tbuckley/cabot-search huggingface dataset:
Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers
Authors: Yi Li, Wei Guo, Xiuqin Li, Jianguo Zhang, Moyi Sun, Zhangui Tang, Wei Ran, Kai Yang, Guilin Huang, Longjiang Li
Journal: International Journal of Oral Science (2021)

Abstract The first gene therapy product, recombinant adenovirus human p53 (rAd- p53 ), has been approved by CFDA since 2013. During these years, most of the clinical trials and the relevant basic research were carried out by Chinese oncologists. Gendicine was proved to be a safe and promising gene therapy drug for patients who suffered from head and neck squamous cell carcinoma (HNSCC). The basic therapeutic theories of gene therapy were totally different from the traditional ones, such as surgeries or radio- and chemotherapy, and the evaluation of treatment outcomes should also be changed simultaneously. However, there still existed a lot of misunderstandings about gene therapy, which resulted in improper administration, insufficient dosage calculation, and treatment cycles, and the treatment outcomes were unsatisfactory, especially for inexperienced oncologists or hospitals. Therefore, we will provide some practical guidance here on the gene therapy of rAd- p53 based on our previous research and experience, which focused on the basic theories and clinical issues, to answer the questions arising during the clinical of gene therapy and to accelerate the development of gene therapy for the benefit of patients bearing malignant tumors.
73 Characterization of tumor-infiltrating T-cell repertoire in human cancers
Authors: Taylor Harding, Qidi Yang, Brittany Mineo, Jenna Malinauskas, Jason Perera, Karl Beutner, Denise Lau, Aly Khan
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background TCR and BCR repertoire profiling is a promising technique that can provide a clinically useful window into the complex interactions between tumor cells and infiltrating lymphocytes. Despite recent advances in repertoire sequencing methods, the characterization of tumor-infiltrating T-cell repertoires has been limited to small sample sizes due to technical and material constraints. In this study, we constructed a large multidimensional database of repertoire data covering a diverse landscape of HLA genotypes and tumor neoantigens from routine clinical sequencing. We present a descriptive summary of repertoire profiles derived from tens of thousands of tumor samples from over fifty different cancer cohorts and characterize the associations between T-cell repertoires and various clinical and molecular features. Methods To enrich immune receptor transcripts detected by the Tempus RNA-sequencing workflow, hybrid capture probes tiling TCR and BCR genes were used. Repertoire profiling reads were aligned, assembled, and annotated against IMGT reference sequences. Repertoires are profiled as a component of Tempus|xT RNA sequencing and are summarized here for &gt;25 thousand tumor samples from over 50 different cancer cohorts. Results We demonstrate that the use of TCR/BCR hybrid capture probes is an effective method for enriching immune receptor transcripts in RNA-sequencing data without interfering with downstream transcriptomic analysis. These repertoires were profiled as part of a larger, multimodal DNA/RNA-sequencing pipeline that quantifies a variety of tumor clinical and molecular features. We explored the correlation between high-level repertoire metrics like richness (the number of unique receptor clonotypes in a given repertoire) and clonality/evenness (Shannon entropy) against both gene expression-based metrics (i.e. immune cell infiltration estimates, etc.) and mutational patterns (mutational burden and neoantigen load). Finally, we observed that the repertoire clonality of B-cell and T-cell driven cancers frequently exhibits clear monoclonal dominance for the tumor cells’ lymphoid receptors. Conclusions TCR/BCR repertoire profiling can be incorporated into high-volume clinical RNA sequencing to generate a diverse multimodal dataset for studying the tumor-immune microenvironment. By creating a large-scale database of TCR/BCR repertoire profiles from a variety of tissue, HLA genotypes, and mutational contexts, we can better resolve the molecular and clinical correlates of cancer with host adaptive immunity.
Variation in Release Factor Abundance Is Not Needed to Explain Trends in Bacterial Stop Codon Usage
Authors: Alexander T Ho, Laurence D Hurst
Journal: Molecular Biology and Evolution (2021)

