bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma
Authors: Thiesler Hauke , Gretenkort Lina , Hoffmeister Leonie , Albers Iris , Ohlmeier Luisa , Röckle Iris , Verhagen Andrea , Banan Rouzbeh , Köpcke Nora , Krönke Nicole , Feuerhake Friedrich , Behling Felix , Barrantes-Freer Alonso , Mielke Dorothee , Rohde Veit , Hong Bujung , Varki Ajit , Schwabe Kerstin , Krauss Joachim K. , Stadelmann Christine , Hartmann Christian , Hildebrandt Herbert 
Published: April 2023

Abstract

Purpose:
Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell–associated polySia on glioblastoma outcome.

Experimental Design:
Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16–positive or Siglec-16–negative macrophages, and by exposing Siglec-16–positive or Siglec-16–negative macrophages to glioblastoma cell–derived membrane fractions.

Results:
Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16–expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell–derived membranes.

Conclusions:
Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.
TIL Therapy: Facts and Hopes
Authors: Monberg Tine J. , Borch Troels H. , Svane Inge M. , Donia Marco 
Published: April 2023

Abstract
After a positive phase III trial, it is evident that treatment with tumor-infiltrating lymphocytes (TIL) is a safe, feasible, and effective treatment modality for patients with metastatic melanoma. Further, the treatment is safe and feasible in diverse solid tumors, regardless of the histologic type. Still, TIL treatment has not obtained the regulatory approvals to be implemented on a larger scale. Therefore, its availability is currently restricted to a few centers worldwide. In this review, we present the current knowledge of TIL therapy and discuss the practical, logistic, and economic challenges associated with implementing TIL therapy on a larger scale. Finally, we suggest strategies to facilitate the widespread implementation of TIL therapy and approaches to develop the next generation of TILs.
Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238
Authors: Larkin James , Del Vecchio Michele , Mandalá Mario , Gogas Helen , Arance Fernandez Ana M. , Dalle Stéphane , Cowey Charles Lance , Schenker Michael , Grob Jean-Jacques , Chiarion-Sileni Vanna , Marquez-Rodas Ivan , Butler Marcus O. , Di Giacomo Anna Maria , Middleton Mark R. , Lutzky Jose , de la Cruz-Merino Luis , Arenberger Petr , Atkinson Victoria , Hill Andrew G. , Fecher Leslie A. , Millward Michael , Nathan Paul D. , Khushalani Nikhil I. , Queirolo Paola , Ritchings Corey , Lobo Maurice , Askelson Margarita , Tang Hao , Dolfi Sonia , Ascierto Paolo A. , Weber Jeffrey 
Published: April 2023

Abstract

Purpose:
In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.

Patients and Methods:
Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.

Results:
At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.

Conclusions:
Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.
See related commentary by Augustin and Luke, p. 3253
DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir 
Published: April 2023

Abstract

Purpose:
Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia.

Experimental Design:
A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT).

Results:
Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status.

Conclusions:
Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.
See related commentary by Heft Neal and Brenner, p. 2954
Abstract CT264: Taking sotorasib with an acidic beverage improves sotorasib exposure for subjects on omeprazole
Authors: Strydom Natasha , Cardona Panli , Spring Marintan , Purkis Jessica , Houk Brett 
Published: April 2023

Abstract
The solubility of KRASG12C inhibitor sotorasib is pH dependent and coadministration with a proton pump inhibitor (omeprazole) decreased sotorasib maximum concentration (Cmax) by 56.9% and the area under the concentration curve from time zero to the time of the last quantifiable concentration (AUClast) by 42.4% under fasted conditions. This study in healthy volunteers evaluated if taking sotorasib with an acidic beverage such as Coca Cola would alter sotorasib absorption when coadministered with omeprazole and improve sotorasib exposure. Two separate phase 1, open-label, fixed sequence, 2-period studies enrolled at least 14 healthy subjects each. In the first study, each subject received a single 960 mg dose of sotorasib under fasted conditions on day 1, followed by omeprazole 40 mg once daily for 5 days on days 4 to 8, and then received omeprazole 40 mg in combination with sotorasib 960 mg on day 9 with water. For the second phase 1 study all conditions were kept the same except subjects received omeprazole in combination with sotorasib on day 9 with an 8-ounce (240 mL) glass of acidic beverage (Coca-Cola) instead of water. In both studies, intensive pharmacokinetic plasma sampling occurred predose and at 13 timepoints up to 48 hours post-dose. Sotorasib plasma concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Non-compartmental analysis was used to calculate pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. Increased sotorasib exposure was observed when sotorasib and omeprazole were taken with an acidic beverage compared to when sotorasib and omeprazole were taken with water for both AUClast (23200 vs 16700 h∙ng/mL respectively) and Cmax (4850 ng/mL vs 3110 ng/mL respectively). Compared to the geometric mean ratio of sotorasib and omeprazole taken with water, taking sotorasib and omeprazole with an acidic beverage resulted in an increase of 19.0 percentage-point in AUClast and a 24.6 percentage-point increase in Cmax. Coadministration of sotorasib and omeprazole with Coca Cola was safe and well tolerated. For patients on acid-reducing drugs, sotorasib taken with an acidic beverage is an effective strategy to increase sotorasib exposure and counteract the reduced exposures resulting from the drug-drug interaction effect of acid-reducing drugs.
Citation Format: Natasha Strydom, Panli Cardona, Marintan Spring, Jessica Purkis, Brett Houk. Taking sotorasib with an acidic beverage improves sotorasib exposure for subjects on omeprazole [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT264.
Abstract LB034: EWSR1, Ewing sarcoma breakpoint region 1, maintains centromere identity by binding to centromeric R-loops
Authors: Kitagawa Risa , Becker Argentina , Houghton Peter , Kitagawa Katsumi 
Published: April 2023

