tbuckley/cabot-search huggingface dataset:
CRISPR/Cas9-Engineered Universal CD19/CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia
Authors: Yongxian Hu, Yali Zhou, Mingming Zhang, Wengang Ge, Yi Li, Li Yang, Guoqing Wei, Lu Han, Hao Wang, Shuhui Yu, Yi Chen, Yanbin Wang, Xiaohong He, Xingwang Zhang, Ming Gao, Jingjing Yang, Xiuju Li, Jiangtao Ren, He Huang
Journal: Clinical Cancer Research (2021)

Autologous chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed/refractory acute lymphoblastic leukemia (r/r ALL). However, certain characteristics of autologous CAR-T cells can delay treatment availability. Relapse caused by antigen escape after single-targeted CAR-T therapy is another issue. Therefore, we aim to develop CRISPR-edited universal off-the-shelf CD19/CD22 dual-targeted CAR-T cells as a novel therapy for r/r ALL.In this open-label dose-escalation phase I study, universal CD19/CD22-targeting CAR-T cells (CTA101) with a CRISPR/Cas9-disrupted TRAC region and CD52 gene to avoid host immune-mediated rejection were infused in patients with r/r ALL. Safety, efficacy, and CTA101 cellular kinetics were evaluated.CRISPR/Cas9 technology mediated highly efficient, high-fidelity gene editing and production of universal CAR-T cells. No gene editing-associated genotoxicity or chromosomal translocation was observed. Six patients received CTA101 infusions at doses of 1 (3 patients) and 3 (3 patients) × 106 CAR+ T cells/kg body weight. Cytokine release syndrome occurred in all patients. No dose-limiting toxicity, GvHD, neurotoxicity, or genome editing-associated adverse events have occurred to date. The complete remission (CR) rate was 83.3% on day 28 after CTA101 infusion. With a median follow-up of 4.3 months, 3 of the 5 patients who achieved CR or CR with incomplete hematologic recovery (CR/CRi) remained minimal residual disease (MRD) negative.CRISPR/Cas9-engineered universal CD19/CD22 CAR-T cells exhibited a manageable safety profile and prominent antileukemia activity. Universal dual-targeted CAR-T cell therapy may offer an alternative therapy for patients with r/r ALL.
Characterizing RNA Pseudouridylation by Convolutional Neural Networks
Authors: Xuan He, Sai Zhang, Yanqing Zhang, Zhixin Lei, Tao Jiang, Jianyang Zeng
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Pseudouridine (Ψ) is the most prevalent post-transcriptional RNA modification and is widespread in small cellular RNAs and mRNAs. However, the functions, mechanisms, and precise distribution of Ψs (especially in mRNAs) still remain largely unclear. The landscape of Ψs across the transcriptome has not yet been fully delineated. Here, we present a highly effective model based on a convolutional neural network (CNN), called PseudoUridyLation Site Estimator (PULSE), to analyze large-scale profiling data of Ψ sites and characterize the contextual sequence features of pseudouridylation. PULSE, consisting of two alternatively-stacked convolution and pooling layers followed by a fully-connected neural network, can automatically learn the hidden patterns of pseudouridylation from the local sequence information. Extensive validation tests demonstrated that PULSE can outperform other state-of-the-art prediction methods and achieve high prediction accuracy, thus enabling us to further characterize the transcriptome-wide landscape of Ψ sites. We further showed that the prediction results derived from PULSE can provide novel insights into understanding the functional roles of pseudouridylation, such as the regulations of RNA secondary structure, codon usage, translation, and RNA stability, and the connection to single nucleotide variants. The source code and final model for PULSE are available at https://github.com/mlcb-thu/PULSE.
Collective sensemaking for action: researchers and decision makers working collaboratively to strengthen health systems
Authors: Lucy Gilson, Edwine Barasa, Leanne Brady, Nancy Kagwanja, Nonhlanhla Nxumalo, Jacinta Nzinga, Sassy Molyneux, Benjamin Tsofa
Journal: BMJ (2021)

