tbuckley/cabot-search huggingface dataset:
Abstract 838: Sugar-sweetened beverage intake and risk of early-onset colorectal cancer
Authors: Jinhee Hur, Ebunoluwa Otegbeye, Hee-Kyung Joh, Katharina Nimptsch, Kimmie Ng, Shuji Ogino, Jeffrey A. Meyerhardt, Andrew T. Chan, Walter C. Willett, Kana Wu, Edward Giovannucci, Yin Cao
Journal: Cancer Research (2021)

Abstract Background: The incidence of early-onset colorectal cancer (EO-CRC) diagnosed under age 50 continues to rise, and the pattern shows a strong birth cohort effect. Sugar-sweetened beverage (SSB) consumption had substantially increased across successive birth cohorts until 2000, and the population under age 50 has the highest level of consumption. Despite the well-documented, adverse metabolic effects of SSBs, their link with EO-CRC remains unexamined. Methods: In the Nurses' Health Study II, consisting of US female registered nurses aged 25-42 in 1989, we prospectively investigated the association between SSB intake and risk of EO-CRC. A total of 95,621 women who had reported beverage intake using validated food frequency questionnaires every 4 years since 1991 were followed up through June 2015. Cox proportional hazards models were used to estimate relative risks (RRs) with 95% confidence intervals (CIs). Results: We documented 109 EO-CRC cases over up to 24 years of follow-up (1,358,158 person-years). SSB consumption was associated with a higher risk of EO-CRC. Compared with individuals who consumed &amp;lt;1 serving/week of SSBs, women who consumed ≥2 servings/day had a more than doubled risk of EO-CRC (RR, 2.18; 95% CI, 1.10-4.35; P for trend=0.02). Each additional serving/day of SSB consumption was associated with a 16% higher risk of EO-CRC (RR, 1.16; 95% CI, 1.00-1.36). Replacing each serving/day of SSB intake with that of artificially sweetened beverages, coffee, reduced fat milk, or total milk was associated with a 17-36% lower risk of EO-CRC. Conclusion: Higher SSB intake was associated with a higher risk of EO-CRC among women. Reduction of SSB consumption among young adults may serve as a potential strategy to alleviate the growing burden of EO-CRC. Citation Format: Jinhee Hur, Ebunoluwa Otegbeye, Hee-Kyung Joh, Katharina Nimptsch, Kimmie Ng, Shuji Ogino, Jeffrey A. Meyerhardt, Andrew T. Chan, Walter C. Willett, Kana Wu, Edward Giovannucci, Yin Cao. Sugar-sweetened beverage intake and risk of early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 838.
Central and peripheral sympathetic activation in heart failure
Authors: Guido Grassi, Giuseppe Mancia, Murray Esler
Journal: Cardiovascular Research (2021)

The sympathetic nervous system overdrive occurring in heart failure has been reported for more than half a century. Refinements in the methodological approaches to assess human sympathetic neural function have allowed during recent years to better define various aspects related to the neuroadrenergic alteration. These include (i) the different participation of the individual regional sympathetic cardiovascular districts at the process, (ii) the role of the central nervous system in determining the neuroadrenergic overdrive, (iii) the involvement of baroreflex, cardiopulmonary reflex, and chemoreflex mechanisms in the phenomenon, which is also closely linked to inflammation and the immune reaction, (iv) the relationships with the severity of the disease, its ischaemic or idiopathic nature and the preserved or reduced left ventricular ejection fraction, and (v) the adverse functional and structural impact of the sympathetic activation on cardiovascular organs, such as the brain, the heart, and the kidneys. Information have been also gained on the active role exerted by the sympathetic activation on the disease outcome and its potential relevance as a target of the therapeutic interventions based on non-pharmacological, pharmacological, and invasive approaches, including the renal denervation, the splanchnic sympathetic nerve ablation, and the carotid baroreflex stimulation. The still undefined aspects of the neurogenic alterations and the unmet goals of the therapeutic approach having the sympathetic activation as a target of the intervention will be finally mentioned.
Abstract 61: Transient "rest" reinvigorates exhausted CAR T cells via epigenetic remodeling
Authors: Evan W. Weber, Crystal Mackall
Journal: Cancer Research (2021)

