the specific TAMs responsible for promoting metastasis during the early stage of PD in GC. We demonstrated the abundant presence of TAMs in CY1 GC ascites using flow cytometry analysis and identified several genes that were significantly expressed in CY1 TAMs using single-cell RNA-seq analysis. Furthermore, we evaluated the potential of these genes to serve as therapeutic targets for the treatment of PD in GC. Citation Format: Wataru Kawase, Yukihiko Hiroshima, Itaru Hashimoto, Shizune Onuma, Mitsuhiro Furuta, Nozomu Machida, Takashi Oshima, Yohei Miyagi. Identification of tumor-associated macrophages promoting early-stage metastasis during peritoneal dissemination in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1561.
Abstract 1556: AMIGO2 is associated with the peritoneal dissemination in serous ovarian cancer by enhancing its adhesion to peritoneal mesothelial cells
Authors: Yuki Iida, Shinya Sato, Koji Yamamoto, Kohei Hikino, Masayo Okawa, Masayo Hosokawa, Mayumi Sawada, Hiroaki Komatsu, Akiko Kudoh, Hee Kyung Seong, Runa Izutsu, Mitsuhiko Osaki, Futoshi Okada, Fuminori Taniguchi
Journal: Cancer Research (2024)

Abstract Amphoterin-induced gene and open reading frame 2 (AMIGO2) has been associated with the prognosis of colorectal, gastric, and cervical cancer. However, its relationship with ovarian cancer remains unclear. This study aimed to clarify the role of AMIGO2 in ovarian cancer. The research involved evaluating AMIGO2 expression in patients with ovarian serous carcinoma using immunohistochemistry. The AMIGO2-high group exhibited significantly shorter progression-free survival (PFS) compared to the AMIGO2-low group. The predictive index of the AMIGO2-high group was considerably higher than that of the AMIGO2-low group. The rate of complete cytoreductive surgery was lower in the AMIGO2-high group than in the AMIGO2-low group. Furthermore, in vitro studies showed that four serous ovarian cancer cell lines expressed AMIGO2 expression and adhesion to mesothelial cells. Adhesion to mesothelial cells was attenuated by AMIGO2 knockdown in SKOV3 cells. Moreover, in a murine model, AMIGO2 downregulation in SKOV3 cells significantly suppressed peritoneal dissemination. These findings suggest that high AMIGO2 expression in serous ovarian carcinoma cells contributes to a poor prognosis by promoting peritoneal metastasis through enhanced cell adhesion to mesothelial cells. Citation Format: Yuki Iida, Shinya Sato, Koji Yamamoto, Kohei Hikino, Masayo Okawa, Masayo Hosokawa, Mayumi Sawada, Hiroaki Komatsu, Akiko Kudoh, Hee Kyung Seong, Runa Izutsu, Mitsuhiko Osaki, Futoshi Okada, Fuminori Taniguchi. AMIGO2 is associated with the peritoneal dissemination in serous ovarian cancer by enhancing its adhesion to peritoneal mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1556.
Abstract 1442: Establishing a papillary renal cell carcinoma mouse model with activating Met mutation
Authors: Preet Lal, Li Ding, Feng Chen
Journal: Cancer Research (2024)

Abstract Renal cell carcinoma (RCC) is a heterogeneous group of cancers of the nephron. Papillary renal cell carcinoma (PRCC) is the second most common type of RCC. c-Met activating mutations have been associated with Type 1 PRCC which are made up of small cells containing basophilic cytoplasm covering papillae and tubular structures. In patients with PRCC, c-MetH1112Y missense mutations are associated with both somatic and germline mutations. Previous functional studies indicate codon H1112 plays an important structural role in maintaining c-Met in the inactive conformation and alterations at this codon, including H1112Y, likely disrupt this interaction facilitating constitutive activation with increased c-MET activity. A c-MetH1112Y (c-MetHY) transgene with tetO promoter sequence was micro-injected into the mouse oocyte. Transgenic mice carrying this transgene have the ability to express this activated Met protein in cells expressing rtTA (reverse tetracycline-controlled transactivator) and when doxycycline is present. Mutant mice harboring this transgene along with additional trp53 mutations showed glomeruloid like Type 1 PRCC. Our in vivo studies confirmed the expression of c-MetHY gene within the kidney and Lrp2 and Ki67 staining indicated that PRCC arises from PT (proximal tubule). PRCC canonical markers CK7, AMACR and MET expression confirmed the Type1 PRCC in our mouse model. Additionally Pan-CK, E-Cad positive expression in mutant mice further confirmed PRCC arises from epithelial cells. We have generated and described type 1 PRCC mouse model with activating-MetHY mutation. This mouse model will help illustrate the oncogenic mechanism of Met activation and identify the critical events during progression of PRCC. Citation Format: Preet Lal, Li Ding, Feng Chen. Establishing a papillary renal cell carcinoma mouse model with activating Met mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1442.
Abstract 1693: Mitochondrial-associated DNAJA3 variant and its role in NASH-driven hepatocellular carcinoma
Authors: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang
Journal: Cancer Research (2024)

