bluuebunny/crossref_metadata_2025 huggingface dataset:
IMG-04. POTENTIAL TARGETS FOR THERANOSTICS IN PEDIATRIC HIGH-GRADE CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Plasschaert Sabine , Tolboom Nelleke , Kester Lennart , Tops Bastiaan , Hoving Eelco , Poot Alex , Wesseling Pieter , Kranendonk Mariëtte
Published: June 2023

Theranostics refers to the combination of a radioactive drug to identify (diagnose) and another radioactive drug to deliver therapy to cancer. In adult cancer several radiopharmaceuticals with specificity for receptors like cx-chemokine-receptor type 4 (CXCR-4), prostate-membrane specific antigen (PSMA), and somatostatine receptor (SSTR2a) are used. Especially PSMA for prostate cancer and SSTR2a ligands for neuro-endocrine tumors have proven their value. Moreover, novel promising targets like B7-H3 are upcoming. In children the potential of such theranostic drugs have been minimally explored.

AIM of this study is to explore the expression of theranostic markers CXCR-4, PSMA, SSTR2a and B7-H3 in a broad cohort of high-grade pediatric CNS tumors to determine the potential of these imaging ligands in this cohort.

METHODS The expression of CXCR-4, PSMA, SSTR2a and B7-H3 were examined both by RNA (by bulk RNAsequencing) and protein level (by immunohistochemistry (IHC)) (RNA n=161/IHC n=52) in pediatric high-grade CNS tumors: ependymomas (n=33/11), atypical teratoid rhabdoid tumors (ATRT) (n=9/7), medulloblastomas (n=51/11), diffuse midline gliomas H3K27-altered (n=27/9) and other high-grade gliomas (n=41/15).

RESULTS mRNA expression of CXCR-4 was present but low in most tumor types, with the highest expression in medulloblastoma. Immunohistochemistry showed variable CXCR-4 expression, with the highest expression in some medulloblastomas, ependymomas and ATRTs. PSMA (FOLH1) mRNA and protein expression was generally very low. As expected SSTR2a showed a very high mRNA and protein expression only in medulloblastoma samples. Remarkably, B7-H3 (CD276) showed a relatively high expression in all high-grade pediatric CNS tumor types, both on RNA and protein level.

CONCLUSION Of the four potential theranostic targets tested, SSTR2a is an interesting antigen in medulloblastoma. CXCR-4 could be of interest for individual patients with medulloblastoma, ATRT or ependymoma. Finally, B7-H3 is widely but variably expressed on all different tumor types, and seems a promising novel target for theranostics in pediatric CNS tumors.
IMMU-04. TARGETING ALTERNATIVE SPLICING VARIANTS TO STIMULATE ANTI-TUMOR IMMUNITY IN A NOVEL SYNGENEIC MOUSE MODEL OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Owens Geoffrey , Pan Yang , Treger Janet , Contreras Erick , Soto Horacio , Armellini Amber , Na Brian , Liau Linda , Prins Robert , Xing Yi , Wang Anthony
Published: June 2023

Juvenile presentation of HGG has been shown to frequently involve somatic mutations of the H3-3A gene, which encodes a histone H3 variant. To address the paucity of identified TSAs in DHG, we utilized a novel computational platform, Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS). The IRIS pipeline is designed to leverage large-scale cancer and normal transcriptomic data to identify peptide sequences that result from alternative splicing events that are highly enriched in cancer cells, and are predicted to bind the HLA class I alleles carried by the individual patient. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant, we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens. We used the RCAS/tv-A system to target the expression of H3/G34R and PDGF-B and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. Implementing IRIS, we identified nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two H3/G34R patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele.
IMMU-21. ELUCIDATING THE CELLULAR MECHANISMS OF THERAPEUTIC BENEFIT UNDERLYING ADOPTIVE CELLULAR THERAPY IN MODELS OF GLIOMA
Authors: Figg John , Francis Connor , Jin Dan , Dean Bayli DiVita , Reid Alexandra , Hilferty David , McDonald Brianna , Flores Catherine , Mitchell Duane
Published: June 2023

Among pediatric cancers, malignancies of the brain carry significant morbidity and mortality, harboring dismal prognosis and poor outcomes. Our group has previously shown that adoptive cellular therapy (ACT) provides therapeutic benefit against central nervous system (CNS) malignancies, including medulloblastoma and high-grade glioma. In this study, we characterized cell cycling differences of immune sub-populations in peripheral lymphoid and tumor tissue compartments in vivo. ACT was conducted in orthotopic KR158 luciferase tumor-bearing mice, a syngeneic murine glioma model. Five days following intracranial implantation of tumor cells, mice were treated with ACT which included the following elements: total body irradiation, hematopoietic stem cell transplantation, one dose of tumor-activated splenocytes and three weekly doses of dendritic cells that had been electroporated with tumor-derived ribonucleic acid. One week after the completion of ACT, bromodeoxyuridine (BRDU) was administered to mice 12-hours prior to tissue collection and flow cytometry was utilized to measure the level of BRDU incorporation. 7-aminoactinomycin-D was used in conjunction with BRDU to provide insight into all phases of the cell cycle. We observed significant differences in cycling populations of myeloid derived suppressor cells (MDSC) and T-cells. In ACT-treated-mice, MDSCs found in secondary lymphoid tissues were significantly more proliferative. In the tumor microenvironment (TME), proliferating MDSCs were significantly reduced compared to mice that did not receive treatment. Frequencies of proliferating CD4+ and CD8+ T-cells were significantly increased in cervical lymph node and TME but reduced in spleen. These findings suggest that ACT alters immune cycling in peripheral lymphoid tissues and TME to potentially promote antitumor T-cell responses and minimize MDSC-mediated immunosuppression. While ACT-mediated alterations to immune cell cycling are likely a major contributor to the therapy’s benefit, it is unlikely to be the sole mechanism. Further exploration into other functional pathways, namely migration, is needed to explain changes to immune populations following ACT.
LGG-03. EXPLORING THE SIGNALING NETWORK INVOLVED IN MAPK PATHWAY INHIBITION BY THE MEK INHIBITOR TRAMETINIB IN BRAF-FUSION-DRIVEN PEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Sigaud Romain , Stefanski Anja , Selt Florian , Hielscher Thomas , Usta Diren , Kocher Daniela , Picard Daniel , Büdenbender Isabel , Remke Marc , Pfister Stefan M , Jones David T W , Brummer Tilman , Witt Olaf , Milde Till
Published: June 2023

