bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silk proteins in reconstructive surgery: Do they possess an inherent antibacterial activity? A systematic review
Authors: Schäfer Sogand , Aavani Farzaneh , Köpf Marius , Drinic Aleksander , Stürmer Ewa K. , Fuest Sandra , Grust Audrey Laure Céline , Gosau Martin , Smeets Ralf 
Published: September 2022

AbstractThe field of reconstructive surgery encompasses a wide range of surgical procedures and regenerative approaches to treat various tissue types. Every surgical procedure is associated with the risk of surgical site infections, which are not only a financial burden but also increase patient morbidity. The surgical armamentarium in this area are biomaterials, particularly natural, biodegradable, biocompatible polymers, including the silk proteins fibroin (SF) and sericin (SS). Silk is known to be derived from silkworms and is mainly composed of 60–80% fibroin, which provides the structural form, and 15–35% sericin, which acts as a glue‐like substance for the SF threads. Silk proteins possess most of the desired properties for biomedical applications, including biocompatibility, biodegradability, minimal immunogenicity, and tunable biomechanical behaviour. In an effort to alleviate or even prevent infections associated with the use of biomaterials in surgery, antibacterial/antimicrobial properties have been investigated in numerous studies. In this systematic review, the following question was addressed: Do silk proteins, SF and SS, possess an intrinsic antibacterial property and how could these materials be tailored to achieve such a property?
Novel peptide-based vaccine targeting heat shock protein 90 induces effective antitumor immunity in a HER2+ breast cancer murine model
Authors: Kang Jinho , Lee Hye-Jin , Lee Jimin , Hong Jinhwa , Hong Kim Yeul , Disis Mary L , Gim Jeong-An , Park Kyong Hwa 
Published: September 2022

BackgroundHeat shock protein 90 (HSP90) is a protein chaperone for most of the important signal transduction pathways in human epidermal growth factor receptor 2-positive (HER2+) breast cancer, including human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor and Akt. The aim of our study is to identify peptide-based vaccines and to develop an effective immunotherapeutics for the treatment of HER2+ breast cancer.MethodsHSP90-derived major histocompatibility complex (MHC) class II epitopes were selected using in silico algorithms and validated by enzyme-linked immunospot (ELISPOT). In vivo antitumor efficacy was evaluated in MMTVneu-transgenic mice. HSP90 peptide-specific systemic T-cell responses were assessed using interferon gamma ELISPOT assay, and immune microenvironment in tumors was evaluated using multiplex immunohistochemistry and TCRβ sequencing.ResultsFirst, candidate HSP90-derived MHC class II epitopes with high binding affinities across multiple human HLA class II genotypes were identified using in silico algorithms. Among the top 10 peptides, p485 and p527 were selected as promising Th1 immunity-inducing epitopes with low potential for Th2 immunity induction. The selected MHC class II HSP90 peptides induced strong antigen-specific T cell responses, which was induced by cross-priming of CD8+T cells in vivo. The HSP90 peptide vaccines were effective in the established tumor model, and their efficacy was further enhanced when combined with stimulator of interferon genes (STING) agonist and/or anticytotoxic T lymphocyte-associated antigen-4 antibody in MMTVneu-transgenic mice. Increased tumor rejection was associated with increased systemic HSP90-specific T-cell responses, increased T-cell recruitment in tumor microenvironment, intermolecular epitope spreading, and increased rearrangement of TCRβ by STING agonist.ConclusionsIn conclusion, we have provided the first preclinical evidence of the action mechanism of HSP90 peptide vaccines with a distinct potential for improving breast cancer treatment.
Fine mapping of a major QTL qPA7-1 for low hydrocyanic acid content in sorghum–sudangrass hybrid
Authors: Wu Guofang , Yu Xiaoxia , Yu Zhuo , Lu Qianqian , Yang Dongsheng , Shi Yue , Li Jiaqi , Li Jingwei 
Published: September 2022