Abstract The efficacy of chimeric antigen receptor (CAR) T cell therapy is limited by T cell exhaustion, whereby continuous CAR signaling induces hierarchical loss of effector function. Current methods to mitigate exhaustion in cancer, like immune checkpoint blockade, are not efficacious when combined with CAR T cells. Thus, new therapeutic approaches that target CAR T cell exhaustion are needed. To test the hypothesis that transient cessation of CAR signaling reverses CAR T cell exhaustion, we engineered human T cells to express a drug-regulatable CAR that demonstrates a high degree of antigen-independent tonic signaling and induces hallmarks of exhaustion within 10 days. Using this in vitro model of CAR T cell exhaustion, we discovered that transient CAR downregulation and concomitant cessation of tonic CAR signaling (i.e. “rest”) resulted in profound phenotypic changes, including decreased inhibitory receptor expression and increased memory-associated markers. Upon CAR re-expression and tumor challenge, rested CAR T cells exhibited improved killing, cytokine secretion, and sensitivity to antigen in vitro, as well as enhanced in vivo potency following adoptive transfer into tumor-bearing mice. Similar results were achieved via pharmacologic treatment with the Src kinase inhibitor dasatinib, which potently and reversibly inhibits CAR signaling. RNA- and ATAC-sequencing revealed that rest induces global transcriptional and epigenetic reprogramming, wherein rested CAR T cells closely resembled healthy, non-exhausted CAR T cells. Notably, epigenetic reprogramming and functional reinvigoration in rested cells were dependent on the activity of the histone methyltransferase EZH2, indicating that epigenetic alterations are required for functional reversal of CAR T cell exhaustion. Finally, providing multiple periods of rest in vivo by toggling CAR expression or pulsing with dasatinib reversed hallmarks of CAR T cell exhaustion and lead to more durable anti-tumor responses in xenograft murine models. This work demonstrates that transient cessation of CAR T cell signaling can enhance anti-tumor potency by preventing or reversing exhaustion and challenges the paradigm that exhaustion is an epigenetically fixed state. These results also raise the prospect that targeting proximal TCR/CAR signaling kinases might represent a novel immunotherapeutic strategy for mitigating exhaustion in human CAR T cells. Citation Format: Evan W. Weber, Crystal Mackall. Transient "rest" reinvigorates exhausted CAR T cells via epigenetic remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 61.
Abstract 1867: Characterization in patient derived tumor organoids of novel oncolytic adenoviruses expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitors
Authors: Firas Hamdan, Erkko Ylösmäki, Jacopo Chiaro, Yvonne Giannoula, Maeve Long, Manlio Fusciello, Sara Feola, Beatriz Martins, Michaela Feodoroff, Gabriella Antignani, Otto Kari, Moon Hee Lee, Petrus Järvinen, Harry Nisen, Anna Kreutzman, Satu Mustjoki, Thomas G McWilliams, Mikaela Grönholm, Vincenzo Cerullo
Journal: Cancer Research (2021)