Lucy Gilson and colleagues draw on experiences from Kenya and South Africa to consider the practice, benefits, and challenges of research co-production for strengthening health systems
Patient-driven discovery and post-clinical validation of NTRK3 fusion as an acquired resistance mechanism to selpercatinib in RET fusion-positive lung cancer
Authors: V. Subbiah, T. Shen, M. Tetzlaff, A. Weissferdt, L.A. Byers, T. Cascone, A. Behrang, F. Meric-Bernstam, B.H.M. Mooers, S.M. Rothenberg, K. Ebata, J. Wu
Journal: Annals of Oncology (2021)
Abstract 19523: Impact of Active Psychiatric Disease and Medical Compliance on 30-Day All-Cause Readmissions in Heart Failure Patients
Authors: Brian J Allen, Clay A Cauthen
Journal: Circulation (2017)

Introduction: Patients with heart failure (HF) are at a greater risk for readmission within 30 days of discharge. The negative effects of psychiatric disease and medical non-adherence on cardiovasc...
How Epigenetic Therapy Beats Adverse Genetics in Monosomy Karyotype AML
Authors: Heather M. O'Hagan, Feyruz V. Rassool, Kenneth P. Nephew
Journal: Cancer Research (2021)

Abstract The study by Greve and colleagues, in this issue of Cancer Research, provides new molecular insights into the intriguing clinical activity of DNA hypomethylating agents (HMA) in patients with acute myeloid leukemia (AML) with monosomal karyotypes. Patients with AML with adverse monosomal karyotypes are known to benefit from HMAs, but not cytarabine, a cytidine analog without HMA activity, but the specific molecular mechanisms remain poorly understood. The authors investigated the mechanistic effects of HMAs on gene reactivation in AML in the context of the most common monosomal karyotypes, genetic deletion of chromosome 7q and 5q. They identified genes with tumor-suppressive properties, an endogenous retrovirus cooperatively repressed by DNA hypermethylation, and increased genetic losses on hemizygous chromosomal regions versus normal biallelic regions in AML cell models. Treatment with HMAs preferentially induced expression of these hemizygous genes to levels similar to those of genes in a biallelic state. In addition to CpG hypomethylation, decitabine treatment resulted in histone acetylation and an open chromatin configuration specifically at hemizygous loci. By using primary blood blasts isolated from patients with AML receiving decitabine and AML patient-derived xenograft models established from patients with either monosomal karyotypes or normal cytogenetics, Greve and colleagues both validated their findings in primary patient samples and demonstrated superior antileukemic activity of decitabine compared with chemotherapy with cytarabine. These mechanistic insights into how epigenetic therapy beats adverse genetics in monosomy karyotype AML will open new therapeutic opportunities for a difficult-to-treat patient group. See related article by Greve et al., p. 834
Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions
Authors: Peter Valent, Alberto Orfao, Stefan Kubicek, Philipp Staber, Torsten Haferlach, Michael Deininger, Karoline Kollmann, Thomas Lion, Irene Virgolini, Georg Winter, Oliver Hantschel, Lukas Kenner, Johannes Zuber, Florian Grebien, Richard Moriggl, Gregor Hoermann, Olivier Hermine, Michael Andreeff, Christoph Bock, Tariq Mughal, Stefan N. Constantinescu, Robert Kralovics, Veronika Sexl, Radek Skoda, Giulio Superti-Furga, Ulrich Jäger
Journal: HemaSphere (2021)

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice.
Abstract PD15-08: The role of purinergic signaling in the chemotherapy response of triple negative breast cancer
Authors: Jasmine Manouchehri, Jharna Datta, Mathew Cherian
Journal: Cancer Research (2021)