INTRODUCTION

Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by MAPK pathway alterations, leading to its constitutive activation and modulating the balance between proliferation and oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP). Little is known about the molecular implications of MAPK pathway inhibition in the proliferating and senescent tumor compartments.

METHODS

DKFZ-BT66 cells derived from a primary KIAA:BRAF-fusion positive PA cell line and BT40 cells derived from pleomorphic xanthoastrocytoma with a BRAFV600E mutation and CDKN2A/B deletion, were used as model systems. RNA-sequencing and phospho-/proteomic datasets were generated in both the proliferative and senescent cells, and treated with the MEKi trametinib for different time-spans. A multi-omics factor analysis tool (MEFISTO) was used to identify key OIS/proliferation effectors.

RESULTS

Differential gene expression analysis revealed that MEK inhibition leads to the inhibition of the OIS/SASP gene program in senescent DKFZ-BT66. In addition, the protein level of several SASP factors was decreased. This translated in reduced sensitivity towards senolytics drugs, indicating inhibition of senescence features upon MEKi. MEFISTO analysis allowed to identify key transcription factors, genes and proteins involved in MAPK-induced OIS in the senescent PA cells, that were mapped using a prior knowledge network approach. Finally, single sample geneset enrichment analysis showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including several RTK pathways) were predicted to be upregulated, in both proliferating and senescent cells.

CONCLUSION

This data suggests that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators, identifying putative co-targets for the treatment of PA. Further validation of the targetability of these pathways is pending. Furthermore, the identification of the MAPK-related OIS/SASP genes provide insight about the regulation of OIS/SASP by the MAPK pathway.
LGG-22. CHARACTERIZATION OF THE TUMOR MICROENVIRONMENT IN PEDIATRIC LOW-GRADE GLIOMA
Authors: Zahedi Shadi , Riemondy Kent , Griesinger Andrea , Donson Andrew , Fu Rui , Crespo Michelle , Groat Madeline , Bratbak Emil , Desisto John , Rheaume John , Green Adam , Vibhakar Rajeev , Willard Nicholas , Forman Nicholas , Levy Jean Mulcahy
Published: June 2023

BACKGROUND

Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children. Although pLGGs represent a significant number of patients with slow-growing, often curable tumors, they are also affected by neurologic injuries, multiple relapses and requiring repeated courses of therapy, including surgery, chemotherapy, and radiotherapy. Novel, more effective therapies are urgently needed.

METHODS

We used a multipronged approach to better understand the complexity of the tumor microenvironment (TME) within pLGG. We utilized scRNA sequencing, spatial transcriptomics, and cytokine analyses on 23 patient-derived pLGG samples including different tumor types (pilocytic astrocytoma (PA), ganglioglioma (GG), and undefined low-grade glioma (LGG)) and mutation profiles (BRAF V600E, BRAF fusions, and BRAF wild-type) to identify cell types, their spatial arrangement within a tissue, and their underlying functional status.

RESULTS

scRNA seq revealed both tumor and immune cells within the TME. Analyses of tumor cell subsets revealed a developmental hierarchy identifying progenitor and mature cell populations. Immune cells comprised both myeloid and T lineage cells, with myeloid cells comprising > 50% of the entire population. Interestingly, there was a significant difference between the prevalence of two major myeloid subclusters between two pLGG subtypes (PA and GG). To better understand the underlying difference, we performed bulk and single-cell cytokine analyses to identify immune signals via which these cells communicate. Cytokine analyses revealed distinct immune phenotypes among tumor samples. Notably, BRAF fusion tumors appeared more immunogenic, especially by secreting higher levels of immune cell activators, chemokines (including CCL3 and CCL4), compared to BRAF V600E tumors. Additionally, spatial transcriptomics revealed the differential expression of these chemokines between PA and GG tumors.