Abstract Despite the success of immune checkpoint inhibitors in the clinic, they only benefit a fraction of patients. A theoretical strategy to increase efficacy would be to enhance such antibodies with Fc-mediated effector mechanisms. Current IgG1 antibodies are excellent activators of natural killer cells yet neglect a crucial effector population, neutrophils. Hence, we designed a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit simultaneously effector mechanisms of an IgG1 but also IgA1, consequently activating neutrophils, in order to combine multiple effector mechanisms. Moreover, to prevent toxicities, these Fc-fusion peptides were cloned in oncolytic adenoviruses whose replication is restricted to the tumor. Our oncolytic adenoviruses were able to selectively infect tumor cells, secrete the cross-hybrid Fc-fusion peptides able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity compared to FDA-approved immune checkpoint inhibitors. We validated this in various human and murine cancer cell lines and also renal cell carcinoma patient derived organoids from four patients. In conclusion, our cross-hybrid Fc-fusion peptides demonstrate that activating multiple immune effector populations increases tumor cytotoxicity potentially leading to improved clinical outcomes. Citation Format: Firas Hamdan, Erkko Ylösmäki, Jacopo Chiaro, Yvonne Giannoula, Maeve Long, Manlio Fusciello, Sara Feola, Beatriz Martins, Michaela Feodoroff, Gabriella Antignani, Otto Kari, Moon Hee Lee, Petrus Järvinen, Harry Nisen, Anna Kreutzman, Satu Mustjoki, Thomas G McWilliams, Mikaela Grönholm, Vincenzo Cerullo. Characterization in patient derived tumor organoids of novel oncolytic adenoviruses expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1867.
Epidemiology and care pathway of vesicovaginal fistulas managed in France between 2010 and 2018
Authors: F. Michel, H. Bensadoun, S. Gaillet, R. Boissier, V. Delaporte, B. Gondran-Tellier, S. Chkir, M. Baboudjian, E. Lechevallier, G. Karsenty
Journal: European Urology (2021)
Abstract 2111: RAD6-mediated epigenetic reprogramming contributes to therapy-induced chemo-resistance in ovarian cancer
Authors: Tasmin Rahman Omy, Shirisha Jonnalagadda, Mark Reedy, Komaraiah Palle
Journal: Cancer Research (2021)

Abstract Epithelial Ovarian Cancer (EOC) is the fifth leading cause of cancer-related deaths in women in the USA, gets diagnosed at an advanced stage (stage III-IV) with local or distant metastasis. The primary therapeutic regimen of EOC involves surgical removal of all the visible tumor mass followed by platinum-based chemotherapy either as a single agent or in combination with a taxane. Despite initial responses, over 70% of EOC patients develop recurrent disease and they are often resistant to available chemotherapeutic drugs, contributing to poor survival. This appalling situation emphasizes the critical need to identify the molecular mechanisms involving recurrence of these tumors' aggressive growth and developing therapeutic resistance. Our analysis from chemo naïve and recurrent tumors from the same patients' samples, and isogenic ovarian cancer cell lines data showed recurrent tumors and resistant cell lines several upregulated cancer stem cell markers including ALDH1A1, SOX2 and altered expression of DNA damage response and repair genes that are involved in the processing of platinum adducts and crosslink repair. Prominently, RAD6, an E2ubiquitin-conjugating enzyme, is significantly (&amp;gt; 6 folds) overexpressed in recurrent ovarian tumors and associated with aggressive tumor cell growth, stemness, chemoresistance to platinum drugs, and poor prognosis. Our studies validated that, chemotherapy induced upregulated RAD6 reprograms epigenetic milieu in tumor cells through ubiquitination of histone variants H2A, H2AX, and H2B, which further recruits additional epigenetic modifiers to these regions and regulates genes involved in DNArepair, cell survival, stemness, and chemoresistance. Additionally, our mechanistic studies demonstrate RAD6 dependent recruitment of several epigenetic modifiers such as histone methylases and demethylases to regions of ubiquitylated histones and their crosstalk. Collectively, our study presents novel chemotherapy induced epigenetic modulator contributing to therapeutic recurrence of EOC and could be an important therapeutic target to treat chemo-resistant EOC and improve the progression-free survival of patients suffering from this deadly disease. Formatted: Right, Indent: Left: 1" Citation Format: Tasmin Rahman Omy, Shirisha Jonnalagadda, Mark Reedy, Komaraiah Palle. RAD6-mediated epigenetic reprogramming contributes to therapy-induced chemo-resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2111.
Is fast-MRI as accurate as multi-parametric MRI in the detection of clinically significant prostate cancer in biopsy naïve men? A prospective, single centre, non-inferiority randomized trial
Authors: M. Manfredi, E. Checcucci, D. Amparore, S. De Cillis, G. Volpi, A. Pecoraro, F. Piramide, A. Piana, M. Sica, S. Granato, J. Meziere, D. Zamengo, G. Cattaneo, F. Russo, S. De Luca, C. Fiori, F. Porpiglia
Journal: European Urology (2021)
Abstract 1972: A novel signaling pathway delays abscission in cytokinesis with chromatin bridges
Authors: Eleni Petsalaki, George Zachos
Journal: Cancer Research (2021)

