tbuckley/cabot-search huggingface dataset:
Single-cell landscapes of primary glioblastomas and matched explants and cell lines show variable retention of inter- and intratumor heterogeneity
Authors: Véronique G. LeBlanc, Diane L. Trinh, Shaghayegh Aslanpour, Martha Hughes, Dorothea Livingstone, Dan Jin, Bo Young Ahn, Michael D. Blough, J. Gregory Cairncross, Jennifer A. Chan, John J.P. Kelly, Marco A. Marra
Journal: Cancer Cell (2022)

Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive inter- and intratumor heterogeneity. Patient-derived models, such as organoids and explants, have recently emerged as useful models to study such heterogeneity, although the extent to which they can recapitulate GBM genomic features remains unclear. Here, we analyze bulk exome and single-cell genome and transcriptome profiles of 12 IDH wild-type GBMs, including two recurrent tumors, and of patient-derived explants (PDEs) and gliomasphere (GS) lines derived from these tumors. We find that PDEs are genetically similar to, and variably retain gene expression characteristics of, their parent tumors. Notably, PDEs appear to exhibit similar levels of transcriptional heterogeneity compared with their parent tumors, whereas GS lines tend to be enriched for cells in a more uniform transcriptional state. The approaches and datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived models, especially in the context of studying cellular heterogeneity.
Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer
Authors: Zemin Hou, Shengsong Huang, Zejie Mei, Longlong Chen, Jiacheng Guo, Yuanyuan Gao, Qian Zhuang, Xuebin Zhang, Qilong Tan, Tao Yang, Ying Liu, Yongnan Chi, Lifengrong Qi, Ting Jiang, Xuefeng Shao, Yan Wu, Xiaojun Xu, Jun Qin, Ruobing Ren, Huiru Tang, Denglong Wu, Zhenfei Li
Journal: Cell Reports Medicine (2022)

Prostate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens. In this study, mass-spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients. High doses of progesterone activate canonical and non-canonical androgen receptor (AR) target genes. Physiological levels of progesterone facilitate cell proliferation via GATA2. Inhibitors of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) has been discovered and shown to suppress the generation of progesterone, eliminating its transient and accumulating oncogenic effects. An increase in progesterone is associated with poor clinical outcomes in patients and may be used as a predictive biomarker. Overall, we demonstrate that progesterone acts as an oncogenic hormone in prostate cancer, and strategies to eliminate its oncogenic effects may benefit prostate cancer patients.
Cuffless Blood Pressure Measurement
Authors: Ramakrishna Mukkamala, George S. Stergiou, Alberto P. Avolio
Journal: Annual Review of Biomedical Engineering (2022)

Cuffless blood pressure (BP) measurement has become a popular field due to clinical need and technological opportunity. However, no method has been broadly accepted hitherto. The objective of this review is to accelerate progress in the development and application of cuffless BP measurement methods. We begin by describing the principles of conventional BP measurement, outstanding hypertension/hypotension problems that could be addressed with cuffless methods, and recent technological advances, including smartphone proliferation and wearable sensing, that are driving the field. We then present all major cuffless methods under investigation, including their current evidence. Our presentation includes calibrated methods (i.e., pulse transit time, pulse wave analysis, and facial video processing) and uncalibrated methods (i.e., cuffless oscillometry, ultrasound, and volume control). The calibrated methods can offer convenience advantages, whereas the uncalibrated methods do not require periodic cuff device usage or demographic inputs. We conclude by summarizing the field and highlighting potentially useful future research directions.
A Recanalized Umbilical Vein Hypermetabolic Thrombosis Mimicked an Hepatocellular Carcinoma Recurrence
Authors: Thibault Fidani, Guillaume Desmarets, Jean Goupil, Jean-Pierre Pouget, Vincent Boudousq
Journal: Clinical Nuclear Medicine (2022)

Abstract A transarterial left hepatic artery radioembolization involving 90 Y microspheres was performed on a cirrhotic man with hypermetabolic 18 F-FDG segment III hepatocellular carcinoma. During the 18 F-FDG PET/CT follow-up, the disappearance of the hypermetabolic lesion was initially observed. Then, a focal segment III hypermetabolism reappeared mimicking a recurrence before disappearing without any treatment. Finally, the hepatic MRI demonstrated that the transitory segment III hypermetabolism matched a thrombus of the dilated recanalized umbilical vein.
Synaptic Variability and Cortical Gamma Oscillation Power in Schizophrenia
Authors: Daniel W. Chung, Matthew A. Geramita, David A. Lewis
Journal: American Journal of Psychiatry (2022)