CONCLUSIONS

Characterization of pLGG demonstrated the complexity of tumor microenvironment among different pLGG subtypes. Further investigation of the immune cells and tumor-immune cell interactions has the potential to unravel novel therapeutic targets against pLGG.
LGG-24. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR MANAGEMENT AND OUTCOME: A SINGLE CENTER EXPERIENCE
Authors: Munir Faryal , He Jiasen , Sheikh Irtiza , Chen Melissa , Johnson Jason , McAleer Mary , McGovern Susan , Paulino Arnold , Huse Jason , Sandberg David , Zaky Wafik
Published: June 2023

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis that was first incorporated into the WHO Classification in 2016. DLGNTs are usually low-grade tumors, with no current standard of care. A retrospective review of patients with a histologic diagnosis of DLGNT, from 2010 to 2022, was done with IRB approval. Eight patients were identified with a median age at diagnosis of 5.5 years (range 4 months - 21 years). Imaging findings included diffuse leptomeningeal enhancement and multifocal nodular lesions in the supratentorial and infratentorial locations. One patient had localized pineal disease and 2 patients had isolated spinal cord involvement. Histologically, 6/8 (75%) patients showed low-grade tumor (Ki-67 index = 2-15%). BRAF-KIAA1549 fusion was reported in 3, NTRK fusion in 1, PTPN11 mutation in 1, and FGFR1 mutation in 1 patient. Seven patients (88%) were treated with proton radiation, 3 at diagnosis and 4 upon progression. Chemotherapy was used at diagnosis on 4 patients (temozolomide, carboplatin and vincristine, and vinblastine). Targeted therapy (NTRK or BRAF-inhibitors) was utilized upon progression in four patients, and at diagnosis in one. All patients showed disease progression at a median time of 24 months from diagnosis. The median progression-free survival (PFS) in the group receiving upfront RT was 2.2 years (range = 0.4 – 6.6 years), versus chemotherapy of 1.4 years (range = 0.15 - 2.6 years) The 2 years PFS and OS are 57% and 100%, respectively. At a median follow-up of 4.5 years (range = 3 months to 9 years), 6 patients have stable disease (of whom 2 are off therapy), and 2 patients have progressive disease. DLGNTs are rare tumors with scarce data about radiological and molecular characteristics, and no established standard of care. Our case series emphasizes the need for further studies on molecular profiling and exploring targeted therapies.
MDB-04. SINGLE-CELL TRANSCRIPTOMIC ANALYSIS REVEALS DISTINCT GENOMIC LANDSCAPES, CELL TRAJECTORIES, AND TUMOUR-MICROENVIRONMENT INTERACTIONS IN FOUR SUBTYPES OF MEDULLOBLASTOMA
Authors: Ruchiy Yana , Tsea Ioanna , Verhoeven Bronte Manouk , Sinha Indranil , Preka Efthalia , Olsen Thale Kristin , Mei Shenglin , Blomgren Klas , Johnsen John Inge , Carlson Lena-Maria , Dyberg Cecilia , Baryawno Ninib
Published: June 2023

Medulloblastoma is the most common paediatric high-grade brain tumour, which comprises four different molecular subtypes (SHH, Wnt, Group 3, and Group 4), each defined by different molecular characteristics, genomic aberrations, and prognosis. High levels of inter- and intra-tumoural heterogeneity, together with the detrimental side effects caused by the current medulloblastoma treatments, need to be addressed in order to develop more personalised treatments and improve the quality of life of these patients. In this study, we analysed single-cell RNA sequencing data from 14 medulloblastoma patients, comprising all four molecular subtypes. We found that these tumours exhibit great levels of heterogeneity with regard to their copy number variation (CNV) profiles analysed using Numbat, as well as immune cell infiltration and composition within these tumours. Tumour-infiltrating immune cells represented a heterogeneous population comprised of monocytes, M1- and M2-like macrophages, dendritic cells, and microglia. Our ligand-receptor analysis also identified a subset of immune cells that send EGF signals to the tumour clusters, potentially contributing to the tumour growth. In addition, we showed that the tissue of origin of the immune cells found within the tumour microenvironment and their medulloblastoma subgroup specificity greatly influence their clustering when projected onto a UMAP. We also found that the clustering of tumour cells is influenced by their CNV levels. Finally, we performed RNA velocity analysis and identified subgroup-specific cell trajectories for each medulloblastoma subtype. As predicted, identified cell trajectories demonstrated that cells move in a direction of increasing CNV levels, making it possible to visualise and track the tumour progression and identify genetic markers specific to either earlier or later tumour stages. Overall, our study underlines high levels of inter-tumoural heterogeneity in medulloblastoma. It also provides opportunities for the identification of subgroup-specific biomarkers for the early stages of medulloblastoma, potentially contributing to the discovery of novel drug targets.
MDB-06. PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA
Authors: Taylor Jessica T , Williams James C , Masih Katherine E , Bonner Sigourney , Lehner Paul , Gilbertson Richard J
Published: June 2023

WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated with major, long-term, debilitating side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. The Gilbertson lab has previously shown that WNT-medulloblastomas are devoid of a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover WNT-medulloblastoma specific antigens for mAb targeting, we have first generated bulk and single-cell RNA sequencing profiles of the wild-type and WNT-medulloblastoma-prone mossy-fibre progenitor lineages in the lower rhombic lip, as well as human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next generated plasma membrane proteome profiles of hindbrain germinal zones and WNT-medulloblastomas. Plasma Membrane Profiling (PMP) deploys an isobaric chemical labelling approach -Tandem Mass Tags (TMT) - that allows multiplexing of up to sixteen variables per mass spectrometry experiment and ex vivo TMT-labelling of primary cells. Using this approach, we have mapped the cell surface proteome of our medulloblastoma models. Interrogation of these developmental and tumour data has unmasked WNT-medulloblastoma associated antigens that are specific for prenatal brain and WNT-medulloblastoma, but that are not expressed on critical postnatal tissues. Our workflow integrates multi-omic data sets to uncover a targetable landscape on the surface of WNT-medulloblastoma cells that we have cross-validated with a large cohort of patient RNA sequencing profiles and histological samples of both mouse and human tumours. To translate this dataset to real patient benefit, we are generating high affinity antibodies of these validated cell-surface proteins for assessment in our pre-clinical mouse models. mAbs directed towards essential receptors may have a therapeutic effect alone, however we will additionally modify mAbs to specifically deliver cytotoxic therapeutics - curing children whilst sparing healthy brain tissue.
MDB-33. REST AND USP37 CONTROL THE MTORC1-AUTOPHAGY AXIS IN MEDULLOBLASTOMA BY REGULATING RAPTOR DEGRADATION
Authors: Cheng Donghang , Singh Ashutosh , Haltom Amanda R , Zheng Yan , Sharma Ajay , Lopez Mariana , Gordon Nancy , Gopalakrishnan Vidya
Published: June 2023

The RE1 Silencing Transcription Factor (REST) is a repressor of neurogenesis. Its expression is elevated in the pediatric brain tumor medulloblastoma (MB) and correlates with poor patient prognosis. RNAseq analyses of MB tumors identified significant differences in the expression of genes associated with autophagy between high- and low-REST expressing samples. Microscopy and biochemical analyses of isogenic high- and low-REST human MB cell lines confirmed REST-dependent changes in autophagy, suggesting that REST controls the process. We had previously shown that REST regulates the activity of the mammalian target of rapamycin complex 2 (mTORC2). However, whether REST controls the mTORC1 pathway, a negative regulator for autophagy, is still unknown. mTORC1 is known to block autophagy initiation by phosphorylation of UNC51-like autophagy activating kinases (ULK)1/2 and the Phosphatidyl Kinase 3 subunit C3 (PIK3C3) to prevent global expression of lysosomal and autophagy genes through Transcription Factor EB (TFEB) phosphorylation. The above findings led us to investigate if REST controls autophagy through modulation of mTORC1 activity in MBs and to understand the underlying mechanisms. Biochemical studies demonstrated that REST elevation promotes proteasomal degradation of Raptor, a key regulatory sub-unit of the mTOR1 complex, to induce autophagy. Specifically, we discovered that Raptor is a novel substrate of the deubiquitylase USP37, which we previously identified as a REST-target gene product. These data show that REST drives autophagy by silencing USP37, destabilizing Raptor, and blocking mTORC1 activity. Finally, the pharmacological blockade of autophagy caused a decline in MB cell growth in a REST-dependent manner, indicating that REST-dependent autophagy is a pro-survival mechanism in MBs.
OTHR-12. LOCATION-RELEVANT GROWTH FACTOR DEPENDENCE ON THE FORMATION OF PEDIATRIC BRAIN TUMOR ORGANOIDS FROM PDOX MODELS AND PATIENT SAMPLES
Authors: Suarez Milagros , Xiao Sophie , Abdallah Aalaa , DuCuypere Michael , Lam Sandi , Wadhwani Nitin , Du Yuchen , Li Xiao-Nan
Published: June 2023

Brain cancer constitutes the most common type of childhood malignancies and the leading cause of death in children. Despite recent advances in diagnostic methods, surgical techniques as well as chemo- and radio-therapeutic strategies; the survival rates in many types of malignant pediatric brain tumors remain dismal, with <25% of children with high grade glioma surviving five years after initial diagnosis and nearly all patients with diffuse intrinsic pontine glioma succumbing to the disease within 9-12 months. Moreover, even among brain tumor survivors, many patients are left with long-term cognitive and/or neuroendocrine sequalae. Therefore, more efficacious therapeutic modalities that can improve the patient’s quality of life and increase their survival are urgently needed. 3D organoid cultures have arisen as clinically relevant and molecularly accurate in vitro brain tumor model systems for preclinical drug testing. These models have demonstrated to faithfully recapitulate the genomic and phenotypic complexities of the original tumor and thereby, can reliably predict the patient response to treatment. Recognizing the impact of the tumor microenvironment and the brain developmental stage on brain tumor growth, we developed a novel protocol to evaluate the impact of tumor location-related niche factors on the development of brain tumoral organoids. Utilizing different growth factor combinations that are unique/selective to different regions of brain development, we were able to develop 39 PDOX-derived organoids from a total of 40 PDOX models tested (success rate: 97.5%) and 23 patient-derived organoids from a total of 29 patient samples tested (success rate: 79%). Furthermore, cellular characterization studies revealed the replication of an heterogenous cell population. Altogether, our study identifies differences on growth factor dependence for the formation of organoids from brain tumors of different locations and demonstrates that PDOX models are valuable tools for the development and optimization of protocols for organoid model establishment.
TRLS-06. A PHASE 1, SAFETY AND DOSE ESCALATION STUDY OF BXQ-350 IN COMBINATION WITH RADIATION IN PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Dorris Kathleen , Fouladi Maryam , Hummel Trent , Raskin Scott , III Richard Curry , Purvis Joseph , Gazda Michael , Tapolsky Gilles , Takigiku Ray
Published: June 2023

This trial (NCT04771897) is currently enrolling at 3 US sites; as of January 2023, a total of 8 patients have been enrolled. Enrollment of cohort 1 (2.4 mg/kg and 54 Gy) and cohort 2 (3.2 mg/kg and 54 Gy) are completed. Enrollment in the expansion cohort is on-going. To date, no dose-limiting toxicity has been observed and the combination of BXQ-350 plus radiation has been well tolerated.