In bacteria stop codons are recognized by one of two class I release factors (RF1) recognizing TAG, RF2 recognizing TGA, and TAA being recognized by both. Variation across bacteria in the relative abundance of RF1 and RF2 is thus hypothesized to select for different TGA/TAG usage. This has been supported by correlations between TAG:TGA ratios and RF1:RF2 ratios across multiple bacterial species, potentially also explaining why TAG usage is approximately constant despite extensive variation in GC content. It is, however, possible that stop codon trends are determined by other forces and that RF ratios adapt to stop codon usage, rather than vice versa. Here, we determine which direction of the causal arrow is the more parsimonious. Our results support the notion that RF1/RF2 ratios become adapted to stop codon usage as the same trends, notably the anomalous TAG behavior, are seen in contexts where RF1:RF2 ratios cannot be, or are unlikely to be, causative, that is, at 3'untranslated sites never used for translation termination, in intragenomic analyses, and across archaeal species (that possess only one RF1). We conclude that specifics of RF biology are unlikely to fully explain TGA/TAG relative usage. We discuss why the causal relationships for the evolution of synonymous stop codon usage might be different from those affecting synonymous sense codon usage, noting that transitions between TGA and TAG require two-point mutations one of which is likely to be deleterious.
Characterization of the Early Humoral and Cellular Response Developed in Oncohematological Patients Post-Vaccination with One Dose Against COVID-19
Authors: Magdalena Corona De Lapuerta, Sara Rodriguez-Mora, Guiomar Casado-Fernandez, Javier Garcia-Pérez, Lorena Vigon, María Aranzazú Murciano-Antón, María Jesús Blanchard, Juan Marquet Palomanes, Fernando Martin Moro, Pablo Palomo Rumschisky, Mayte Pérez-Olmeida, Javier López Jiménez, Maria Rosa López-Huertas, Maria Teresa Coiras, Valentín Garcia Gutierrez
Journal: Blood (2021)
Abstract 9052: Upregulation of Cardiac SERCA 2a is a Key Molecular Mechanism of the Protective Effect on Myocardial Aging in Beta3-Adrenergic Receptor Deficiency Mice
Authors: Heng Cheng, Zhe Chen, Peng Zhou, Jing Cao, Xiaoqiang Sun, David M Herrington, David Zhao, Dalane W Kitzman, Che Ping Cheng
Journal: Circulation (2021)

Background: We have shown previously that aging-induced cardiomyocyte dysfunction and impaired β-adrenergic regulation were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) aged mice. However, the molecular mechanism is unclear. We hypothesize that reversal of aging-induced down-regulation of SR Ca 2+ -ATPase (SERCA 2a) and β 1 -ARs by β 3 -AR deficiency may play a key role for the protective effect. Methods: We compared cardiac SERCA 2a, phospholamban (PLB), β 1 - and β 3 -AR protein expression and myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO, 10 -8 M) in left ventriclar (LV) myocytes obtained from 2 young (Y)(~4-6 mo) and 2 aged (A) (~18-24 mo) groups (7/group) of wild-type (WT) and β 3 KO mice, respectively. Results: Compared with YWT, AWT myocytes had significantly decreased SERCA 2a (66%, AWT: 0.21 vs YWT: 0.61), SERCA 2a/PLB ratio (0.76 vs 1.77) and β 1 -AR (33%, 0.39 vs 0.58), but