The purpose of this study was to study the genetic mechanism of low hydrocyanic acid (HCN) content. The segregation of HCN content trait in fresh stems and leaves was determined in the sorghum ( Sorghum bicolor (L.) Moench)–sudangrass ( Sorghum sudanense (Piper) Stapf) hybrid F2 population ( N = 1200), also used to detect a quantitative trait locus (QTL) for HCN content. Our hypothesis was that the additive effect of QTL was negative, showing that QTL was associated with low HCN. In the present research, a total of 11 simple sequence repeats (SSR) polymorphic primers were screened, and four SSR markers associated with low HCN content were developed based on the bulked segregant analysis method. A high-resolution genetic linkage group of the previously known qPA7-1 locus of the low HCN trait was constructed by analyzing different populations, families, and recombinants. Then, the QTL qPA7-1 of sorghum–sudangrass hybrid was fine-mapped to a 203.6 kb region between markers SORBI4G4-120 and SORBI4G4-680, and seven candidate genes for low HCN were predicted in this region based on sequence comparison with the sorghum reference genome. According to gene annotation, the candidate genes related to low HCN content may be different from those involved in the known regulation mode of sorghum dhurrin biosynthesis and metabolism.
Abstract A002: Dynamic single cell imaging of cancer stem cells and clonality in fusion-negative rhabdomyosarcoma
Authors: Eng Tiffany , Wei Yun , Qin Qian , Yan Chuan , Yang Qiqi , Veloso Alexandra , McCarthy Karin , Langenau David 
Published: September 2022

Abstract
Rhabdomyosarcoma (RMS) accounts for 50% of all soft-tissue childhood sarcomas and is characterized by tumor cells that molecularly and morphologically resemble undifferentiated skeletal muscle. Treatment involves an aggressive regimen of chemotherapy followed by surgical resection and/or radiation therapy. Although survival rates can be as high as 70-90% in low-risk or localized disease, patients with oligoclonal or relapsed disease have extremely poor prognoses. Thus, there is a clinical imperative to identify novel therapeutic targets, particularly ones that could reduce clonality and suppress cancer stem cell self-renewal. Our lab has recently shown that fusion-negative (FN-)RMS contain four dominant tumor cell states: proliferative, ground, mesenchymal cancer stem cells (mCSCs) and differentiated muscle. Importantly, the mCSCs are largely quiescent under normal growth conditions but re-enter the cell cycle to promote tumor growth following stress. This suggests that mCSCs are likely responsible for driving therapy resistance and relapse. Building on our previous successes in live imaging cancer stem cells using transgenic zebrafish models that express fluorophores under control of developmentally restricted muscle promoters, we are now developing similar approaches to drive fluorescent protein expression in human FN-RMS cell lines to trace lineage fate and to witness the division history of mCSCs in real time. Using a combination of CRISPR/Cas9 gene inactivation and these newly developed tools, we are poised to identify new self-renewal pathways by the direct, live-cell imaging of FN-RMS engrafted into optically clear, immune-deficient zebrafish. In addition, we are also using tumor clonality as a surrogate of increased tumor aggression and cancer stem cell potential in the zebrafish RAS-induced RMS model. We have adapted the transgenic zebrafish model of kRASG12D-induced RMS to analyze tumor clonality using multispectral Zebrabow and GESTALT, a CRISPR barcoding technique that tracks cell fate. Using RMS-specific gene expression datasets that are associated with cancer stem cells, we are now screening for genes that elevate tumor clonality, increase tumor penetrance and accelerate tumor growth. Ultimately, by developing these lineage tracing tools in both human RMS cell lines and our transgenic Zebrafish RMS model, we will identify new modulators of the mCSC transcriptional cell states and possible therapeutic targets.
Citation Format: Tiffany Eng, Yun Wei, Qian Qin, Chuan Yan, Qiqi Yang, Alexandra Veloso, Karin McCarthy, David Langenau. Dynamic single cell imaging of cancer stem cells and clonality in fusion-negative rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A002.
Abstract A006: Defining the microenvironment of alveolar soft part sarcoma & it’s role in therapeutic outcomes
Authors: Philippot Alexis M. , Dang Ngoc Ha , Menon Shyam V. , Bourdage Jennifer , Lun Xueqing , Ahn Bo Young , Robbins Stephen M. , Senger Donna L. 
Published: September 2022