BXQ-350 is a nanovesicle formulation of Saposin C that induces apoptosis of cancer cells and an anti-tumoral immune response by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations. Saposin C is a human protein encoded by the Psap gene and is an allosteric activator of enzymes involved in sphingolipid/ceramide metabolism. The significance of sphingolipid metabolism in brain cancers has been demonstrated and enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers.

BXQ-350 was investigated in a Phase 1 dose-escalation safety study in pediatric brain cancer patients (NCT03967093); results showed that it was well-tolerated, a MTD was not established, and the safety profile warranted the investigation of combination studies at the highest dose tested (3.2 mg/kg). Additionally, results from a Phase 1 safety and dose escalation study in adult patients with advanced solid malignancies (NCT02859857) indicated that BXQ-350 was well tolerated and showed single agent activity with evidence of modulating sphingolipid metabolism and favorably influencing the tumor microenvironment.

The primary objective of this dose-escalation study is to describe the safety profile and to determine the maximum tolerated dose of BXQ-350 in combination with radiation. BXQ-350 is administered intravenously concurrently with radiation therapy followed by adjuvant BXQ-350 until disease progression. Multiple secondary parameters are included to characterize BXQ-350’s pharmacokinetic parameters and efficacy profile and to investigate potential biomarkers.
Scouting for Boys
Authors: Baden-Powell Robert
Published: June 2023

A startling amalgam of Zulu war-cry and imperial and urban myth, of borrowed tips on health and hygiene, and object lessons in woodcraft, Robert Baden-Powell’s Scouting for Boys (1908) is the original blueprint and ‘self-instructor’ of the Boy Scout Movement. One of the all-time bestsellers in the English-speaking world, this primer of ‘yarns and pictures’ constitutes probably the most influential manual for youth ever published. Yet the book is at the same time a roughly composed hodge-podge of jingoist lore and tracker legend, padded with lengthy quotations from adventure fiction and Baden-Powell’s own autobiography, and seamed through with the multiple anxieties of its time: fears of degeneration, concerns about masculinity and self-restraint, invasion paranoia.

Elleke Boehmer’s edition of Scouting for Boys reprints the original text and illustrations, and her fine introduction investigates a book that has been cited as an authority by militarists and pacifists, capitalists and environmentalists alike.
The Beautiful and Damned
Authors: Fitzgerald F. Scott
Published: June 2023

F. Scott Fitzgerald’s second novel, The Beautiful and Damned (1922), is a devastating portrait of a generation of wealthy young Americans who struggle to find meaning and happiness in their lives. The sophisticated but emotionally fragile Anthony Patch enjoys an initially idyllic marriage to the beautiful Gloria Gilbert. But their intense romance turns sour as they waste their time and energy in decadent leisure and luxury. Their happiness comes to depend on gaining a vast inheritance from Anthony’s grandfather, but they are stifled by their inner fears and are ill-prepared for the inevitable loss of youth and prosperity. Set amid the vibrant social and commercial world of New York in the early twentieth century, the novel expresses the promise and disillusionment of America at the start of the Jazz Age.

This is the novel that confirmed Fitzgerald’s status as the most celebrated young American writer of the Twenties. The author’s exuberant and enchanting style is on full display, three years before the critical triumph of The Great Gatsby.
Mrs Dalloway
Authors: Woolf Virginia
Published: June 2023

Mrs Dalloway, Virginia Woolf’s fourth novel, offers the reader an impression of a single June day in London in 1923. Clarissa Dalloway, the wife of a Conservative member of parliament, is preparing to give an evening party, while the shell-shocked Septimus Warren Smith hears the birds in Regent’s Park chattering in Greek. There seems to be nothing, except perhaps London, to link Clarissa and Septimus. She is middle-aged and prosperous, with a sheltered happy life behind her; Smith is young, poor, and driven to hatred of himself and the whole human race. Yet both share a terror of existence, and sense the pull of death.

The world of Mrs Dalloway is evoked in Woolf’s famous stream of consciousness style, in a lyrical and haunting language which has made this, from its publication in 1925, one of her most popular novels.
Of the Quest of the Golden Fleece
Authors: Du Bois W. E. B.
Published: June 2023

But the Brute said in his breast, “Till the mills I grind have ceased, The riches shall be dust of dust, dry ashes be the feast!
Dubliners
Authors: Joyce James
Published: June 2023

‘I regret to see that my book has turned out un fiasco solenne’

James Joyce’s disillusion with the publication of Dubliners in 1914 was the result of ten years battling with publishers, resisting their demands to remove swear words, real place names and much else, including two entire stories. Although only 24 when he signed his first publishing contract for the book, Joyce already knew its worth: to alter it in any way would ‘retard the course of civilisation in Ireland’.