Objective: Cognitive impairments in schizophrenia are associated with lower gamma oscillation power in the prefrontal cortex (PFC). Gamma power depends in part on excitatory drive to fast-spiking parvalbumin interneurons (PVIs). Excitatory drive to cortical neurons varies in strength, which could affect how these neurons regulate network oscillations. The authors investigated whether variability in excitatory synaptic strength across PVIs could contribute to lower prefrontal gamma power in schizophrenia. Methods: In postmortem PFC from 20 matched pairs of comparison and schizophrenia subjects, levels of vesicular glutamate transporter 1 (VGlut1) and postsynaptic density 95 (PSD95) proteins were quantified to assess variability in excitatory synaptic strength across PVIs. A computational model network was then used to simulate how variability in excitatory synaptic strength across fast-spiking (a defining feature of PVIs) interneurons (FSIs) regulates gamma power. Results: The variability of VGlut1 and PSD95 levels at excitatory inputs across PVIs was larger in schizophrenia relative to comparison subjects. This alteration was not influenced by schizophrenia-associated comorbid factors, was not present in monkeys chronically exposed to antipsychotic medications, and was not present in calretinin interneurons. In the model network, variability in excitatory synaptic strength across FSIs regulated gamma power by affecting network synchrony. Finally, greater synaptic variability interacted synergistically with other synaptic alterations in schizophrenia (i.e., fewer excitatory inputs to FSIs and lower inhibitory strength from FSIs) to robustly reduce gamma power. Conclusions: The study findings suggest that greater variability in excitatory synaptic strength across PVIs, in combination with other modest synaptic alterations in these neurons, can markedly lower PFC gamma power in schizophrenia.
An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer
Authors: Yunting Zhang, Min Jiang, Guangsheng Du, Xiaofang Zhong, Chunting He, Ming Qin, Yingying Hou, Rong Liu, Xun Sun
Journal: Acta Pharmaceutica Sinica B (2022)

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70 nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. In vivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.
Transmission dynamics and epidemiological characteristics of SARS-CoV-2 Delta variant infections in Guangdong, China, May to June 2021
Authors: Min Kang, Hualei Xin, Jun Yuan, Sheikh Taslim Ali, Zimian Liang, Jiayi Zhang, Ting Hu, Eric HY Lau, Yingtao Zhang, Meng Zhang, Benjamin J Cowling, Yan Li, Peng Wu
Journal: Eurosurveillance (2022)

BackgroundThe Delta variant of SARS-CoV-2 had become predominant globally by November 2021.AimWe evaluated transmission dynamics and epidemiological characteristics of the Delta variant in an outbreak in southern China.MethodsData on confirmed COVID-19 cases and their close contacts were retrospectively collected from the outbreak that occurred in Guangdong, China in May and June 2021. Key epidemiological parameters, temporal trend of viral loads and secondary attack rates were estimated. We also evaluated the association of vaccination with viral load and transmission.ResultsWe identified 167 patients infected with the Delta variant in the Guangdong outbreak. Mean estimates of latent and incubation period were 3.9 days and 5.8 days, respectively. Relatively higher viral load was observed in infections with Delta than in infections with wild-type SARS-CoV-2. Secondary attack rate among close contacts of cases with Delta was 1.4%, and 73.1% (95% credible interval (CrI): 32.9-91.4) of the transmissions occurred before onset. Index cases without vaccination (adjusted odds ratio (aOR): 2.84; 95% CI: 1.19-8.45) or with an incomplete vaccination series (aOR: 6.02; 95% CI: 2.45-18.16) were more likely to transmit infection to their contacts than those who had received the complete primary vaccination series.DiscussionPatients infected with the Delta variant had more rapid symptom onset compared with the wild type. The time-varying serial interval should be accounted for in estimation of reproduction numbers. The higher viral load and higher risk of pre-symptomatic transmission indicated the challenges in control of infections with the Delta variant.
CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma
Authors: Galabina Bozhanova, Jehanne Hassan, Lizzie Appleton, Victoria Jennings, Shane Foo, Martin McLaughlin, Charleen ML Chan Wah Hak, Emmanuel C Patin, Eva Crespo-Rodriguez, Gabby Baker, Edward Armstrong, Matthew Chiu, Hardev Pandha, Adel Samson, Victoria Roulstone, Joan Kyula, Richard Vile, Fiona Errington-Mais, Malin Pedersen, Kevin Harrington, Masahiro Ono, Alan Melcher
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI). Methods Using a BRAF V600E -driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the ‘Timer of Cell Kinetics and Activity’ system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics. Results Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity. Conclusions Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors.
RIGHT VENTRICULAR STRAIN ANALYSIS IN A LARGE COHORT OF PATIENTS WITH SICKLE CELL DISEASE
Authors: Crystal N. Azu, Mayank Kansal, Seethal A. Jacob, Devang Parikh, Vandana Sachdev, Amit R. Patel, Mark Gladwin, Roberto M. Lang, Roberto F. Machado, Ankit Desai
Journal: Journal of the American College of Cardiology (2022)
Pulmonary microbiome and gene expression signatures differentiate lung function in pediatric hematopoietic cell transplant candidates
Authors: Matt S. Zinter, A. Birgitta Versluys, Caroline A. Lindemans, Madeline Y. Mayday, Gustavo Reyes, Sara Sunshine, Marilynn Chan, Elizabeth K. Fiorino, Maria Cancio, Sabine Prevaes, Marina Sirota, Michael A. Matthay, Sandhya Kharbanda, Christopher C. Dvorak, Jaap J. Boelens, Joseph L. DeRisi
Journal: Science Translational Medicine (2022)

Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pretransplant lung function has hindered the development of lung-targeted interventions. In this study, we quantified the association between bronchoalveolar lavage (BAL) metatranscriptomes and paired pulmonary function tests performed a median of 1 to 2 weeks before allogeneic HCT in 104 children in The Netherlands. Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung injury-related mortality after HCT. Depletion of commensal supraglottic taxa, such as Haemophilus, and enrichment of nasal and skin taxa, such as Staphylococcus, in the BAL microbiome were associated with worse measures of lung capacity and gas diffusion. In addition, BAL gene expression signatures of alveolar epithelial activation, epithelial-mesenchymal transition, and down-regulated immunity were associated with impaired lung capacity and diffusion, suggesting a postinjury profibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality. These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.
NEUTROPHILS AND NETOSIS IN WOMEN WITH CORONARY MICROVASCULAR DYSFUNCTION: A HYPOTHESIS GENERATING STUDY
Authors: Rebecca Levit, Lanfang Wang, Scott Gaignard, Michael Sayegh, Nishant Vatsa, Fauzia A. Rashid, Ashley McDowell, Puja K. Mehta
Journal: Journal of the American College of Cardiology (2022)
Prophylactic anticoagulation with low molecular weight heparin in COVID-19: cohort studies in Denmark and Sweden
Authors: Lars Christian Lund, Pontus Hedberg, Anne Helms Andreasen, Janne Petersen, Tonny Studsgaard Petersen, Anton Pottegård, Jacob Bodilsen, Pontus Naucler, Jesper Hallas, Espen Jimenez-Solem
Journal: Clinical Microbiology and Infection (2022)

To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19.Using healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis.We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47).We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH.
A PROSPECTIVE TRIAL OF CARVEDILOL IN EARLY-STAGE BREAST CANCER PATIENTS WITH ABNORMAL STRAIN TREATED WITH ANTI-HER-2 THERAPY (PROTECT HER-2)
Authors: Fei Fei Gong, Woo Bin Voss, Vibhav S. Rangarajan, Sasan Ryan Raissi, Kimberly Y. Chow, Lua Jafari, Nikita P. Patel, Inga Vaitenas, Milica Marion, Haydee Ramirez, Manyun Zhao, Adin-Cristian Andrei, Abigail Baldridge, Gillian Murtagh, Kameswari Maganti, Vera H. Rigolin, Nausheen Akhter
Journal: Journal of the American College of Cardiology (2022)
Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses
Authors: Kanve N. Suvilesh, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Aadel A. Chaudhuri, Chi-Ren Shyu, Guangfu Li, Klaus Pantel, Wesley C. Warren, Jonathan B. Mitchem, Jussuf T. Kaifi
Journal: Molecular Cancer (2022)

Abstract Background Circulating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group. Methods Surgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into naïve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4). Results Out of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients’ metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel. Conclusions To overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients’ primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.
THE “STAR” OF THE SHOW: STEREOTACTIC ARRHYTHMIA RADIOABLATION AS SALVAGE THERAPY FOR REFRACTORY VENTRICULAR TACHYCARDIA IN LATE-PRESENTATION MYOCARDIAL INFARCTION
Authors: Michael Nestasie, Abhas Khurana, Mian Tanveer Ud Din, Mark Trombetta, John Chenarides, Amit Thosani, Hayah Kassis-George
Journal: Journal of the American College of Cardiology (2022)
MANAGEMENT AND OUTCOMES OF CORONARY ARTERY ANEURYSMS: A PATIENT-LEVEL SYSTEMATIC REVIEW
Authors: Preeyal Patel, Danial Ahmad, Anjali Upadhyaya, Elizabeth Maynes, Daniella Wong, Colin Yost, Alec Vishnevsky, Nicholas J. Ruggiero, John Entwistle, Rohinton Morris, Vakhtang Tchantchaleishvili
Journal: Journal of the American College of Cardiology (2022)
Determining clinical course of diffuse large B-cell lymphoma using targeted transcriptome and machine learning algorithms
Authors: Maher Albitar, Hong Zhang, Andre Goy, Zijun Y. Xu-Monette, Govind Bhagat, Carlo Visco, Alexandar Tzankov, Xiaosheng Fang, Feng Zhu, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Fredrick B. Hagemeister, Jooryung Huh, Maurilio Ponzoni, Andrés J. M. Ferreri, Michael B. Møller, Benjamin M. Parsons, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Bing Xu, Ken H. Young
Journal: Blood Cancer Journal (2022)

Abstract Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology; however, these biological subgroups overlap clinically. Using machine learning, we developed an approach to stratify patients with DLBCL into four subgroups based on survival characteristics. This approach uses data from the targeted transcriptome to predict these survival subgroups. Using the expression levels of 180 genes, our model reliably predicted the four survival subgroups and was validated using independent groups of patients. Multivariate analysis showed that this patient stratification strategy encompasses various biological characteristics of DLBCL, and only TP53 mutations remained an independent prognostic biomarker. This novel approach for stratifying patients with DLBCL, based on the clinical outcome of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, can be used to identify patients who may not respond well to these types of therapy, but would otherwise benefit from alternative therapy and clinical trials.