bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality after multivessel revascularisation involving the proximal left anterior descending artery
Authors: Ono Masafumi , Hara Hironori , Gao Chao , Kawashima Hideyuki , Wang Rutao , O’Leary Neil , Wykrzykowska Joanna J , Piek Jan J , Mack Michael J , Holmes David , Morice Marie-Claude , Head Stuart , Kappetein Arie Pieter , Noack Thilo , Davierwala Piroze M , Mohr Friedrich W , Garg Scot , Onuma Yoshinobu , Serruys Patrick W 
Published: June 2022

ObjectiveWe sought to investigate whether long-term clinical outcomes differ following percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with three-vessel disease (3VD) and lesions in the proximal left anterior descending artery (P-LAD).MethodsThis post-hoc analysis of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Extended Survival study included patients with 3VD who were classified according to the presence or absence of lesions located in the P-LAD. Ten-year all-cause death and 5-year major adverse cardiac or cerebrovascular events (MACCE) were assessed.ResultsAmong 1088 patients with 3VD, 559 (51.4%) had involvement of P-LAD and their 10-year mortality was numerically higher following PCI versus CABG (28.9% vs 21.9%; HR: 1.39, 95% CI 0.99 to 1.95). Although patients without P-LAD lesions had significantly higher 10-year mortality following PCI compared with CABG, there was no evidence of a treatment-by-subgroup interaction (28.8% vs 20.2%; HR: 1.47, 95% CI 1.03 to 2.09, pinteraction=0.837). The incidence of MACCE at 5 years was significantly higher with PCI than CABG, irrespective of involvement of P-LAD (with P-LAD: HR: 1.86, 95% CI 1.36 to 2.55; without P-LAD: HR: 1.54, 95% CI 1.11 to 2.12; pinteraction=0.408). Individualised assessment using the SYNTAX Score II 2020 established that a quarter of patients with P-LAD lesions had significantly higher mortality with PCI than CABG, whereas in the remaining three-quarters CABG had similar mortality.ConclusionsAmong patients with 3VD, the presence or absence of a P-LAD lesion was not associated with any treatment effect on long-term outcomes following PCI or CABG.Trial registration numberSYNTAXES:NCT03417050; SYNTAX:NCT00114972.
BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma
Authors: Kremenovic Mirela , Chan Alfred A , Feng Bing , Bäriswyl Lukas , Robatel Steve , Gruber Thomas , Tang Li , Lee Delphine J , Schenk Mirjam 
Published: June 2022

BackgroundThe use of intralesionalMycobacterium bovisBCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival.MethodsWe generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8+T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed.ResultsHere, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8+T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival.ConclusionsThese findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.
Use of intravenous cangrelor in the treatment of ruptured and unruptured cerebral aneurysms: an updated single-center analysis and pooled analysis of current studies
Authors: Entezami Pouya , Dalfino John C , Boulos Alan S , Yamamoto Junichi , Holden Devin N , Field Nicholas C , Rock Andrew K , Najera Edinson , Paul Alexandra R 
Published: June 2022

BackgroundIntracranial stent placement for the treatment of cerebral aneurysms is increasingly utilized in both ruptured and unruptured scenarios. Intravenous (IV) cangrelor is a relatively new antiplatelet agent that was initially approved for coronary interventions. In addition to our institution, five other centers have published their results using IV cangrelor in neurointerventional procedures. This article combines the aneurysm treatment data from all prior studies to provide insight into the safety and efficacy of cangrelor for intracranial aneurysm treatment.MethodsA prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during aneurysm embolization. 20 additional patients were identified who had not been previously published. In addition, a literature search was performed to identify prior publications regarding cangrelor in neurointervention. The data from these were combined with our institutional results in a pooled-analysis.ResultsOverall, 85 patients who received IV cangrelor during aneurysm embolization were identified, including 46 ruptured and 39 unruptured cases. The asymptomatic and symptomatic intracranial hemorrhage rates were 4% (2/46) for ruptured cases and 2.6% (1/39) for unruptured cases. The rate of retroperitoneal hematoma and gastrointestinal bleeding was 0%. There were no incidents of intraprocedural thromboembolic complication or intraprocedural in-stent thrombosis in either cohort. One subject suffered an ischemic stroke at 24 hours secondary to in-stent thrombosis in a ruptured case.ConclusionsIV cangrelor during aneurysm embolization appears to be safe, with a symptomatic intracranial hemorrhage rate of 4% in ruptured cases and 2.6% in unruptured cases. More research is needed to determine the ideal dosing regimen.
IGFBP7 as a preoperative predictor of congestive acute kidney injury after cardiac surgery
Authors: MacMillan Yannick S , Mamas Mamas A , Sun Louise Y 
Published: June 2022