Abstract Triple negative breast cancer (TNBC) affects women worldwide with a higher incidence in minority populations. Patients with TNBCs often have poorer prognoses in comparison to other breast cancer sub-types due to a lack of effective therapeutic options. Chemotherapy and immunotherapy are the only effective treatments, but these modalities generally result in short-term response. Therefore, there is a need to identify additional therapies to intensify the chemotherapeutic response in TNBC. When cancer cells are exposed to chemotherapy, they release adenosine triphosphate (ATP) into the extracellular space. Extracellular ATP is degraded by CD39 (E-NTPDase) to adenosine diphosphate (ADP) and then adenosine monophosphate (AMP), and AMP is broken down to adenosine by CD73. We examined the potential role of extracellular ATP in chemotherapy- induced cancer cell death. We hypothesized that extracellular ATP sensitizes TNBC cells to chemotherapy and that ATP degrading enzymes such as CD39 and CD73 attenuate this effect. TNBC MDA-MB 231, MDA-MB 468, and Hs 578t cell lines were treated with the chemotherapeutic agent paclitaxel for different time courses. Extracellular ATP was measured via the ATPlite 1step luminescence assay, and cell viability was assessed by applying PrestoBlue HS cell viability reagent. Paclitaxel-treated TNBC cell lines revealed a dose-dependent increase in extracellular ATP release in the presence of an inhibitor of CD39 (POM-1), accompanied by a dose-dependent decrease in cell viability. In addition, the general P2X receptor (P2RX) inhibitor iso-PPADS and the P2RX7 specific inhibitor (A438079) were added separately to observe if the P2X receptors are necessary for the release of ATP upon paclitaxel treatment. After paclitaxel treatment, TNBC cell lines showed a decline in the amount of ATP released with the addition of the inhibitors iso-PPADS and A438079. Treatment of non-tumorigenic immortalized MCF-10A mammary epithelial cells with paclitaxel in the presence and absence of the inhibitors iso-PPADS and A438079 did not result in a significant increase in extracellular ATP or a decrease in cell viability. These results indicate that P2RX7 is necessary for ATP release in TNBC cell lines exposed to chemotherapy. Furthermore, when TNBC cell lines were treated with increasing concentrations of ATP, there was a dose-dependent decrease in cell viability. Overall, these findings suggest that extracellular ATP may impact the chemotherapeutic response in TNBC cell lines through the activation of the ATP-gated channel P2RX7. Citation Format: Jasmine Manouchehri, Jharna Datta, Mathew Cherian. The role of purinergic signaling in the chemotherapy response of triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-08.
Therapeutic depletion of CCR8<sup>+</sup>tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy
Authors: Helena Van Damme, Bruno Dombrecht, Máté Kiss, Heleen Roose, Elizabeth Allen, Eva Van Overmeire, Daliya Kancheva, Liesbet Martens, Aleksandar Murgaski, Pauline Madeleine Rachel Bardet, Gillian Blancke, Maude Jans, Evangelia Bolli, Maria Solange Martins, Yvon Elkrim, James Dooley, Louis Boon, Julia Katharina Schwarze, Frank Tacke, Kiavash Movahedi, Niels Vandamme, Bart Neyns, Sebahat Ocak, Isabelle Scheyltjens, Lars Vereecke, Frank Aboubakar Nana, Pascal Merchiers, Damya Laoui, Jo Agnes Van Ginderachter
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. Methods We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. Results We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4 + and CD8 + T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. Conclusions Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
Arterial and Venous Thromboembolism in Covid-19: A Study-level Meta-analysis
Authors: V. Mai, K. B. Tan, S. Mainbourg, A. Frigerri, L. Bertoletti, M. Douplat, Y. Dargaud, C. Grange, S. Provencher, J. C. Lega
Journal: Circulation (2020)
Miniaturized Needle Array‐Mediated Drug Delivery Accelerates Wound Healing
Authors: Mohamadmahdi Samandari, Fariba Aghabaglou, Kristo Nuutila, Hossein Derakhshandeh, Yuteng Zhang, Yori Endo, Seth Harris, Lindsay Barnum, Craig Kreikemeier‐Bower, Elmira Arab‐Tehrany, Nicholas A. Peppas, Indranil Sinha, Ali Tamayol
Journal: Advanced Healthcare Materials (2021)

A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing.
Abstract 16173: Clinical Characteristics and Short-term Outcomes of Hospitalized Patients With Sars-cov-2 Infection and Reduced Left Ventricular Ejection Fraction
Authors: Gatha G Nair, Joanne Michelle M Gomez, Setri S Fugar, Jeanne du Fay de Lavallaz, Max Ruge, Alexander Hlepas, Annas Rahman, Priya P Patel, nusrat jahan, Alan Simmons, Anupama Rao, Charlotte J Bai, Karolina Marinescu, Kim A Williams, Annabelle S Volgman, Tisha Suboc
Journal: Circulation (2020)