Joyce’s aim was to tell the truth - to create a work of art that would reflect life in Ireland at the turn of the last century and by rejecting euphemism, reveal to the Irish the unromantic reality the recognition of which would lead to the spiritual liberation of the country. Each of the fifteen stories offers a glimpse of the lives of ordinary Dubliners - a death, an encounter, an opportunity not taken, a memory rekindled - and collectively they paint a portrait of a nation.
Araby
Authors: Joyce James
Published: June 2023

North Richmond Street, being blind, was a quiet street except at the hour when the Christian Brothers’ School set the boys free. An uninhabited house of two storeys stood at the blind end, detached from its neighbours in a square ground. The other houses...
Ivy Day in the Committee Room
Authors: Joyce James
Published: June 2023

Old Jack raked the cinders together with a piece of cardboard and spread them judiciously over the whitening dome of coals. When the dome was thinly covered his face lapsed into darkness but, as he set himself to fan the fire again, his crouching...
The Man Without a Temperament
Authors: Mansfield Katherine
Published: June 2023

He stood at the hall door turning the ring, turning the heavy signet ring upon his little finger while his glance travelled coolly, deliberately, over the round tables and basket-chairs scattered about the glassed-in verandah. He pursed his lips—he might have been going to whistle—but...
The Interpretation of Dreams
Authors: Freud Sigmund , Crick Joyce , Robertson Ritchie
Published: June 2023

This groundbreaking new translation of The Interpretation of Dreams is the first to be based on the original text published in November 1899. It restores Freud’s original argument, unmodified by revisions he made following the book’s critical reception which included, under the influence of his associate Wilhelm Stekel, the theory of dream symbolism. Reading the first edition reveals Freud’s original emphasis on the use of words in dreams and on the difficulty of deciphering them and Joyce Crick captures with far greater immediacy and accuracy than previous translations by Strachey’s Freud’s emphasis and terminology. An accessible introduction by Ritchie Robertson summarizes and comments on Freud’s argument and relates it to his early work. Close annotation explains Freud’s many autobiographical, literary and historical allusions and makes this the first edition to present Freud’s early work in its full intellectual and cultural context.
Greenmantle
Authors: Buchan John
Published: June 2023

In Greenmantle (1916) Richard Hannay, hero of The Thirty-Nine Steps, travels across war-torn Europe in search of a German plot and an Islamic Messiah. He is joined by three more of Buchan’s heroes: Peter Pienaar, the old Boer Scout; John S. Blenkiron, the American determined to fight the Kaiser; and Sandy Arbuthnot, Greenmantle himself, modelled on Lawrence of Arabia. The intrepid four move in disguise through Germany to Constantinople and the Russian border to face their enemies - the grotesque Stumm and the evil beauty of Hilda von Einem.

In this classic espionage adventure Buchan shows his mastery of the thriller and the Stevensonian romance, and also his enormous knowledge of world politics before and during the First World War. This edition illuminates for the first time the many levels beneath the stirring plot and romantic characters.
Sons and Lovers
Authors: Lawrence D. H.
Published: June 2023

Lawrence’s first major novel was also the first in the English language to explore ordinary working-class life from the inside. No writer before or since has written so well about the intimacies enforced by a tightly-knit mining community and by a family where feelings are never hidden for long.

When the marriage between Walter Morel and his sensitive, high-minded wife begins to break down, the bitterness of their frustration seeps into their children’s lives. Their second son, Paul, craves the warmth of family and community, but knows that he must sacrifice everything in the struggle for independence if he is not to repeat his parents’ failure.

Lawrence’s powerful description of Paul’s single-minded efforts to define himself sexually and emotionally through relationships with two women - the innocent, old-fashioned Miriam Leivers and the experienced, provocatively modern Clara Dawes - makes this a novel as much for the beginning of the twenty-first century as it was for the beginning of the twentieth.
The Age of Innocence
Authors: Wharton Edith
Published: June 2023

‘They lived in a kind of hieroglyphic world, where the real thing was never said or done or even thought, but only represented by a set of arbitrary signs.’

Edith Wharton’s most famous novel, written immediately after the end of the First World War, is a brilliantly realized anatomy of New York society in the 1870s, the world in which she grew up, and from which she spent her life escaping. Newland Archer, Wharton’s protagonist, charming, tactful, enlightened, is a thorough product of this society; he accepts its standards and abides by its rules but he also recognizes its limitations. His engagement to the impeccable May Welland assures him of a safe and conventional future, until the arrival of May’s cousin Ellen Olenska puts all his plans in jeopardy. Independent, free-thinking, scandalously separated from her husband, Ellen forces Archer to question the values and assumptions of his narrow world. As their love for each other grows, Archer has to decide where his ultimate loyalty lies.
Up from Slavery
Authors: Washington Booker T.
Published: June 2023

‘My life had its beginning in the midst of the most miserable, desolate, and discouraging surroundings.’

For half a century from its publication in 1901 Up from Slavery was the best known book written by an African American. The life of ex-slave Booker T Washington embodied the legendary rise of the American self-made man, and his autobiography gave prominence for the first time to the voice of a group which had to pull itself up from extreme adversity. Washington attributes his success to his belief in many of the virtues celebrated by Benjamin Franklin: selflessness, industry, pragmatism, and optimism. But from behind the mask of the humble, plainspoken schoolmaster come hints that reveal Washington the ambitious and tough-minded analyst of power who had to balance the demands of blacks with the constraints imposed on him by whites.

To read Up from Slavery is to explore the means by which Washington rose to become the most influential and powerful black American of his time. How far he compromised African American rights in order to achieve his aims remains a matter of controversy.
The Rainbom
Authors: Lawrence D.H.
Published: June 2023

This is the insight that flashes upon Ursula as she struggles to assert her individuality and to stand separate from her family and her surroundings on the brink of womanhood and the modern world.