Abstract Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major risk factor for hepatocellular carcinoma (HCC). Despite the known progression from NAFLD to nonalcoholic steatohepatitis (NASH) and eventually HCC, the genetic underpinnings driving this transition remain underexplored. A comprehensive genomics assessment was conducted, encompassing a genome-wide study of variants linked to body fat distribution in 344,369 individuals. Correlating these, significant variants associated with NASH and HCC were discerned in a cohort of 1,009 participants from the NCI-UMD study. Candidate variants underwent further eQTL analysis. Our investigation unveiled the rs3747579-TT variant emerged as significantly associated with NASH-related HCC, serving as an eQTL for mitochondrial DNAJA3. HCC patients harboring this variant presented with diminished DNAJA3 expression, correlating with an unfavorable prognosis. Exploration into the 3D genome architecture has identified potential chromatin topology sites that may influence the regulation of DNAJA3 by rs3747579. Specifically, enhancer loops exhibit allele-specific interactions with rs3747579 in the regulation of DNAJA3. Notably, the rs3747579-CC variant was found to interact with RBFOX2. Beyond its known RNA splicing functions, RBFOX2 might have implications in the chromatin landscape, influencing chromatin dynamics and gene transcription. RBFOX2 knockdown experiments showcased significantly reduced DNAJA3 expression, and luciferase assays highlighted increased activity for the rs3747579-CC allele versus its TT counterpart. In summary, our findings spotlight the rs3747579-TT variant as a potential oncogenic factor in DNAJA3, elucidating its role in the genesis of NASH and progression to HCC. This understanding could pave the way for novel therapeutic interventions in HCC stemming from NAFLD/NASH. Citation Format: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang. Mitochondrial-associated DNAJA3 variant and its role in NASH-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1693.
Abstract 829: Phthalate exposure results in circadian rhythm-induced BBB dysfunction increasing the risk for breast cancer brain metastasis
Authors: Destiny Tiburcio, Sarah Adolphe, Ijeoma B. Akpu, Timea Teglas, Oandy Naranjo, Sophia H. George, Michal J. Toborek
Journal: Cancer Research (2024)

Abstract Phthalates, classified as plasticizers, represent a group of chemicals pervasive in the general U.S. population, with notably higher levels in non-Hispanic Blacks compared to non-Hispanic Whites. These persistent organic pollutants (POPs) have been identified for their impact on the circadian rhythms of the brain and vascular system. Several studies indicate that phthalates can elevate neuroinflammation and reduce levels of the junctional protein ZO-1 in the hypothalamus, home to the master circadian clock known as the suprachiasmatic nucleus (SCN). The SCN regulates cellular and tissue circadian rhythms, including tight junction proteins essential for the blood-brain barrier's (BBB) main barrier function. Interestingly, experimental studies reveal that prolonged chronic circadian rhythm disruption (CRD) in mice leads to increased breast cancer metastasis. However, the effects of phthalates on CRD concerning brain cancer and metastasis remain poorly understood. Given their significant prevalence and biological impact, we hypothesize that phthalate exposure induces CRD through hypothalamic dysregulation, resulting in BBB dysfunction and an elevated risk of brain metastasis. Results. We developed an in vitro BBB model using endothelial cells and exposed them to an environmentally relevant mixture of five phthalates simulating chronic low-grade exposure. Analysis showed dysregulation of critical clock genes (Bmal1 and Clock), along with a substantial decrease in BBB tight junction proteins (claudin-5 and occludin) at the protein and mRNA levels. The tumor trans-endothelial migration assay using breast adenocarcinoma cells along with endothelial cells demonstrated an increased metastatic potential following phthalate exposure. Conclusion. These findings offer crucial insights into the molecular mechanisms underlying phthalate exposure, suggesting potential targets for future brain metastasis treatments. Additionally, they hold implications for the future regulation and management of phthalate usage and policy. This work was supported by the University of Miami U-LINK Resilience Challenge grant. Citation Format: Destiny Tiburcio, Sarah Adolphe, Ijeoma B. Akpu, Timea Teglas, Oandy Naranjo, Sophia H. George, Michal J. Toborek. Phthalate exposure results in circadian rhythm-induced BBB dysfunction increasing the risk for breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 829.