tbuckley/cabot-search huggingface dataset:
Recent progress of carbon dots in targeted bioimaging and cancer therapy
Authors: Cheng-Long Shen, Hang-Rui Liu, Qing Lou, Feng Wang, Kai-Kai Liu, Lin Dong, Chong-Xin Shan
Journal: Theranostics (2022)

Carbon dots (CDs), as one new class of carbon nanomaterials with various structure and extraordinary physicochemical properties, have attracted tremendous interest for their potential applications in tumor theranostics, especially in targeted bioimaging and therapy. In these areas, CDs and its derivatives have been employed as highly efficient imaging agent for photoluminescence bioimaging of tumors cells. With unique structure, optical and/or dose attention properties, CDs have been harnessed in various nanotheranostic strategies for diverse tumors through integrating with other functional nanoparticles or utilizing their inherent physical properties. Up to now, CDs have been approved as novel biomaterials by their excellent performances in precise targeted bioimaging and therapy for tumors. Herein, the latest progress in the development of CDs in targeted bioimaging and tumor therapy are reviewed. Meanwhile, the challenges and future prospects of the application of CDs in promising nanotheranostic strategies are discussed and proposed.
Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis
Authors: Andrei Maiseyeu, Lin Di, Anastasia Ravodina, Alma Barajas-Espinosa, Atsushi Sakamoto, Alice Chaplin, Jixin Zhong, Huiyun Gao, Matthew Mignery, Navneet Narula, Aloke V. Finn, Sanjay Rajagopalan
Journal: Theranostics (2022)

