bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma
Authors: Creasy Caitlin A. , Meng Yuzhong Jeff , Forget Marie-Andrée , Karpinets Tatiana , Tomczak Katarzyna , Stewart Chip , Torres-Cabala Carlos A. , Pilon-Thomas Shari , Sarnaik Amod A. , Mulé James J. , Garraway Levi , Bustos Matias , Zhang Jianhua , Patel Sapna P. , Diab Adi , Glitza Isabella C. , Yee Cassian , Tawbi Hussein , Wong Michael K. , McQuade Jennifer , Hoon Dave S.B. , Davies Michael A. , Hwu Patrick , Amaria Rodabe N. , Haymaker Cara , Beroukhim Rameen , Bernatchez Chantale 
Published: May 2022

AbstractPurpose:Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%–50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.Experimental Design:We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.Results:Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.Conclusions:Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.
Targeted Analysis of Cell-free Circulating Tumor DNA is Suitable for Early Relapse and Actionable Target Detection in Patients with Neuroblastoma
Authors: Lodrini Marco , Graef Josefine , Thole-Kliesch Theresa M. , Astrahantseff Kathy , Sprüssel Annika , Grimaldi Maddalena , Peitz Constantin , Linke Rasmus B. , Hollander Jan F. , Lankes Erwin , Künkele Annette , Oevermann Lena , Schwabe Georg , Fuchs Jörg , Szymansky Annabell , Schulte Johannes H. , Hundsdörfer Patrick , Eckert Cornelia , Amthauer Holger , Eggert Angelika , Deubzer Hedwig E. 
Published: May 2022

Abstract

Purpose:
Treating refractory or relapsed neuroblastoma remains challenging. Monitoring body fluids for tumor-derived molecular information indicating minimal residual disease supports more frequent diagnostic surveillance and may have the power to detect resistant subclones before they give rise to relapses. If actionable targets are identified from liquid biopsies, targeted treatment options can be considered earlier.

Experimental Design:
Droplet digital PCR assays assessing MYCN and ALK copy numbers and allelic frequencies of ALK p.F1174L and ALK p.R1275Q mutations were applied to longitudinally collected liquid biopsies and matched tumor tissue samples from 31 patients with high-risk neuroblastoma. Total cell-free DNA (cfDNA) levels and marker detection were compared with data from routine clinical diagnostics.

Results:
Total cfDNA concentrations in blood plasma from patients with high-risk neuroblastoma were higher than in healthy controls and consistently correlated with neuron-specific enolase levels and lactate dehydrogenase activity but not with 123I-meta-iodobenzylguanidine scores at relapse diagnosis. Targeted cfDNA diagnostics proved superior for early relapse detection to all current diagnostics in 2 patients. Marker analysis in cfDNA indicated intratumor heterogeneity for cell clones harboring MYCN amplifications and druggable ALK alterations that were not detectable in matched tumor tissue samples in 17 patients from our cohort. Proof of concept is provided for molecular target detection in cerebrospinal fluid from patients with isolated central nervous system relapses.

Conclusions:
Tumor-specific alterations can be identified and monitored during disease course in liquid biopsies from pediatric patients with high-risk neuroblastoma. This approach to cfDNA surveillance warrants further prospective validation and exploitation for diagnostic purposes and to guide therapeutic decisions.
Association ofTP53andCDKN2AMutation Profile with Tumor Mutation Burden in Head and Neck Cancer
Authors: Deneka Alexander Y. , Baca Yasmine , Serebriiskii Ilya G. , Nicolas Emmanuelle , Parker Mitchell I. , Nguyen Theodore T. , Xiu Joanne , Korn W. Michael , Demeure Michael J. , Wise-Draper Trisha , Sukari Ammar , Burtness Barbara , Golemis Erica A. 
Published: May 2022