Abstract
The centromere DNA-kinetochore complex is the specialized chromatin structure that mediates chromosome attachment to microtubules and is required for high-fidelity chromosome transmission. CENP-A is the centromere-specific histone H3 variant that epigenetically determines centromere position on the chromosome to ensure kinetochore assembly. Despite its importance, the precise mechanism of maintenance of CENP-A, i.e., the maintenance of centromere identity, remains obscure. In this study, we found that EWSR1 (Ewing Sarcoma Breakpoint Region 1) is required for CENP-A deposition at centromeres by binding to centromeric RNA. We determined that the CENP-A binding domain of EWSR1 is the SYGQ2 region within the prion-like domain, which plays an important role in phase separation for chromatin remodeling. Our data suggest that EWSR1 guards CENP-A in centromeric chromatins by binding to centromeric RNA. This is a novel mechanism to maintain the position of the centromere on the chromosome i.e., centromere identify. As EWSR1-FLI1 is the oncogenic fusion protein in Ewing sarcoma and as it inhibits EWSR1 function as a dominant negative mutant, it contributes to chromosome instability in Ewing sarcoma, which may lead to therapy resistance and metastasis.
Citation Format: Risa Kitagawa, Argentina Becker, Peter Houghton, Katsumi Kitagawa. EWSR1, Ewing sarcoma breakpoint region 1, maintains centromere identity by binding to centromeric R-loops [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB034.
Abstract LB048: AR-targeted linked-read sequencing reveals complex AR structural variants in CRPC tumors
Authors: Zivanovic Andrej , Munro Sarah A. , Miller Jeffrey T. , Li Yingming , Passow Courtney N. , Dehm Scott M. 
Published: April 2023

Abstract
Inhibition of the androgen receptor (AR) transcription factor is the mainstay therapeutic strategy for systemic prostate cancer. However, development of a resistance phenotype termed castration resistant prostate cancer (CRPC) enables disease progression that underlies virtually all prostate cancer mortality. In the majority of CRPC, AR is transcriptionally re-activated in part due to accumulation of numerous alterations in the AR gene. These genomic alterations include missense mutations in exons that encode the ligand binding domain of AR, amplification of the AR gene body and/or an upstream transcriptional enhancer, and AR structural variants (SVs) resulting from inaccurate repair of DNA double strand breaks. In CRPC patient samples, these AR genomic alterations co-occur within tumors, which makes elucidating the fitness contribution of each alteration difficult. While short-read DNA sequencing has allowed for characterization of these events, they are underpowered to preserve linkage information. To address this challenge, we performed AR-targeted linked-read DNA-sequencing of CRPC cell line and patient derived xenograft (PDX) models with the goal of resolving sub-clonal and complex AR SVs. This approach confirmed the heterogeneity of AR SVs in these PDXs, including phased AR SVs that can be traced back to a single high molecular weight DNA molecule. These phased AR SVs were consistently found to co-occur in CRPC specimens with amplification of AR. Our results define a new class of AR SVs where multiple rearrangements co-occur on amplified DNA molecules to yield a complex array of AR gene structures in CRPC.
Citation Format: Andrej Zivanovic, Sarah A. Munro, Jeffrey T. Miller, Yingming Li, Courtney N. Passow, Scott M. Dehm. AR-targeted linked-read sequencing reveals complex AR structural variants in CRPC tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB048.
Abstract LB049: ALKBH5 emerges as a novel regulator of the BCR pathway
Authors: Kapadia Bandish B. , Roychowdhury Anirban , Kayastha Forum , Nanaji Nahid , Windle Jolene , Gartenhaus Ronald B. 
Published: April 2023