ObjectiveCongestive acute kidney injury (c-AKI) refers to AKI in the presence of right ventricular failure (RVF) and is a highly morbid complication of cardiac surgery. However, treatment has traditionally been reactive rather than proactive due to limited modalities to predict this complication. The objective of this study was to investigate the ability of insulin-like growth-factor binding protein 7 (IGFBP7), to predict c-AKI, AKI and RVF in patients undergoing cardiac surgery, as compared to N-terminal prohormone B-type natriuretic peptide (NT-pro-BNP) and pulmonary artery pulsatility index (PAPi).MethodsThis prospective nested case–control study consisted of 350 adult patients who underwent elective cardiac surgery. The outcomes were c-AKI, AKI and RVF. Unadjusted and adjusted conditional logistic regression models and areas under the receiver operating characteristic curve (AUC) were used to assess the predictive performance of each marker.ResultsFor the prediction of c-AKI, the unadjusted IGPBP7 model had an AUC of 0.81, as compared with 0.51 for NT-pro-BNP and 0.61 for PAPi. The adjusted c-AKI models had AUCs of 0.90 for IGFBP7, 0.87 for NT-pro-BNP and 0.77 for PAPi. For AKI and RVF, the predictive performance of IGFBP7 was moderate and exceeded that of NT-pro-BNP and PAPi in univariable analysis. IGFBP7 remained a robust independent predictor of all outcomes in multivariable analysis, whereas the other markers did not.ConclusionsIGFBP7 is a promising biomarker for prediction of AKI, RVF and c-AKI and could have value for preoperative optimisation and risk stratification of patients undergoing cardiac surgery.
Reduction games, provability and compactness
Authors: Dzhafarov Damir D. , Hirschfeldt Denis R. , Reitzes Sarah 
Published: June 2022

Hirschfeldt and Jockusch (2016) introduced a two-player game in which winning strategies for one or the other player precisely correspond to implications and non-implications between [Formula: see text] principles over [Formula: see text]-models of [Formula: see text]. They also introduced a version of this game that similarly captures provability over [Formula: see text]. We generalize and extend this game-theoretic framework to other formal systems, and establish a certain compactness result that shows that if an implication [Formula: see text] between two principles holds, then there exists a winning strategy that achieves victory in a number of moves bounded by a number independent of the specific run of the game. This compactness result generalizes an old proof-theoretic fact noted by H. Wang (1981), and has applications to the reverse mathematics of combinatorial principles. We also demonstrate how this framework leads to a new kind of analysis of the logical strength of mathematical problems that refines both that of reverse mathematics and that of computability-theoretic notions such as Weihrauch reducibility, allowing for a kind of fine-structural comparison between [Formula: see text] principles that has both computability-theoretic and proof-theoretic aspects, and can help us distinguish between these, for example by showing that a certain use of a principle in a proof is “purely proof-theoretic”, as opposed to relying on its computability-theoretic strength. We give examples of this analysis to a number of principles at the level of [Formula: see text], uncovering new differences between their logical strengths.
The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response
Authors: Berchuck Jacob E. , Adib Elio , Abou Alaiwi Sarah , Dash Amit K. , Shin Jin Na , Lowder Dallin , McColl Collin , Castro Patricia , Carelli Ryan , Benedetti Elisa , Deng Jenny , Robertson Matthew , Baca Sylvan C. , Bell Connor , McClure Heather M. , El Zarif Talal , Davidsohn Matthew P. , Lakshminarayanan Gitanjali , Rizwan Kinza , Skapura Darlene G. , Grimm Sandra L. , Davis Christel M. , Ehli Erik A. , Kelleher Kaitlin M. , Seo Ji-Heui , Mitsiades Nicholas , Coarfa Cristian , Pomerantz Mark M. , Loda Massimo , Ittmann Michael , Freedman Matthew L. , Kaochar Salma 
Published: June 2022

Abstract

African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men.