Abstract
Alveolar soft part sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes due to a propensity to metastasize along with a complete lack of chemotherapeutic options. One additional difficulty of this rare tumor is an absence of established in vivo models. Here, we describe the establishment of a patient derived xenograft model (PDX), and corresponding cell line, from the lung metastases of a 14-year-old female diagnosed with ASPS. Using this model, we performed a drug screen, from which the proteasome inhibitor carfilzomib inhibited tumor cell viability and growth in vitro and in vivo. To further elucidate factors implicated in tumor progression and chemotherapy resistance, we characterized the microenvironment and secretome of the ASPS PDX. In keeping with recent literature showing large numbers of tumor associated macrophage (TAMs) in ASPS, we found that 96% of the myeloid cells present in the PDX were TAMS, with 35% taking on a pro-tumor phenotype. Further, factors secreted by the tumor microenvironment largely support immune cell recruitment and pro-tumor phenotypes. Interestingly, in vivo assessment demonstrates that Iba1+ macrophage populations decrease by 60% with carfilzomib treatment. This prompted investigation into the potential impact of TAMs on ASPS growth and progression, and if they are implicated in the therapeutic response to carfilzomib. Based on preliminary findings that carfilzomib targets the pro-tumor phenotypic states of bone marrow derived macrophage in vitro, we hypothesize that carfilzomib alters the recruitment and phenotype of TAMs, decreasing tumor cell viability in vitro, and thus tumor burden in vivo.
Citation Format: Alexis M. Philippot, Ngoc Ha Dang, Shyam V. Menon, Jennifer Bourdage, Xueqing Lun, Bo Young Ahn, Stephen M. Robbins, Donna L. Senger. Defining the microenvironment of alveolar soft part sarcoma & it’s role in therapeutic outcomes [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A006.
Abstract A007: Resident memory T cells express PD-1 in high grade liposarcoma
Authors: Angeles Christina V. , Han Jichang , Wilkoswki Jodi , Bresler Scott 
Published: September 2022

Abstract
Objective: Memory T cells play crucial roles in anti-tumor immunity. Tumor-associated resident memory T cells (TRM) have been associated with durable immune response and improved patient survival across multiple tumor types. SARC028, a phase II, multicenter trial of pembrolizumab, a programmed death 1 (PD-1) checkpoint inhibitor immunotherapy, showed promising activity in select histologic subtypes of advanced soft tissue sarcoma (STS), including dedifferentiated liposarcoma (DDLPS). However, there was only a 20% overall response rate. Notably, the patients who did respond to immunotherapy had durable responses, supporting our enthusiasm to understand the potential role for TRM in liposarcoma anti-tumor immunity. The characterization of memory T cells in liposarcoma, and whether TRM are present has not been explored. Design: Fresh retroperitoneal liposarcoma specimens from 8 patients: 3 well-differentiated liposarcoma (WDLPS) and 5 DDLPS were collected. Lymphocytes were analyzed by flow cytometry using T-cell (CD45, CD3, CD4, CD8) and phenotypic markers (CD69, CD62L, CD103, CD49a, PD-1, TIM-3). Results: DDLPS had a 4-fold higher overall T-cell infiltration and a 2.5-fold higher CD8+/CD4+ T-cell ratio than WDLPS. DDLPS contained CD8+ T cells with a CD45RA− CCR7− CD69hi CD62Llo phenotype, characteristic of a TRM response, and well as CD69lo effector memory T (TEM) cells. DDLPS had 3-fold more TRM than WDLPS. DDLPS had a much higher level of activated PD-1+ CD69+ CD8+ resident memory T-cell population compared to WDLPS. Additionally, the population of TRM had higher PD-1 expression compared to TEM in both DDLPS and WDLPS. Conclusions: These data suggest that TRM subsets may contribute to the responsiveness to anti-PD1 therapy in patients with DDLPS. Further investigations may lead to the discovery of TRM-targeted T-cell therapies in DDLPS, which currently has limited treatment options.
Citation Format: Christina V. Angeles, Jichang Han, Jodi Wilkoswki, Scott Bresler. Resident memory T cells express PD-1 in high grade liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A007.
Abstract A021: Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma
Authors: Robbins Gabrielle , Yamomoto Kenta , Lahr Walker , Skeate Joseph 
Published: September 2022