Abstract
Global epitranscriptomic methylation of mRNA at the N6 position (m6A) is reported to be altered in B-cell and tumor development. However, the mechanistic underpinnings of its role in the pathogenesis of Diffuse large B cell lymphoma (DLBCL) are unknown. It is well established that the B-cell receptor (BCR) pathway is a primary oncogenic driver in aggressive B-cell lymphomas. We previously reported that the Ataxia Telangiectasia Mutated (ATM)/Hu Antigen R (HuR)axis, as well as Eukaryotic Translation Initiation Factor 4A (eIF4A), modulate BCR signaling. However, the impact of RNA modifications on BCR induction is still poorly understood. Addressing this burgeoning question, we noted enhanced expression of AlkB Homolog 5 (ALKBH5), an m6A demethylase, in naïve B-cells treated with BCR mimetics. Similarly, mRNA levels of ALKBH5 were reported to be modestly enhanced in IgM-treated human B-cells (GSE156195). Consistently, immunization of C57BL/6 mice with sheep red blood cells (SRBC) significantly enhanced ALKBH5 in splenic B-cells. Next, evaluating the impact of BCR induction in lymphomagenesis, we observed a robust increase in the demethylase expression in BCR mimetic-treated DLBCL cells. Notably, increased expression of ALKBH5 was observed in a murine EµMyc model and primary DLBCL tumors. In coherence, the enhanced transcript levels of ALKBH5 in TCGA-DLBCL have prognostic implications. To gain functional insight, we depleted ALKBH5, which resulted in a robust reduction of BCR pathway proteins. Unexpectedly, the mRNA levels of CD79a and BLK were minimally modified, while the SYK, BTK, and CARD11 messages were reduced. Further studies are ongoing to evaluate the potential mechanism of mRNA transport and/or stability.
Citation Format: Bandish B. Kapadia, Anirban Roychowdhury, Forum Kayastha, Nahid Nanaji, Jolene Windle, Ronald B. Gartenhaus. ALKBH5 emerges as a novel regulator of the BCR pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB049.
Abstract LB065: Interface-guided phenotyping of coding variants
Authors: Ozturk Kivilcim , Panwala Rebecca , Sheen Jeanna , Mali Prashant , Carter Hannah 
Published: April 2023

Abstract
Understanding the consequences of single amino acid substitutions in cancer driver genes remains an unmet need. High-throughput mutagenesis is emerging as a powerful tool to probe the varying consequences of different amino acid substitutions across the length of a protein or protein domain, however it is currently limited to specific functional readouts such as target protein abundance or functional assays. Studying the effects of genetic perturbations on cellular programs and fitness has been challenging using traditional pooled screens. Over the last few years, there has been a surge of interest in Perturb-seq style assays to measure the transcriptional consequences of genetic perturbations ranging from whole gene knockout to amino acid substitutions in single cells. While providing greater function insight, these sequencing-based methods are not yet scalable to exhaustive mutagenesis, necessitating selection of target mutations. In this work, we hypothesized that examining the consequences of perturbing distinct protein interactions could provide a useful abstraction of the phenotypic space reachable by individual amino acid substitutions. To explore this hypothesis, we employed a Perturb-seq style approach to generate mutations at physical interfaces of the transcription factor RUNX1, with the potential to perturb different interactions, and therefore produce transcriptional readouts implicating different aspects of the RUNX1 regulon. We analyzed these readouts to identify functionally distinct groups of RUNX1 mutations, characterize their effects on cellular programs and study the implications for cancer mutations. Our work demonstrates the potential of targeting protein interaction interfaces to better define the landscape of prospective phenotypes reachable by amino acid substitutions.
Citation Format: Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Prashant Mali, Hannah Carter. Interface-guided phenotyping of coding variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB065.
Abstract LB074: Towards the next generation cancer dependency map
Authors: Wienand Kirsty , Stokes Samantha , Montgomery Philip G. , Sullivan Kelly , Dempster Joshua M. , Hahn William C. , Roth Jennifer A. , Vazquez Francisca 
Published: April 2023

Abstract
Cancer genome alterations that cause cancer cells to grow also confer vulnerabilities, which normal cells lack. The challenge is that, for the majority of cancers, we do not understand the relationship between the genetic alterations and the dependencies they cause. To solve this problem, we are creating a Cancer Dependency Map (DepMap) by systematically identifying genetic dependencies and small molecule sensitivities as well as discovering the biomarkers that predict them. Since its inception, DepMap has compiled data for over eighteen hundred cell line models, performed more than a thousand CRISPR screens, and drug sensitivity profiles using PRISM in over 500 cell lines as well as developed new analytic methods for the identification of cancer vulnerabilities. DepMap is being used by researchers around the world and numerous potential therapeutic targets have been identified using this resource. However, we are still in the early stages of having a complete map and we will discuss our ongoing work towards making the Cancer Dependency Map more powerful. The next generation DepMap will include more complex cellular models including 3D models, representing pediatric and rare cancers, and expanding the perturbation space to include combinations. Additionally, we are performing novel types of omics characterization and building new computational and visualizations tools. These new scientific directions will help make progress towards our identification of the landscape of cancer vulnerabilities and create a roadmap for cancer therapeutics.
Citation Format: Kirsty Wienand, Samantha Stokes, Philip G. Montgomery, Kelly Sullivan, Joshua M. Dempster, William C. Hahn, Jennifer A. Roth, Francisca Vazquez. Towards the next generation cancer dependency map [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB074.