increased β 3 -AR (93%, 0.27 vs 0.14). These changes were associated with reduced basal cell contraction (dL/dt max ) (AWT: 84.3 vs YWT: 124.8 μm/s), relaxation (dR/dt max ) (60.1 vs 89.8 μm/s) and [Ca 2+ ] iT (0.17 vs 0.22). This was accompanied by diminished ISO-stimulated positive inotropic effect; in AWT myocytes, ISO (10 -8 M) caused significantly less increases in dL/dt max (AWT: 33% vs YWT: 81%), dR/dt max (24% vs 58%), and [Ca 2+ ] iT (14% vs 34%). Compared with YWT, Yβ 3 KO did not alter basal contraction and ISO response of myocytes, but SERCA 2a (Yβ 3 KO: 1.2 vs YWT: 0.61) and SERCA 2a/PLB ratio were doubled with relatively unchanged β 1 -AR (0.62 vs 0.58); Aβ 3 KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ 3 KO myocytes, the increased SERCA 2a (1.1) and β 1 -AR (0.61) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated positive inotropic response. ISO caused similar increases in dL/dt max (84% vs 82%) and [Ca 2+ ] iT (32% vs 34%) compared to Yβ 3 KO mice. Conclusions: Chronic β 3 -AR deficiency upregulates cardiac SERCA 2a, prevents aging-induced downregulation of β 1 -ARs, and leads to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic responsiveness in aged hearts. Thus, antagonizing β 3 -AR could be a new therapeutic strategy for age-related decline in myocardial function.
Ixazomib Plus Lenalidomide/Dexamethasone (IRd) Versus Lenalidomide /Dexamethasone (Rd) Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial
Authors: Laura Rosinol, Albert Oriol, Rafael Ríos Tamayo, María Jesús Blanchard, Isidro Jarque, Joan Bargay, Miguel-Teodoro Hernández, Jose Maria Moraleda, Estrella Carrillo-Cruz, Anna Sureda, Joaquín Martínez-López, Isabel Krsnik, Esther González Garcia, Felipe Casado, Josep M Marti, Cristina Encinas, Felipe De Arriba, Luis Palomera, Antonia Sampol, Yolanda Gonzalez-Montes, Elena Cabezudo, Maria-Victoria Mateos, Jesus San-Miguel, Juan Jose Lahuerta, Joan Bladé Creixenti
Journal: Blood (2021)
High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study
Authors: Habib El-Khoury, Jean-Baptiste Alberge, Hadley Barr, Ciara Murphy, D.J. Sakrikar, Tara Krause, David Barnidge, Mark Bustoros, Houry Leblebjian, Annie Cowan, Maya Davis, Julia Amstutz, Jacqueline Perry, Cody J. Boehner, Elizabeth D. Lightbody, Tarek H Mouhieddine, Romanos Sklavenitis-Pistofidis, Mark C Perkins, Stephen Harding, Prashant Kapoor, Clifton C. Mo, David L. Murray, Ivan M. Borrello, Gad Getz, Timothy R Rebbeck, Catherine R. Marinac, Irene M. Ghobrial
Journal: Blood (2021)
The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis
Authors: Samar M. Said, Alejandro Best Rocha, Anthony M. Valeri, Paisit Paueksakon, Surendra Dasari, Jason D. Theis, Julie A. Vrana, Modupe O. Obadina, Darius Saghafi, Mariam Priya Alexander, Sanjeev Sethi, Christopher P. Larsen, Florent Joly, Angela Dispenzieri, Frank Bridoux, Christophe Sirac, Nelson Leung, Agnes B. Fogo, Ellen D. McPhail, Samih H. Nasr
Journal: Kidney International (2021)
Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA
Authors: Christopher P. Pacia, Jinyun Yuan, Yimei Yue, Lu Xu, Arash Nazeri, Rupen Desai, H. Michael Gach, Xiaowei Wang, Michael R. Talcott, Aadel A. Chaudhuri, Gavin P. Dunn, Eric C. Leuthardt, Hong Chen
Journal: Theranostics (2021)

Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks.Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis.Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy.Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans.Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor.Contrast-enhanced T1-weighted MR images were acquired to evaluate the BBB permeability change.Blood was collected immediately after FUS sonication.Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA).Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy.Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model.It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model.Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA.Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer.
Abstract 8963: Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells is Associated With Heart Failure in Patients With Single Ventricle Congenital Heart Disease
Authors: Phillip M Zegelbone, ANGELA BAYBAYON-GRANDGEORGE, Brian Stauffer, Carmen Sucharov, Shelley Miyamoto, Anastacia M Garcia
Journal: Circulation (2021)

Introduction: Heart failure (HF) remains a leading cause of death and indication for heart transplant in children with single ventricle congenital heart disease (SV). The purpose of this study was to evaluate mitochondrial function in circulating peripheral blood mononuclear cells (PBMCs) from failing pediatric SV patients compared to age-matched nonfailing controls (NF). Prior data obtained at the time of cardiac transplant shows associations between SV PBMC mitochondrial function and ex-vivo high-resolution respirometry analysis conducted on permeabilized myocardial fibers, suggesting that PBMCs may be surrogates for myocardial mitochondrial function. Hypothesis: SV patients will have impaired mitochondrial respiratory capacity in circulating PBMCs. Methods: Subjects were recruited from Children’s Hospital Colorado. SV patients ages 0-18 years were included. Healthy children 0-18 years of age with normal biventricular cardiac function were included as a control group. PBMCs were isolated from whole blood (EDTA) using density gradient centrifugation in Histopaque Accuspin tubes. Oxygen consumption rates (OCR) of intact PBMCs were measured using the Seahorse XFe Bioanalyzer (Agilent). OCR is measured under 4 different conditions (Figure 1): baseline, after addition of oligomycin, after addition of carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, and after addition of antimycin A and rotenone. Results: Baseline respiratory capacity, coupling efficiency, and mitochondrial oxygen flux were decreased in failing SV PBMCs relative to NF controls (Figure 2). Conclusions: Our results demonstrate impaired mitochondrial respiratory capacity in circulating PBMCs of pediatric SV patients relative to healthy age-matched controls. Combined with our ex vivo data showing decreased mitochondrial function in failing SV myocardium, our findings suggests PBMCs may serve as a viable non-invasive biomarker of myocardial respiratory capacity.
Type I Calreticulin Mutations Result in Hyperactivation of Its Acetyltransferase Function and Iron Metabolism, Inducing a Susceptibility to Ferroptosis
Authors: Harrison S Greenbaum, Maria Evers, Alex Rosencrance, Luke Maxwell, Katarzyna Kurylowicz, Nicole S Arellano, Michele Ciboddo, Jinjun Gao, Juan Ibarra, Shannon Elf
Journal: Blood (2021)
Expansion of T Follicular Helper Cells in NLC Co-Cultures Reinforces the Concept of Co-Evolution of CLL and Supportive T Helper Cell Clones
Authors: Alicia Vaca, Nikolaos Ioannou, Mariela Sivina, Elisavet Vlachonikola, Karen Clise-Dwyer, Ekaterina Kim, Dan Li, Qing Ma, Alessandra Ferrajoli, Zeev E. Estrov, William G. Wierda, Piers E.M. Patten, Alan G. Ramsay, Jan A. Burger
Journal: Blood (2021)
Signature required: The transcriptional response to tuberculosis
Authors: Clifton E. Barry, Katrin D. Mayer-Barber
Journal: The Journal of Experimental Medicine (2021)

The majority of humans infected with Mycobacterium tuberculosis never experience clinical symptoms or signs, but predicting those who will remains out of reach. Here, we discuss recent studies that reveal patterns and pathways that determine who is at highest risk for progression.
Persistence of Chronic Inflammation Despite Years of Transfusion Program in SCD Patients: Changing Red Blood Cells Is Not Sufficient to Treat Sickle Cell Disease
Authors: Abdoul Karim Dembele, Patricia Hermand-Tournamille, Florence Missud, Emmanuelle Lesprit, Malika Benkerrou, Caroline Le Van Kim, Berengere Koehl
Journal: Blood (2021)
Abstract 9550: Sex and Ethnicity Specific Burden of Coronary Artery Calcium Among Middle-Aged and Older Adults: Multi-Ethnic Study of Atherosclerosis
Authors: Seamus P Whelton, Omar Dzaye, Alexander C Razavi, Zeina Dardari, Todd Villines, Matthew J Budoff, Roger S Blumenthal, Robyn McClelland, Michael J Blaha, Khurram Nasir
Journal: Circulation (2021)

Introduction: Detection of coronary artery calcium (CAC) at a low score is the ideal phase of the atherosclerotic process to start primary prevention therapies. A better understanding of how the proportion of individuals with zero, low, or moderate/high CAC changes with age, sex, and race/ethnicity may aid in determining the optimal age to perform general CAC scoring before there is a severe burden of atherosclerosis. Methods: We calculated the proportion of individuals with 1) CAC ≥1 and CAC ≥100 based on population percentiles from 6,110 participants without diabetes from the Multi-Ethnic Study of Atherosclerosis (MESA) who had a CAC scan at Visit 1 (2000-02). Results: There was an approximately 12 year age difference for when 25% of men had CAC ≥1 compared to CAC ≥100 (&lt;45-51 years old vs 58-63 years old) compared to an approximately 14 year age difference for women (54-59 years old vs 69-75 years old). Women had a 50% prevalence of CAC ≥1 by age 69 years old (71 for Black women vs 67 for White women) compared to age 57 years old for men (62 for Black men vs 53 for White men). White men had a 50% prevalence of CAC ≥100 at age 68 years old, which was between 8-15 years younger than men of other races/ethnicities while women did not have a 50% prevalence of CAC ≥100 until age 80 years or older. In order to have at least a 25 to 50% probability of CAC ≥100, testing should be considered at ages of 55-64 for White men, 65-74 for men of other races/ethnicities and White women, and 75-84 years old for women of other races/ethnicities. Conclusion: Women developed CAC ≥1 approximately 12 years later in life than men. White men developed CAC ≥100 at a much younger age than men of other races/ethnicities, while a majority of women did not develop CAC ≥100 until age ≥80 years old. These findings may provide additional information to aid in the clinician-patient decision making process on the ideal age to perform CAC scoring, especially for those individuals who wish to rule out the presence of a moderate or high CAC score.
Abstract 12994: Invasive Left Atrial Pressure Monitoring and Survival on Veno-Arterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock
Authors: Joseph E Tonna, Craig H Selzman, Filio Billia, Adriana Luk, David Baran, Wayne B Batchelor, Behnam N Tehrani, Qussay Marashly, Christos P Kyriakopoulos, Iosif Taleb, Tara Jones, Jose Nunez, E. Wilson Grandin, Navin K Kapur, Peter Rycus, Stavros G Drakos
Journal: Circulation (2021)