AbstractPurpose:Head and neck squamous cell carcinoma (HNSCC) is a frequently devastating cancer that affects more than a half million people annually worldwide. Although some cases arise from infection with human papillomavirus (HPV), HPV-negative HNSCC is more common, and associated with worse outcome. Advanced HPV-negative HNSCC may be treated with surgery, chemoradiation, targeted therapy, or immune checkpoint inhibition (ICI). There is considerable need for predictive biomarkers for these treatments. Defects in DNA repair capacity and loss of cell-cycle checkpoints sensitize tumors to cytotoxic therapies, and can contribute to phenotypes such as elevated tumor mutation burden (TMB), associated with response to ICI. Mutation of the tumor suppressors and checkpoint mediators TP53 and CDKN2A is common in HPV-negative HNSCC.Experimental Design:To gain insight into the relation of the interaction of TP53 and CDKN2A mutations with TMB in HNSCC, we have analyzed genomic data from 1,669 HPV-negative HNSCC tumors with multiple criteria proposed for assessing the damaging effect of TP53 mutations.Results:Data analysis established the TP53 and CDKN2A mutation profiles in specific anatomic subsites and suggested that specific categories of TP53 mutations are more likely to associate with CDKN2A mutation or high TMB based on tumor subsite. Intriguingly, the pattern of hotspot mutations in TP53 differed depending on the presence or absence of a cooccurring CDKN2A mutation.Conclusions:These data emphasize the role of tumor subsite in evaluation of mutational profiles in HNSCC, and link defects in TP53 and CDKN2A to elevated TMB levels in some tumor subgroups.
Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia
Authors: Rice William G. , Howell Stephen B. , Zhang Hongying , Rastgoo Nasrin , Local Andrea , Kurtz Stephen E. , Lo Pierrette , Bottomly Daniel , Wilmot Beth , McWeeney Shannon K. , Druker Brian J. , Tyner Jeffrey W. 
Published: May 2022

Abstract
Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild-type (WT) and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations. It is a more potent inhibitor of the activity of FLT3—internal tandem duplication, FLT3 kinase domain and gatekeeper mutants than against WT FLT3. Broad kinase screens disclosed that it also inhibits other kinases that can drive oncogenic signaling and rescue pathways, but spares kinases known to be associated with clinical toxicity. In vitro profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, isocitrate dehydrogenase-1/2, ASXL1, NPM1, SRSF2, TP53, or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously orally every 12 hours at a dose that yielded a mean Cmin plasma concentration of 1.0 ± 0.3 μmol/L (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase I trial for patients with AML and myelodysplastic/myeloproliferative neoplasms.
Nonclinical Characterization of Bexmarilimab, a Clever-1–Targeting Antibody for Supporting Immune Defense Against Cancers
Authors: Hollmén Maija , Maksimow Mikael , Rannikko Jenna H. , Karvonen Matti K. , Vainio Marita , Jalkanen Sirpa , Jalkanen Markku , Mandelin Jami 
Published: May 2022

Abstract
Common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) is a multifunctional type-1 transmembrane protein that plays an important role in immunosuppression against tumors. Clever-1 is highly expressed in a subset of human tumor-associated macrophages and associated with poor survival. In mice, Clever-1 supports tumor growth and metastasis formation, and its deficiency or blockage induces T-cell–dependent killing of cancer cells. Therefore, targeting Clever-1 could lead to T-cell activation and restoration of immune response also in patients with cancer. This is studied in an on-going clinical trial [Macrophage Antibody To INhibit immune Suppression (MATINS); NCT03733990] in patients with advanced solid tumors where bexmarilimab, a humanized IgG4 antibody against human Clever-1, shows promising safety and efficacy.
Here, we report the humanization and nonclinical characterization of physicochemical properties, biological potency, and safety profile of bexmarilimab.
Bexmarilimab showed high affinity to Clever-1 on KG-1 cells and bound to Clever-1 on the surface of classical and intermediate monocytes derived from healthy human blood. Bexmarilimab inhibited the internalization of its natural ligand acetylated low-density lipoprotein into KG-1 cells and increased TNFα secretion from macrophages but did not impair phagocytic clearance. Bexmarilimab did not induce significant cytokine release in human whole-blood cultures, did not contain nonsafe immunogenic glycans, or show any significant binding to human Fcγ receptors or complement pathway component C1q. In vivo, bexmarilimab showed dose-dependent duration of monocyte Clever-1 receptor occupancy in cynomolgus monkeys but did not induce a cytokine storm up to a dose of 100 mg/kg.
In conclusion, these data support the clinical development of bexmarilimab for the restoration of immune response in cancers.
Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy
Authors: Awasthi Niranjan , Schwarz Margaret A. , Zhang Changhua , Klinz Stephan G. , Meyer-Losic Florence , Beaufils Benjamin , Thiagalingam Arunthathi , Schwarz Roderich E. 
Published: May 2022

Abstract
Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was &gt;156% and &gt;94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.
MOZ and Menin–MLL Complexes Are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor
Authors: Hemming Matthew L. , Benson Morgan R. , Loycano Michael A. , Anderson Justin A. , Andersen Jessica L. , Taddei Madeleine L. , Krivtsov Andrei V. , Aubrey Brandon J. , Cutler Jevon A. , Hatton Charlie , Sicinska Ewa , Armstrong Scott A. 
Published: May 2022

Abstract

Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin-modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin–MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin–MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique ﻿chromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application.