In The Rainbow (1915) Lawrence challenged the customary limitations of language and convention to carry into the structure of his prose the fascination with boundaries and space that characterize the entire novel. Condemned and suppressed on its first publication for its open treatment of sexuality and its ‘unpatriotic’ spirit, the novel chronicles the lives of three generations of the Brangwen family over a period of more than 60 years, setting them against the emergence of modern England. The central figure of ursula becomes the focus of Lawrence’s examination of relationships and the conflicts they bring, and the inextricable mingling of the physical and the spiritual. Suffused with biblical imagery, The Rainbow addresses searching human issues in a setting of precise and vivid detail.

In her introduction to this edition Kate Flint illuminates Lawrence’s aims and achievements against the background of the burgeoning century.
The Virginian
Authors: Wister Owen
Published: June 2023

The Virginian (1902) is Owen Wister’s classic popular romance, and the most significant shaping influence on cowboy fiction. Its narrator, fresh from the East, encounters in Wyoming cattle country a strange, seductive and often violent land where the handsome figure of the Virginian battles for supremacy with Trampas and other ne’er-do-wells. His courtship of the genteel Vermont schoolteacher, Molly Wood, is a humourously observed battle of the sexes, demonstrating that the ‘customs of the country’ must eventually prevail. Rich in vernacular wit and portraying a romanticized escape from the decorum of the patrician East, The Virginian exudes a sense of redemptive possibility, drawing on Wister’s experience of a summer spent on a Wyoming ranch in 1895.

This edition includes Wister’s neglected essay, ‘The Evolution of the Cow-Puncher’ (1895), a revealing companion to a novel that has disturbing undercurrents.
Chapter I
Authors: Woolf Virginia
Published: June 2023

He—for there could be no doubt of his sex, though the fashion of the time did something to disguise it—was in the act of slicing at the head of a Moor* which swung from the rafters. It was the colour of an...
Chapter II
Authors: Woolf Virginia
Published: June 2023

The biographer is now faced with a difficulty which it is better perhaps to confess than to gloss over. Up to this point in telling the story of Orlando’s life, documents, both private and historical, have made it possible to fulfil the first duty...
Chapter IV
Authors: Woolf Virginia
Published: June 2023

With some of the guineas left from the sale of the tenth pearl of her string, Orlando bought herself a complete outfit of such clothes as women then wore, and it was in the dress of a young Englishwoman of rank that she now...
Chapter v
Authors: Woolf Virginia
Published: June 2023

The great cloud which hung, not only over London, but over the whole of the British Isles on the first day of the nineteenth century stayed, or rather, did not stay, for it was buffeted about constantly by blustering gales, long enough to have...
A Stereoselective Strigolactone Biosynthesis Catalyzed by a 2-Oxoglutarate-Dependent Dioxygenase in Sorghum
Authors: Yoda Akiyoshi , Xie Xiaonan , Yoneyama Kaori , Miura Kenji , McErlean Christopher S P , Nomura Takahito
Published: June 2023

Seeds of root parasitic plants, Striga, Orobanche and Phelipanche spp., are induced to germinate by strigolactones (SLs) exudated from host roots. In Striga-resistant cultivars of Sorghum bicolor, the loss-of-function of the Low Germination Stimulant 1 (LGS1) gene changes the major SL from 5-deoxystrigol (5DS) to orobanchol, which has an opposite C-ring stereochemistry. The biosynthetic pathway of 5DS catalyzed by LGS1 has not been fully elucidated. Since other unknown regulators, in addition to LGS1 encoding a sulfotransferase, appear to be necessary for the stereoselective biosynthesis of 5DS, we examined Sobic.005G213500 (Sb3500), encoding a 2-oxoglutarate-dependent dioxygenase, as a candidate regulator, which is co-expressed with LGS1 and located 5ʹ-upstream of LGS1 in the sorghum genome. When LGS1 was expressed with known SL biosynthetic enzyme genes including the cytochrome P450 SbMAX1a in Nicotiana benthamiana leaves, 5DS and its diastereomer 4-deoxyorobanchol (4DO) were produced in approximately equal amounts, while the production of 5DS was significantly larger than that of 4DO when Sb3500 was also co-expressed. We also confirmed the stereoselective 5DS production in an in vitro feeding experiment using synthetic chemicals with recombinant proteins expressed in Escherichia coli and yeast. This finding demonstrates that Sb3500 is a stereoselective regulator in the conversion of the SL precursor carlactone to 5DS, catalyzed by LGS1 and SbMAX1a, providing a detailed understanding of how different SLs are produced to combat parasitic weed infestations.
Acetylation of inorganic pyrophosphatase by S-RNase signaling induces pollen tube tip swelling by repressing pectin methylesterase
Authors: Tang Chao , Wang Peng , Zhu Xiaoxuan , Qi Kaijie , Xie Zhihua , Zhang Hao , Li Xiaoqiang , Gao Hongru , Gu Tingting , Gu Chao , Li Shan , de Graaf Barend H J , Zhang Shaoling , Wu Juyou
Published: June 2023