Significance:
With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.
Abstract A01: Clinical detection of melanoma via endogenous fluorophore lifetime imaging
Authors: Pellionisz Peter A. , Hu Yong , Kim Jenny , Grundfest Warren , St. John Maie A. 
Published: June 2022

Abstract
Objective: The 5-year survival for cutaneous malignant head and neck melanoma is very poor (17%). As proof of principle, we detect variations in endogenous fluorophore lifetimes by illuminating tissue with pulsed ultraviolet (UV) light. We have previously shown that dynamic optical contrast imaging is capable of delineating tumor margins. Our aim herein was to acquire clinical and intraoperative multispectral images that permit selection of regions of interest (ROI) to reliably and noninvasively perform a rapid optical biopsy in the patient.
Methods: Patient cases of cutaneous melanoma were acquired with pulsed UV illumination utilizing a 6-diode in-series system. Emitted fluorescence was detected with a nanosecond gated CCD detector. The acquired signal is transformed into a relative difference value representing tissue fluorophore lifetime.
Results: From (n=4) patient cases we acquired DOCI images both pre- and post-resection leading to a database of in vivo relative lifetime values that align to histology sections from corresponding locations via pathology. The spectral features of our images enabled classification of clinician-determined regions of interest in DOCI images in order to establish measures of internal and external validity of our novel device.
Conclusion: Our device augments native tissue contrast via wide-field imaging to produce spatially resolved and pathology-specific maps of tissue. Our database of histology-matched real-time images is aimed to permit intraoperative guidance for tumor margin delineation in dermatologic surgery.
Citation Format: Peter A. Pellionisz, Yong Hu, Jenny Kim, Warren Grundfest, Maie A. St. John. Clinical detection of melanoma via endogenous fluorophore lifetime imaging [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A01.
Abstract B09: Nitric oxide stimulates PI3K-AKT pathway activation by S-nitrosylation of PTEN in human melanoma cells
Authors: Ding Zhen , Ogata Dai , Roszik Jason , Qin Yong , Kim Sun-Hee , Ekmekcioglu Suhendan , Grimm Elizabeth A. 
Published: June 2022

Abstract
Based on our previous finding that inflammation associated nitric oxide synthase (NOS) expression in melanoma and its association with poor prognosis in melanoma patients, we investigated the role of nitric oxide (NO) on the PI3K-Akt pathway. Human melanoma cell lines were exposed in vitro to the NO donor (DETA NONOate), and increased Akt Serine 473 phosphorylation (pAkt S473) was detected after addition of 50-500μM DETA NONOate at as early as 2 hours. Significant increases of pAkt S473 were observed mostly in cell lines with wild-type PTEN, such as A375 and MeWo, which under our conditions do not have elevated basal Akt phosphorylation. A375 cells were further examined for DETA NONOate-induced functional consequences of Akt phosphorylation and activation; enhanced kinase activity was found to increase phosphorylation of 12 of 16 AKT signaling proteins, which include GSK, MAPK, Bad, and others. By analyzing melanoma data in The Cancer Genome Atlas (TCGA), we found a similar result that patients with positive iNOS mRNA expression have higher pAkt S473 levels compared with those without iNOS. When both PTEN and iNOS expression status were analyzed, pAkt S473 is only significantly (P&lt;0.05) increased in patients with positive iNOS and intact PTEN, supporting our hypothesis that NO may inhibit the role of PTEN as the PI3K antagonist. Further examination in A375 cells expressing iNOS confirmed the endogenous formation of PTEN S-nitrosylation (SNO), a NO-dependent post-translational modification. PTEN in cells treated with NO showed attenuated phosphatase activity. Consistent with this view, an analysis from stage III melanoma patient tissue microarray also revealed that patients with PTEN expression had a lower survival rate when they also had positive iNOS expression. In summary, our study revealed NO can stimulate the PI3K-Akt pathway in human melanoma cells, which could be promoted by NO-mediated PTEN SNO. These experimental discoveries are supported by clinical association data and have provided one plausible mechanistic insight into the possible functional consequences of inflammatory NO produced in human melanoma cells and microenvironment.
Citation Format: Zhen Ding, Dai Ogata, Jason Roszik, Yong Qin, Sun-Hee Kim, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Nitric oxide stimulates PI3K-AKT pathway activation by S-nitrosylation of PTEN in human melanoma cells [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B09.
Abstract B28: A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment
Authors: Kiefel Helena , Haria Dhwani , Katlinskaya Yuliya , Ravichandar Divya , Jain Sunit , Weinmaier Thomas , Iwai Shoko , DeSantis Todd , Takeuchi Toshi , Dabbagh Karim , Graham Kareem 
Published: June 2022