Abstract
Over the last decade, Chimeric Antigen Receptor based T cell (CAR-T) therapy has developed into an effective immunotherapy for several cancers, primarily limited to those of hematological origin. In other cancers, especially solid tumors, CAR-T cell therapies have several shortcomings and clinical success has been underwhelming. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells can mediate the direct killing of transformed cells with reduced or absent MHC expression in addition to carrying out antibody dependent cell mediated cytotoxicity (ADCC) of cells bound by antibodies via the NK cell CD16A receptor. Engineering NK cells to express CARs will effectively enable them with additional antigen specific killing. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion or persistence, and suppression by the tumor microenvironment. NK cells activated and expanded with engineered feeder cells expressing membrane bound interleukin-21 (mbIL-21) and 4-1BBL have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded CAR-NK cells that have been genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over forty years. Our proposed objective is to evaluate the non-viral KI of several CARs, either alone or in combination, that optimally activate NK cell antigen-specific killing. Genetically engineered CAR-NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that CAR-NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered CAR-NK cells.
Citation Format: Gabrielle Robbins, Kenta Yamomoto, Walker Lahr, Joseph Skeate. Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A021.
Abstract A025: Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas
Authors: Lee Eun-Young , Kang Hyun Guy , Kim June Hyuk , Park Jong Woong , Park Seog Yun , Yun Tak , You Hye Jin 
Published: September 2022

Abstract
The tumor microenvironment is closely associated with tumor development and progression, which is made up of tumor cells, blood vessels, immune cells, fibroblast, and so on. Especially, immune cells within tumor microenvironments have been attracted in clinicians and researchers for unexpected therapeutic responses. Even in sarcoma, which is rare, and heterogenous leading to few options for cure, immune therapy has been tried and shown to be promising. However, the information of immune cells within soft tissue sarcomas were limited, which mostly have been obtained and characterized by omics-based analyses or tissue staining such as immunohistochemistry. Here, we established platform to profile tumor infiltrating immune cells by flow cytometry. About thirty sarcoma tissues were obtained, in which tumor infiltrating immune cells were profiled. The profiled data were confirmed by immunohistochemistry for correlation. It was shown that infiltrated leukocytes and CD3+ T cells were remarkably increased, whereas NKT and CD4+ T cells were decreased in tumor tissues compared to adjacent normal tissues. M1 macrophage was also increased in tumor tissues. High CD3+ T cell population was positively correlated with CD8+ T cells and PD1+ CD8+ T cell population. Especially, PD1+CD8+ T cells are usually expressed exhaustion-related conditions and low levels of cytotoxic immune cells. This study provides resources to understand immune cell population of soft tissue sarcoma, and will gain a fundamental matrix to study immunotherapy. These studies might show the possibility to find potential prognostic and immunotherapeutic targets.
Citation Format: Eun-Young Lee, Hyun Guy Kang, June Hyuk Kim, Jong Woong Park, Seog Yun Park, Tak Yun, Hye Jin You. Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A025.
Abstract A027: Characterization of WEE1 kinase activity in myxoid liposarcoma
Authors: Heinst Lorena , Berthold Ruth , Isfort Ilka , Wosnig Svenja , Kindler Thomas , Åman Pierre , Wardelmann Eva , Scholl Claudia , Fröhling Stefan , Hartmann Wolfgang , Trautmann Marcel 
Published: September 2022