Introduction: Elevated left atrial pressures (LAP) are associated with worse outcomes among patients with cardiogenic shock (CS), yet there are limited data on the utility of continuous invasive monitoring of LAPs on outcomes for CS. This is additionally true among refractory CS patients on peripheral VA ECMO, which itself can increase arterial afterload. Hypothesis: Our objective was to determine whether invasive LAP monitoring impacts survival for patients with refractory CS after 24 hours of VA ECMO support. Methods: We performed a cohort analysis among 10,906 patients ≥18yrs of age from the Extracorporeal Life Support Organization (ELSO) Registry from 2015 - 2020, with refractory CS treated with VA ECMO. The presence of invasive LAP monitoring was defined as either pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) values at 24 hours on VA ECMO. The exposure was measurement of LAPs at 24 hours on VA ECMO support, and the primary outcome was 30 day survival. We performed Kaplan Meier survival analysis, adjusting for age, PaO2/FiO2, pH, SCAI classification stage prior to ECMO, presence of a pre-ECMO cardiac arrest, mean arterial blood pressure on ECMO and year. Results: Median age of patients was 57 [IQR,46; 65] years with 31% females. Thirty two percent (n=3,465) presented with acute myocardial infarction, 29% (n=3,112) with acute heart failure and 1% (n=965) with both etiologies. Invasive LAP monitoring at 24 hours was performed in 33% (n=3608) of patients. The use of invasive LAP was associated with lower mortality (adjusted Hazard Ratio 0.88 [95% CI 0.81 to 0.95]; p=0.002). Conclusions: Implementation of invasive LAP monitoring may be associated with higher adjusted hospital survival in patients with refractory CS requiring VA-ECMO support. These findings merit further investigation and prospective validation to assess the relationship between invasive hemodynamic monitoring and outcomes in this patient population.
Abstract 13465: UFM1 Binding Protein 1 (UFBP1) is Indispensable for Normal Heart Function and Endoplasmic Reticulum (ER) Homeostasis
Authors: Jie Li, Guihua Yue, Wenxia Ma, Aizhen Zhang, Juan Ayala, Honglin Li, Huabo Su
Journal: Circulation (2021)

UFM1 (ubiquitin-fold modifier 1) is a novel ubiquitin-like protein that modifies protein targets via UFM1-specific conjugation enzymes. Dysregulation of UFM1 modification, termed ufmylation, has been linked to multiple human diseases but its importance in the heart remain unclear. We have previously reported that ufmylation is dysregulated in failing human hearts. Through deletion of the E3 UFM1 ligase 1 (UFL1) in mouse hearts, we demonstrated that ufmylation is essential for normal cardiac function and protects against pathological cardiac remodeling. However, how ufmylation exerts its cardioprotective effect remains unclear. Here, we report that UFBP1 (UFM1 binding protein 1), an ER-resident ufmylation target, is an important downstream effector of ufmylation in the heart. While deletion of UFBP1 in mouse hearts has no impact on ufmylation, the knockout (KO) mice developed dilated cardiomyopathy at resting condition, as indicated by left ventricular wall thinning, chamber dilatation and significantly decreased cardiac contractility at 6 months of age. Moreover, loss of UFBP1 exacerbated pressure overload-induced cardiac remodeling and dysfunction, recapitulating multiple aspects of the phenotypes of UFL1-deficient hearts. Mechanistically, inhibition of ufmylation destabilized UFBP1, and depletion of UFBP1 promoted ER stress-induced cell injury in cultured cardiomyocytes. Furthermore, excess ER stress is implicated in UFBP1KO hearts and is aggravated with the progression of cardiomyopathy. Interestingly, ER stress inducers upregulated the expression of ufmylation pathway components at both transcript and protein levels in cultured cardiomyocytes and mouse hearts, indicating an intimate cross-talk between ufmylation and ER stress. Collectively, our data identify a novel UFM1-UFL1-UFBP1 axis in constraining pathological cardiac remodeling and maintaining ER homeostasis.