Significance:
Although many malignancies rely on oncogene amplification, GIST instead depends upon epigenetic regulation of KIT and other essential genes. Utilizing genome-scale CRISPR dependency screens, we identified complementary chromatin-modifying complexes essential to GIST and characterize the consequences of their disruption, elucidating a novel therapeutic approach to this disease.
This article is highlighted in the In This Issue feature, p. 1599
Colorectal Cancer Genomics by Genetic Ancestry
Authors: Eng Cathy , Holowatyj Andreana N. 
Published: May 2022

Summary:
Understanding molecular features of colorectal cancer across diverse populations is an indispensable step toward reducing the pronounced disparities in this disease burden. Based on the findings that individuals of African ancestry have an observed increase in the frequency of KRAS, AOC, and PIK3CA mutations, Myer and colleagues suggest that patients of African ancestry should consider treatment and clinical trials specific to these mutations.
See related article by Myer et al., p. 1282 (2).
Design and analysis of wide and multi-bands multi-input multi-output antenna for 5G communications
Authors: Muttair Karrar Shakir , Ghazi Zahid Ali Zuhair , Shareef Oras Ahmed , Chyad Alfilh Raed Hameed , Qasim Kamil Ahmed Mohammed , Farhan Mosleh Mahmood 
Published: May 2022

A <span>good antenna design has played an essential role in the design of wireless communication systems, international companies are looking for the best design that suits their products in terms of size, bandwidth, gain, cost, and performance. In this paper, three antenna models are designed for fifth-generation (5G) communications, the first model is a single antenna, the second model is a two-ports multi-input multi-output (MIMO) antenna, and the third model is a four-ports MIMO antenna. The geometric dimensions of a single antenna are 20×37×1.6 mm<sup>3</sup>, the two-ports antenna dimensions are 44×37×1.6 mm<sup>3</sup>, while the four-ports antenna dimensions are 74×44×1.6 mm<sup>3</sup>. The design of these antennas was based on the latest strategies in terms of their small sizes and operating from 13.5 to 20 GHz in wide and multiple bands to be compatible with all advanced communication devices. Based on the results that emerged, it was noted that the reflection coefficient (S11) &lt; -10 dB and has better isolation between the ports is &lt; -26 dB. While the envelope correlation coefficient (ECC) value is &lt; 1.036×10<sup>-9</sup>, and the diversity gain (DG) value is 10 dB. All antennas proposed operate in ultra-wideband (UWB) which is very necessary for 5G communications devices.</span>
Mulheres-Onça: mitologia, gênero e antropofagia no Complexo do Marico
Authors: Soares-Pinto Nicole 
Published: May 2022

As narrativas mitológicas dos povos originários dos afluentes da margem direita do médio rio Guaporé revelam uma íntima conexão entre relações de gênero e a diferença humano/animal/espírito. Enfatizam, por um lado, as condições de possibilidade de uma sociedade composta por relações de sexo oposto, e por outro lado, a “antropofagia” praticada pelas mulheres. A partir da articulação com a etnografia cotidiana, em particular referente à produção e consumo de bebida fermentada, o artigo sugere que a antropofagia feminina, i.e., a identificação virtual das mulheres com as onças, é a condição para a diferença (atual) que separa os humanos dos não-humanos e os humanos entre si.
O diário de Anita Malfatti de 1914
Authors: Pires Carlos 
Published: May 2022

O artigo apresenta parte de uma pesquisa sobre o diário que Anita Malfatti escreveu em 1914. O diário, que estava desaparecido desde meados dos anos 1980, traz um relato detalhado da primeira exposição em São Paulo da pintora depois do retorno de sua primeira viagem para a Europa.
“O que causa prazer”: lundu entre neoclássicos e românticos na Casa da Ópera de Ouro Preto
Authors: Mayor Mariana 
Published: May 2022