Abstract
Introduction: Myxoid liposarcomas (MLS), malignant soft tissue tumors of adipocyte origin, are genetically characterized by a chromosomal t(12;16)(q13;p11) translocation encoding the chimeric FUS-DDIT3 fusion gene. The resulting fusion protein drives MLS pathogenesis via (dys-)regulation of oncogenic signaling pathways. Since FUS-DDIT3 is not selectively antagonizable, counteracting the oncogenic effects of FUS-DDIT3 fusion protein represents the most promising strategy to target MLS cells. In this study, we identified cell cycle checkpoint kinase WEE1 as FUS-DDIT3 depending effector and investigated the functional requirement for WEE1 kinase activity in MLS pathogenesis. Experimental Procedures: Characterization of WEE1 expression and kinase activity was performed in multiple MLS cell lines, cell lines derived from other liposarcoma subtypes and a mesenchymal stem cell system. Modulation of WEE1 signaling was carried out by means of small-molecule inhibitor Adavosertib (MK-1775) and RNA interference (RNAi)-mediated depletion, and effects were analyzed in immunoblots, cell proliferation assays and caspase 3/7 activity-based apoptosis assays in vitro. Results: Functional genomic RNAi screening uncovered dependence of FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines on WEE1 kinase activity. Additional expression analysis revealed increased WEE1 protein levels in MLS cell lines. Moreover, pharmacologic inhibition of WEE1 demonstrated significant reduction of MLS cell viability. Accordingly, functional loss of WEE1 by inhibition or RNAi-mediated depletion was found to induce DNA damage accompanied by unscheduled mitotic entry and cell death via activation of the apoptotic program in MLS cells. Conclusions: Our results identify WEE1 kinase activity as functional liability of FUS-DDIT3 expressing MLS cells and provide first evidence that overactive WEE1 signaling represents a promising target for therapeutic intervention in MLS.
Citation Format: Lorena Heinst, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Thomas Kindler, Pierre Åman, Eva Wardelmann, Claudia Scholl, Stefan Fröhling, Wolfgang Hartmann, Marcel Trautmann. Characterization of WEE1 kinase activity in myxoid liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A027.
Abstract A031: Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma
Authors: Isfort Ilka , Berthold Ruth , Heinst Lorena , Wardelmann Eva , Trautmann Marcel , Hartmann Wolfgang 
Published: September 2022

Abstract
Introduction: Synovial sarcoma (SySa) is a rare soft-tissue malignancy characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives SySa pathogenesis by dysregulating gene transcription. As therapeutic targeting of SS18-SSX is notoriously difficult, the identification of SS18-SSX-dependent pathomechanisms may uncover novel molecular vulnerabilities. Since previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional co-regulators YAP1/TAZ and β-catenin, this study examined a potential crosstalk between these effectors in SySa. Experimental Procedures: Nuclear abundance of YAP1/TAZ and β-catenin was analyzed by immunohistochemistry in a large cohort of SySa tissue specimens. Two SySa cell lines were employed to modulate YAP1/TAZ/β-catenin transcriptional activity by RNAi-mediated knockdown, small molecule inhibitors, and overexpression vectors in vitro. Changes in transcriptional activity were determined via luciferase reporter assays. As YAP1 and β-catenin showed highest interdependence, co-immunoprecipitation experiments were performed to investigate their interplay with the SS18-SSX fusion protein in SySa cells. Results: Immunohistochemically, a substantial subset of SySa tissue specimens showed concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, SS18-SSX was found to promote YAP1/TAZ and β-catenin transcriptional activity. RNAi-mediated knockdown of YAP1, TAZ or β-catenin and small molecule inhibitor treatment mutually downregulated TEAD and TCF luciferase reporter activity, while expression of hyperactive variants led to a reciprocal luciferase reporter induction. Finally, co-immunoprecipitation assays demonstrated nuclear co-localization of SS18-SSX with YAP1 and β-catenin in SySa cell lines. Conclusions: This study reveals an interdependency between YAP1 and β-catenin activation and a complex interplay with the SySa-specific SS18-SSX fusion protein.
Citation Format: Ilka Isfort, Ruth Berthold, Lorena Heinst, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann. Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A031.