Background: Glucagon-like peptide-1 receptor (GLP-1R) agonists are powerful glycemia-lowering agents, which have systematically been shown to lower cardiovascular events and mortality.These beneficial effects were difficult to pinpoint within atherosclerotic plaque due to lack of particular specificity of such agonists to the vascular cells and an inadequate understanding of the GLP-1R expression in atherosclerosis.Here, we hypothesized that the direct engagement of the GLP-1R in atherosclerosis by targeted agonists will alleviate vascular inflammation and plaque burden, even at a very low dose.Methods: The expression of GLP-1 receptor (GLP-1R, Glp1r mRNA) in human lesions with pathologic intimal thickening, Apoe -/-mouse atheroma and cultured immune/non-immune cells was investigated using genetic lineage tracing, Southern blotting and validated antisera against human GLP-1R.Protease-resistant and "activatable" nanoparticles (NPs) carrying GLP-1R agonist liraglutide (GlpNP) were engineered and synthesized.Inclusion of gadolinium chelates into GlpNP allowed for imaging by MRI.Atherosclerotic Apoe -/-mice were treated intravenously with a single dose (30 µg/kg of liraglutide) or chronically (1 µg/kg, 6 weeks, 2x/week) with GlpNP, liraglutide or control NPs, followed by assessment of metabolic parameters, atheroma burden, inflammation and vascular function.Results: Humal plaque specimens expressed high levels of GLP-1R within the locus of de-differentiated smooth muscle cells that also expressed myeloid marker CD68.However, innate immune cells under a variety of conditions expressed very low levels of Glp1r, as seen in lineage tracing and Southern blotting experiments examining full-length open reading frame mRNA transcripts.Importantly, de-differentiated vascular smooth muscle cells demonstrated significant Glp1r expression levels, suggesting that these could represent the cells with predominant Glp1r-positivity in atherosclerosis.GlpNP resisted proteolysis and demonstrated biological activity including in vivo glycemia lowering at 30 µg/kg and in vitro cholesterol efflux.Activatable properties of GlpNP were confirmed in vitro by imaging cytometry and in vivo using whole organ imaging.GlpNP targeted CD11b + /CD11c + cells in circulation and smooth muscle cells in aortic plaque in Apoe -/-mice when assessed by MRI and fluorescence imaging.At a very low dose of 1 µg/kg, previously known to have little effect on glycemia and weight loss, GlpNP delivered i.v. for six weeks reduced triglyceride-rich lipoproteins in plasma, plaque burden and plaque cholesterol without significant effects on weight, glycemia and plasma cholesterol levels. Ivyspring International
CONTEMPORARY IN-HOSPITAL OUTCOMES OF CHRONIC TOTAL OCCLUSION INTERVENTIONS: UPDATE FROM THE PROGRESS-CTO (PROSPECTIVE GLOBAL REGISTRY FOR THE STUDY OF CHRONIC TOTAL OCCLUSION INTERVENTION) INTERNATIONAL REGISTRY
Authors: Spyridon Kostantinis, Bahadir Simsek, Judit Karacsonyi, Khaldoon Alaswad, Michael Megaly, Oleg Krestyaninov, Dmitrii Khelimskii, Dimitrios I. Karmpaliotis, Farouc A. Jaffer, Jaikirshan J. Khatri, Paul Poommipanit, Mitul P. Patel, Ehtisham Mahmud, Michael Koutouzis, Ioannis Tsiafoutis, Sevket Gorgulu, Basem Elbarouni, William Nicholson, Wissam Jaber, Stephane Rinfret, Nidal Abi Rafeh, Omer Goktekin, Ahmed ElGuindy, Bavana V. Rangan, Emmanouil S. Brilakis
Journal: Journal of the American College of Cardiology (2022)
B cells imprint adoptively transferred CD8<sup>+</sup>T cells with enhanced tumor immunity
Authors: Aubrey S Smith, Hannah M Knochelmann, Megan M Wyatt, Guillermo O Rangel Rivera, Amalia M Rivera-Reyes, Connor J Dwyer, Michael B Ware, Anna C Cole, David M Neskey, Mark P Rubinstein, Bei Liu, Jessica E Thaxton, Eric Bartee, Chrystal M Paulos
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Adoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity. Methods In this study we investigated how tumor-specific murine CD8 + T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG. Results Herein we reveal a new way to reverse the tolerant state of adoptively transferred CD8 + T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell—B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8 + T cells acquired a unique proteomic signature hallmarked by an IL-2Rα high ICOS high CD39 low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2Rα high ICOS high CD39 low phenotype. CpG fostered the expansion of potent CD8 + T cells with the signature phenotype and antitumor ability via empowering a direct B–T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture. Conclusions Our results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8 + T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.
Abstract EP06: Serum Water T <sub>2</sub> And Its Association With Cardiometabolic Health: The Premier Study
Authors: Jacob Nicasio, Diana Sandoval, Erin Campbell, Joshua Garza, Juan Aldana, Alok Dwivedi, David P Cistola
Journal: Circulation (2022)

Introduction: Plasma and serum water T 2 are global markers of metabolic syndrome and cardiometabolic health. Serum, in contrast with plasma, lacks fibrinogen, one of the key drivers of the association of plasma water T 2 with metabolic syndrome. Yet, serum water T 2 was able to detect metabolic syndrome with high sensitivity and specificity through its association with other underlying components. Here we examined bio-banked serum samples from a large, diverse study population to investigate the use of serum water T 2 as a marker of cardiometabolic health. Hypothesis: Among PREMIER participants at baseline, serum water T 2 is associated with multiple measures of cardiometabolic health. Materials and Methods: This is an auxiliary study of the PREMIER trial and has an observational, cross-sectional design. A total of 810 mildly hypertensive participants without diabetes or CVD (63% females, 35% black, and 65% non-black) were enrolled in the parent study. Here, a subset of those participants (n=455) were analyzed based on the availability of serum samples that had undergone a single freeze-thaw cycle. Using a Bruker mq20 benchtop nuclear magnetic resonance relaxometer, T 2 decay curves were recorded at 37°C for unmodified human serum. Water T 2 was distinguished from non-water components using a discrete inverse Laplace transform algorithm. The association of serum water T 2 , the outcome variable, with other potential predictors was examined in four stages: (1) screening of predictors using a bootstrap forest machine learning algorithm, (2) clustering of predictors using principal component analysis, (3) associations with serum water T 2 using multiple linear regression, and (4) validation of regression models using a bootstrap forest algorithm. Results: The final model for serum water T 2 included albumin, globulins, non-HDL-cholesterol, household income, urine phosphate, TG/HDL ratio, family history of CVD and the interaction between BMI and race. The adjusted R 2 for this model was 0.55. Thus, serum water T 2 values were independently associated with markers of dyslipidemia, inflammation, insulin resistance, kidney function, family history of CVD, household income, and the categorical interaction between BMI and race. Compared with obese/Black individuals (reference group), non-obese/non-Black individuals showed higher T 2 values (p&lt;0.0001) reflecting improved cardiometabolic health. By contrast, serum water T 2 values for the non-obese/Black (p=0.7417) and obese/non-Black (p=0.7262) participants were not statistically different from the reference group. Conclusion: Analysis of bio-banked samples from PREMIER validates serum water T 2 as a biomarker of cardiometabolic health in mildly hypertensive individuals without diabetes or CVD. Serum water T 2 , while similar to plasma water T 2 , revealed some distinct associations with measures of cardiometabolic health.
Comparison and evaluation of statistical error models for scRNA-seq
Authors: Saket Choudhary, Rahul Satija
Journal: Genome biology (2022)