Self-incompatibility (SI) is a widespread genetically determined system in flowering plants that prevents self-fertilization to promote gene flow and limit inbreeding. S-RNase–based SI is characterized by the arrest of pollen tube growth through the pistil. Arrested pollen tubes show disrupted polarized growth and swollen tips, but the underlying molecular mechanism is largely unknown. Here, we demonstrate that the swelling at the tips of incompatible pollen tubes in pear (Pyrus bretschneideri [Pbr]) is mediated by the SI-induced acetylation of the soluble inorganic pyrophosphatase (PPA) PbrPPA5. Acetylation at Lys-42 of PbrPPA5 by the acetyltransferase GCN5-related N-acetyltransferase 1 (GNAT1) drives accumulation of PbrPPA5 in the nucleus, where it binds to the transcription factor PbrbZIP77, forming a transcriptional repression complex that inhibits the expression of the pectin methylesterase (PME) gene PbrPME44. The function of PbrPPA5 as a transcriptional repressor does not require its PPA activity. Downregulating PbrPME44 resulted in increased levels of methyl-esterified pectins in growing pollen tubes, leading to swelling at their tips. These observations suggest a mechanism for PbrPPA5-driven swelling at the tips of pollen tubes during the SI response. The targets of PbrPPA5 include genes encoding cell wall–modifying enzymes, which are essential for building a continuous sustainable mechanical structure for pollen tube growth.
Democratic Backsliding: Comparative Reflections on the American Experience
Authors: Encarnación Omar G
Published: June 2023

Democratic backsliding, or the debilitation of democracy by those elected to protect it, looms large in the current debate about the global crisis of democracy, including Sara Wallace Goodman's Citizenship in Hard Times: How Ordinary People Respond to Democratic Threat. In keeping with the prevailing view of backsliding as a political phenomenon rooted in extreme partisanship and polarization, Goodman is concerned with strengthening the citizenry's commitment to democratic norms and practices—in other words, boosting democratic citizenship. Placing the roots of backsliding in the political system itself, this essay argues for pushing the debate about backsliding beyond citizen solutions and toward institutional remedies, especially accountability against those who harm democracy and modernizing the democratic infrastructure.
Single Stitch Vicryl Mesh Wrap for Prepectoral Implant Breast Reconstruction
Authors: Mookerjee Vikram G. , Stögner Viola A. , Alper David P. , Evans Brogan G.A. , Pomahac Bohdan
Published: June 2023

Acellular dermal matrices are commonly used in prepectoral breast reconstruction for implant coverage and support, but they are associated with significant costs. The authors describe a technique for prepectoral breast reconstruction in which the implant is completely wrapped in a knitted Vicryl mesh and then positioned on the chest, without the need for any tacking sutures. A retrospective review was performed on all consecutive prepectoral breast reconstructions, using this technique at a single institution. A separate cohort undergoing prepectoral reconstruction with a conventional acellular dermal matrix technique was also reviewed for comparison. Patient demographics, oncologic and reconstruction characteristics, outcomes, complications, and materials cost were analyzed. Twelve patients (23 breasts) underwent prepectoral reconstruction with Vicryl mesh, and 34 patients (55 breasts) underwent prepectoral reconstruction with acellular dermal matrices. Overall complication rates in the Vicryl group were low (two infections, one case of skin necrosis, one hematoma) and did not differ statistically from the acellular dermal matrix group. Operative time per breast was nearly twice as fast (35.7 versus 68.0 min, P < 0.01). Calculated materials cost savings was $8273 per breast. Prepectoral breast reconstruction with Vicryl mesh only is a safe technique that is much faster and significantly cheaper compared with conventional reconstructive techniques utilizing acellular dermal matrices.
Analysis of a National Database Investigating Development of Trigger Finger after Treatment of Dupuytren Disease
Authors: Gehring Michael B. , Constantine Ryan S. , Le Elliot L. H. , Wolfe Brandon , Greyson Mark A. , Iorio Matthew L.
Published: June 2023

Background:

Dupuytren disease is associated with inflammation and myofibroblast overgrowth, as is stenosing tenosynovitis (trigger finger). Both are linked with fibroblast proliferation, but a potential associative link between the diseases is unknown. The purpose of this study was to evaluate the progression of trigger finger following treatment for Dupuytren contracture in a large database.

Methods:

A commercial database encompassing 53 million patients was utilized from January 1, 2010 to March 31, 2020. The study cohort included patients diagnosed with either Dupuytren disease or trigger finger utilizing International Classification Codes 9 and 10. Terminology codes were used to identify common Dupuytren procedures, as well as trigger finger release. Logistic regression analysis was used to define independent risk factors for developing trigger finger.

Results:

A total of 593,606 patients were diagnosed with trigger finger. Of these patients, 15,416 (2.6%) were diagnosed with trigger finger after diagnosis of Dupuytren disease, whereas 2603 (0.4%) patients were diagnosed with trigger finger after treatment of Dupuytren contracture. Independent risk factors for trigger finger included age 65 years or older (OR 1.00, P < 0.05), diabetes (OR 1.12, P < 0.05) and obesity (OR 1.20, P < 0.005). Patients who received collagenase clostridium histolyticum treatment (OR 0.34, P < 0.005) for Dupuytren contracture were significantly less likely to develop trigger finger.

Conclusions:

Dupuytren contracture is associated with inflammation and subsequent trigger finger development at a higher rate than the background population frequency. Collagenase clostridium histolyticum injection may lead to a decreased risk of trigger finger requiring surgical intervention in patients with risk factors.