Introduction: Early studies of coronavirus disease 2019 (COVID-19) patients suggested that heart failure (HF) may lead to poorer prognosis. We evaluated demographics and short-term clinical outcomes of patients with evidence of left ventricular systolic dysfunction (LVSD) in comparison to those with preserved LV systolic function (PSF). Methods: In this retrospective study of patients hospitalized for COVID-19 between March and June 2, 2020 at Rush Health Systems in Metro Chicago, demographics, comorbidities and clinical outcomes of patients who demonstrated LVSD (ejection fraction [EF] &lt;50%) on transthoracic echocardiogram (TTE) were compared to that of controls with PSF. Results: Out of 1,312 hospitalized patients, 225 underwent TTE, and 44 patients showed LVSD. Demographics were similar between two groups, with exception of a higher prevalence of African American (AA) race (48 % vs. 29%; p=0.03) in the LVSD group. While 82% of patients in the LVSD cohort had history of chronic HF, only 26% of patients in the PSF had pre-existing HF (p&lt;0.001). Underlying comorbidities were similar between groups: obesity (39% vs. 36%; p=0.86), diabetes (57% vs. 57%; p=1.0), hypertension (70% vs. 66%; p=0.72) and end-stage renal disease (20% vs. 19%; p=0.83). Coronary artery disease trended toward a higher frequency (50% vs. 34%; p=0.058) in the LVSD group. Troponin elevation (18% vs. 12%; p=0.43), vasopressor use (57% vs. 56%; p=1.0), endotracheal intubation (59% vs. 57%; p=0.87), myocardial infarction (30% vs. 23%; p=0.43), ICU admission (75% vs. 75%; p=1.0), hospital length of stay (median 11 days vs. 15 days; p=0.4), and death (25% vs. 23%; p=0.84) were similar between groups. Patients with LVSD had higher incidence of sustained ventricular tachycardia or fibrillation than those with PSF (18% vs. 6%; p=0.016). Conclusions: In our COVID-19 admissions, LVSD was more common in AA patients. Patients with LVSD had a higher risk of ventricular arrhythmias. However, there were no differences between need for ICU admission or intubation, vasopressor requirements, length of stay or death between patients with LVSD and those without. Longitudinal follow-up studies are needed to identify differences in long-term sequelae of COVID-19 infection with evidence for LVSD.
Molecular imaging and biochemical response assessment after a single cycle of [<sup>225</sup>Ac]Ac-PSMA-617/[<sup>177</sup>Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [<sup>177</sup>Lu]Lu-PSMA-617 monotherapy
Authors: Florian Rosar, Fabian Hau, Mark Bartholomä, Stephan Maus, Tobias Stemler, Johannes Linxweiler, Samer Ezziddin, Fadi Khreish
Journal: Theranostics (2021)

Rationale: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted 177 Lu radioligand therapy in metastatic castration-resistant prostate carcinoma (mCRPC), some patients do not respond and other patients with initially good response develop resistance to this treatment.In this study, we investigated molecular imaging and biochemical responses after a single cycle of [ 225 Ac]Ac-PSMA-617/[ 177 Lu]Lu-PSMA-617 tandem therapy in patients who had progressed on [ 177 Lu]Lu-PSMA-617 monotherapy.Methods: Seventeen patients with mCRPC were included in a retrospective, monocenter study.Molecular imaging-based response was assessed by modified PERCIST criteria using the whole-body total lesion PSMA (TLP) and molecular tumour volume (MTV) derived from [ 68 Ga]Ga-PSMA-11 PET/CT.Biochemical response was evaluated according to PCWG3 criteria using the prostate-specific antigen (PSA) serum value.Concordance and correlation statistics as well as survival analyses were performed.Results: Based on the molecular imaging-based response assessment, 5 (29.4%) patients showed partial remission and 7 (41.2%)had stable disease.The remaining 5 (29.4%) patients had further progression, four with an increase in TLP/MTV of >30% and one with stable TLP/MTV but appearance of new metastases.Based on the biochemical response assessment, 5 (29.4%), 8 (47.1%), and 4 (23.5%)patients showed partial remission, stable disease, and progressive disease, respectively.A comparison of the response assessment methods showed a concordance of 100% (17/17) between TLP and MTV and 70.6% (12/17) between TLP/MTV and PSA.Patients with partial remission, independently assessed by each method, had better overall survival (OS) than patients with either stable or progressive disease.The difference in OS was statistically significant for the molecular imaging response assessment (median OS not reached vs. 8.3 m, p = 0.044), but not for the biochemical response assessment (median OS 18.1 m vs. 9.4 m, p = 0.468). Conclusion:Based on both assessment methods, [ 225 Ac]Ac-PSMA-617/[ 177 Lu]Lu-PSMA-617 tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on [ 177 Lu]Lu-PSMA-617 monotherapy.Molecular imaging response and biochemical PSA response were mostly concordant, though a considerable number of cases (29.4%) were discordant.Molecular imaging response reflecting the change in total viable tumour burden appears to be superior to PSA change in estimating survival outcome after tandem therapy.