Abstract
The composition of the gut microbiota affects cancer development, progression, and response to therapy. A number of commensal bacteria, including Bifidobacterium, have been associated with increased response to immune checkpoint inhibitors in mouse tumor models, as well as in melanoma patients. We hypothesized that secreted peptides or proteins contribute to the effects mediated by Bifidobacterium strains in vivo. We used our unique bioinformatics-driven discovery platform to nominate putatively secreted Bifidobacterium-derived peptides for evaluation in immune cell effector assays. We have previously described bacterial peptides that induce secretion of proinflammatory cytokines (e.g., IL-6, TNF) by in vitro-generated mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes in vitro. To investigate the function of Bifidobacterium-derived peptides in the context of the tumor microenvironment, we injected a candidate peptide, termed SG-A, directly into the tumors of tumor-bearing mice. We then performed immune phenotyping via the Nanostring PanCancer Immune Profiling panel, as well as by flow cytometry. Both Nanostring and flow cytometry analysis demonstrated an increase in CD45+ lymphocytes within the tumors of mice treated with SG-A. Peptide SG-A also induced upregulation of dendritic cell function genes (CD40, CD83, and CD86) and multiple effector cytokines and chemokines. Restimulation of tumor-draining lymph node cells with a tumor-derived peptide antigen also increased induction of IFNγ in SG-A treated animals (vs. vehicle-treated controls). Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunomodulatory factors. This platform offers the potential to identify agents that may complement or enhance efficacy of existing approaches to immunotherapy for melanoma and other cancers.
Citation Format: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B28.
Abstract PR16: Specific activation of the G protein-coupled estrogen receptor inhibits melanoma and other cancers and potentiates immune and targeted therapies
Authors: Natale Chris , Li Jinyang , Zhang Jun , Aquirre Cristina , Dahal Ankit , Dentchev Tzvete , Seykora John , Stanger Ben , Ridky Todd 
Published: June 2022

Abstract
Modern immune and targeted therapies appear more effective against advanced melanoma in women than in men. Melanoma incidence is also lower in women. Similar sex differences are observed in other tumors that are not classically considered sex hormone responsive. Here, we show that much of the protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on tumor cells. Selective GPER activation in primary male and female melanocytes, and in melanoma cells, induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemic delivery of a small-molecule, selective GPER agonist was well tolerated, and cooperated with PD-1 directed immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against rechallenge with naive tumor cells. Specific GPER activation in the BRaf-driven murine melanoma model (YUMM1.7) also delayed resistance to targeted BRaf inhibition in vivo. Similar antitumor responses were observed in genetically defined KRas-driven syngeneic pancreatic ductal carcinoma (PDAC) models. The GPER agonist used has favorable pharmacokinetics and oral bioavailability in mice and higher vertebrates and appears to have a large therapeutic window. Together, these data suggest that GPER may be a useful, pharmacologically accessible target for melanoma and other common cancers.
This abstract is also being presented as Poster B15.
Citation Format: Chris Natale, Jinyang Li, Jun Zhang, Cristina Aquirre, Ankit Dahal, Tzvete Dentchev, John Seykora, Ben Stanger, Todd Ridky. Specific activation of the G protein-coupled estrogen receptor inhibits melanoma and other cancers and potentiates immune and targeted therapies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR16.