O artigo analisa uma polêmica de jornal entre um empresário teatral e um sócio anônimo da Casa da Ópera de Ouro Preto, publicada no O Universal, de Minas Gerais, em 1826. Os textos trocados revelam expectativas, frustrações e a realidade do trabalho teatral da casa de espetáculos sobre repertório, formas cênicas e relação com espectadores na construção do Brasil independente. As disputas entre o imaginário neoclássico e romântico estão presentes, num jogo com o mercado teatral e o sucesso do gênero de origem afrodiaspórica lundu.
Os carbonários, 40 anos, de Alfredo Sirkis (1950-2020): testemunho e sobrevivência
Authors: Pereira Rogério Silva 
Published: May 2022

Estudo da narrativa de Os carbonários, de Alfredo Sirkis (1950-2020), partindo da análise do paratexto das várias edições do livro, apontando eventuais contradições, explicitando e detalhando a construção do personagem-narrador, o próprio Sirkis, que ostenta bem delineadas características de testemunha e de sobrevivente. Para tanto, arregimenta os conceitos de sobrevivente (Agamben, 2008) e de testemunho (Agamben, 2008; Ricoeur, 2007; Sarlo, 2007).
Western Pacific Premoistening for Eastward-Propagating BSISO and Its ENSO Modulation
Authors: Wei Yuntao , Liu Fei , Ren Hong-Li , Chen Guosen , Feng Chengfeng , Chen Bin 
Published: May 2022

Abstract
The boreal summer intraseasonal oscillation (BSISO) is a major source of subseasonal predictability of the East Asian summer monsoon. However, modeling and prediction of the BSISO remain major challenges partly due to an incomplete understanding of its eastward propagation. Our moisture budget analysis suggests that western Pacific (WPAC) premoistening leading the eastward-propagating (EP) BSISO is mainly attributed to the horizontal moisture advection with two centers in the lower and middle troposphere, respectively. The lower-tropospheric center is rooted in the linear moisture advection by flows from both the mean state and BSISO, while the middle-tropospheric center is induced by the nonlinear eddy moistening effect from the suppressed activity of synoptic tropical depression (TD) disturbances. The vertical profile of WPAC premoistening is significantly modulated by El Niño–Southern Oscillation (ENSO), with the premoistening being enhanced in the lower troposphere and weakened in the middle troposphere during an El Niño summer, and vice versa in a La Niña summer. During an El Niño summer, the nonlinear eddy moistening effect is weakened in the middle troposphere due to less southwest–northeast tilt of the TD, while the linear moisture advection is enhanced in the lower troposphere due to strengthened background cross-equatorial flows and moisture gradients. These results suggest an urgent need to improve the simulation fidelity of the BSISO’s scale interactions with synoptic and interannual variabilities in climate models.

Significance Statement
In this work, we use statistical analysis to explore multiscale interactions of BSISO with synoptic and interannual variabilities using observations and reanalysis data. Our key finding shows that the ENSO significantly modulates the premoistening process of the BSISO over the WPAC. In an El Niño summer, the WPAC nonlinear eddy moistening effect leading the BSISO is weakened in the midtroposphere due to smaller southwest–northeast tilt of the TD, while the linear moistening effect is enhanced in the lower troposphere due to enhanced background cross-equatorial flow and moisture gradient. These results offer new metrics for validating climate models and for projecting BSISO’s future change under different global warming scenarios.
Turbulent Mixing Variability in an Energetic Standing Meander of the Southern Ocean
Authors: Cyriac Ajitha , Phillips Helen E. , Bindoff Nathaniel L. , Polzin Kurt 
Published: May 2022

Abstract
This study presents novel observational estimates of turbulent dissipation and mixing in a standing meander between the Southeast Indian Ridge and the Macquarie Ridge in the Southern Ocean. By applying a finescale parameterization on the temperature, salinity, and velocity profiles collected from Electromagnetic Autonomous Profiling Explorer (EM-APEX) floats in the upper 1600 m, we estimated the intensity and spatial distribution of dissipation rate and diapycnal mixing along the float tracks and investigated the sources. The indirect estimates indicate strong spatial and temporal variability of turbulent mixing varying from O(10−6) to O(10−3) m2 s−1 in the upper 1600 m. Elevated turbulent mixing is mostly associated with the Subantarctic Front (SAF) and mesoscale eddies. In the upper 500 m, enhanced mixing is associated with downward-propagating wind-generated near-inertial waves as well as the interaction between cyclonic eddies and upward-propagating internal waves. In the study region, the local topography does not play a role in turbulent mixing in the upper part of the water column, which has similar values in profiles over rough and smooth topography. However, both remotely generated internal tides and lee waves could contribute to the upward-propagating energy. Our results point strongly to the generation of turbulent mixing through the interaction of internal waves and the intense mesoscale eddy field.