Abstract Chromatin bridges are strands of missegregated chromatin connecting the anaphase poles or daughter nuclei and have been linked to tumourigenesis. In response to chromatin bridges in cytokinesis, cells delay abscission, the severing of the narrow cytoplasmic canal that connects the two daughter cells, to prevent chromatin breakage or tetraploiudization that are associated with genomic instability and cancer predisposition. In mammalian cells, this abscission delay is called “the abscission checkpoint” and is dependent on the localization and catalytic activity of the Chromosomal Passenger Complex (CPC) at the midbody. The CPC comprises the catalytic subunit Aurora B kinase, the scaffolding protein INCENP and the non-enzymatic subunits Survivin and Borealin; however, the molecular mechanisms that signal chromatin bridges to the CPC have not been previously identified. In the present study, we show that inhibition of the DNA damage kinases ATM or Chk2 impairs CPC-localization to the midbody and correlates with premature abscission and chromatin breakage in cytokinesis with trapped chromatin in human carcinoma cell lines. ATM phosphorylates Chk2-threonine 68 (T68) to activate Chk2 at the midbody. In turn, active Chk2 phosphorylates INCENP at the newly identified site serine 91 (S91) to promote CPC-localization to the midbody, to delay abscission and prevent chromatin breakage. Expression of siRNA-resistant phosphomimetic mutant INCENP-S91D or GFP:INCENP(FB) that is constitutively targeted to the Flemming body (FB), but not WT INCENP, rescues CPC-midbody-localization and prevents chromatin breakage in Chk2-deficient or ATM-deficient cells. In contrast, in the absence of the endogenous INCENP, the non-phosphorylatable mutant INCENP-S91A does not localize to the midbody and its expression promotes chromatin breakage. Furthermore, the Mre11-Rad50-Nbs1 (MRN) complex is required for ATM activation at the midbody. These results identify an MRN-ATM-Chk2-INCENP signaling pathway that prevents chromosome breakage in cytokinesis with chromatin bridges, by promoting CPC-midbody localization. Citation Format: Eleni Petsalaki, George Zachos. A novel signaling pathway delays abscission in cytokinesis with chromatin bridges [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1972.
Three-dimensional virtual modelling for anatomical comprehension of renal anatomy: Validation of CSA, RENAL, PADUA, ABC scores before partial nephrectomy
Authors: L. Bianchi, R. Schiavina, B. Bortolani, L. Cercenelli, F. Chessa, A. Mottaran, M. Droghetti, S. Boschi, C. Gaudiano, A. Rustici, M. Salvador, A. Bertaccini, R. Golfieri, E. Marcelli, E. Brunocilla
Journal: European Urology (2021)
Identification of the best candidates for PSMA PET/CT among patients experiencing biochemical recurrence after radical prostatectomy. A new tool to optimize of Patient Selection
Authors: G. Gandaglia, D. Robesti, N. Fossati, F. Barletta, S. Scuderi, G. Rosiello, A. Necchi, V. Cucchiara, E. Mazzone, U. Capitanio, A. Salonia, A. Larcher, P.I. Karakiewicz, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 2966: Novel ex vivo model for ERα positive breast cancer
Authors: Pauliina M. Munne, Lahja Martikainen, Iiris Räty, Kia Bertula, Nonappa Nonappa, Aino Peura, Minna Mutka, Marjut Leidenius, Tuomo Meretoja, Panu Kovanen, Johanna Mattson, Paivi Heikkila, Heikki Joensuu, Olli Ikkala, Juha T. Klefstrom
Journal: Cancer Research (2021)

Abstract Three-dimensional ex vivo cultures from patient-derived tumor tissue offer new opportunities for drug development and personalized treatment of cancer. However, one of the main challenges in establishing a tumor type faithful ex vivo tissue culture system is in optimization of biochemical and physical microenvironment to preserve desired phenotypic features. A collaboration with the Helsinki University Hospital enables us to receive live patient-derived breast cancer tissue samples from most breast cancer surgeries performed in the Southern Finland, typically samples arriving twice a week. Together with a group of materials scientists from Aalto Technical University we have explored seven different 3D culture matrices and defined their biomechanical properties and stiffness values with rheological measurements. Four investigated matrices preserved the luminal CK8+ cell phenotype of the luminal cancers they derived from, whereas rest of the matrices that included commonly used Matrigel and collagen scaffolds promoted a switch in the cell identity from luminal CK8+ to basal CK14+ phenotype. Furthermore, the genetic expression profiles examined with NGS corresponded to observed phenotypic switch. We noticed significant species-specific differences between mouse mammary and human breast samples in their morphology, phenotypic responses and ERα+ preservation to microenvironmental matrix stiffness. Furthermore, a combination of scaffold stiffness and composition of biochemical matrix constituency is required for long-term maintenance of ERα+ luminal tumour phenotype. Therefore, both physical properties and composition of the microenvironment need to be optimized for maintenance of breast tumor type specific phenotype and genetic profiles of ex vivo tumor explant cultures. Citation Format: Pauliina M. Munne, Lahja Martikainen, Iiris Räty, Kia Bertula, Nonappa Nonappa, Aino Peura, Minna Mutka, Marjut Leidenius, Tuomo Meretoja, Panu Kovanen, Johanna Mattson, Paivi Heikkila, Heikki Joensuu, Olli Ikkala, Juha T. Klefstrom. Novel ex vivo model for ERα positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2966.
Abstract 14834: A Nationwide Survey of the Effects of the Accessibility of Emergency Medical Systems on Cardiovascular Mortality
Authors: Akiko Kada, Naohiro Yonemoto, Hiroyuki Yokoyama, Hiroshi Nonogi, J-Pulse Iii Investigators
Journal: Circulation (2011)

Objective: Rapid emergency cardiovascular care for patients with acute cardiac diseases is necessary for better prognoses, especially with acute myocardial infarctions. To decrease the time until t...
Abstract 1980: Non-canonical regulation and function of anti-apoptotic protein c-FLIP
Authors: Matyas Abel Tsegaye, Kyle McGeehan, Mati Nemera, Zachary T. Schafer
Journal: Cancer Research (2021)

Abstract The metastasis of cancer cells to distant sites accounts for over 90% of cancer related deaths. In order to metastasize, cancer cells must be able to survive during extracellular matrix (ECM) detachment, namely by blocking anoikis (a caspase-dependent cell death) and restoring metabolic deficiencies. Such barriers during tumorigenesis are abrogated through activation of oncogenic signaling, and/or inhibition of tumor suppressors. Elucidating the signaling pathways involved in cancer cell metastasis is a crucial step in designing effective therapeutic interventions. Surprisingly, our investigation has revealed that cellular FLICE-like Inhibitory Protein (c-FLIP), a protein well known for its pro-survival function, instead antagonizes the viability of ECM-detached cancer cells. Additionally, we demonstrated that signaling emanating from oncogenic growth factor receptors results in the downregulation of c-FLIP expression providing additional evidence that cancer cells may benefit from diminished FLIP levels. Interestingly, this repression of c-FLIP expression by activated oncogenes is a consequence of PI3K signaling. Our study also suggests that low c-FLIP levels are beneficial in cancer cells due to capacity of c-FLIP to induce β-catenin degradation. Taken together, our study has revealed an unexpected role for c-FLIP in restricting the viability of tumor cells and raises the idea that the c-FLIP may have context-dependent pro- and anti-cell death roles during tumorigenesis. Citation Format: Matyas Abel Tsegaye, Kyle McGeehan, Mati Nemera, Zachary T. Schafer. Non-canonical regulation and function of anti-apoptotic protein c-FLIP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1980.