Heterogeneity in single-cell RNA-seq (scRNA-seq) data is driven by multiple sources, including biological variation in cellular state as well as technical variation introduced during experimental processing. Deconvolving these effects is a key challenge for preprocessing workflows. Recent work has demonstrated the importance and utility of count models for scRNA-seq analysis, but there is a lack of consensus on which statistical distributions and parameter settings are appropriate.
Effectiveness of the<i>Activate</i>injury prevention exercise programme to prevent injury in schoolboy rugby union
Authors: Craig Barden, Matthew V Hancock, Keith A Stokes, Simon P Roberts, Carly D McKay
Journal: British Journal of Sports Medicine (2022)

The efficacious Activate injury prevention exercise programme has been shown to prevent injuries in English schoolboy rugby union. There is now a need to assess the implementation and effectiveness of Activate in the applie setting.This quasi-experimental study used a 24-hour time-loss injury definition to calculate incidence (/1000 hours) and burden (days lost/1000 hours) for individuals whose teams adopted Activate (used Activate during season) versus non-adopters. The dose-response relationship of varying levels of Activate adherence (median Activate sessions per week) was also assessed. Player-level rugby exposure, sessional Activate adoption and injury reports were recorded by school gatekeepers. Rate ratios (RR), adjusted by cluster (team), were calculated using backwards stepwise Poisson regression to compare rates between adoption and adherence groups.Individuals in teams adopting Activate had a 23% lower match injury incidence (RR 0.77, 95% CI 0.55 to 1.07), 59% lower training injury incidence (RR 0.41, 95% CI 0.17 to 0.97) and 26% lower match injury burden (95% CI 0.46 to 1.20) than individuals on non-adopting teams. Individuals with high Activate adherence (≥3 sessions per week) had a 67% lower training injury incidence (RR 0.33, 95% CI 0.12 to 0.91) and a 32% lower match injury incidence (RR 0.68, 95% CI 0.50 to 0.92) than individuals with low adherence (<1 session per week). While 65% of teams adopted Activate during the season, only one team used Activate three times per week, using whole phases and programme progressions.Activate is effective at preventing injury in English schoolboy rugby. Attention should focus on factors influencing programme uptake and implementation, ensuring Activate can have maximal benefit.
Congenital deficiency reveals critical role of ISG15 in skin homeostasis
Authors: Muhammad Nasir Hayat Malik, Syed Fakhar-ul-Hassnain Waqas, Jana Zeitvogel, Jingyuan Cheng, Robert Geffers, Zeinab Abu-Elbaha Gouda, Ahmed Mahrous Elsaman, Ahmed R. Radwan, Matthias Schefzyk, Peter Braubach, Bernd Auber, Ruth Olmer, Mathias Müsken, Lennart M. Roesner, Gisa Gerold, Sven Schuchardt, Sylvia Merkert, Ulrich Martin, Felix Meissner, Thomas Werfel, Frank Pessler
Journal: Journal of Clinical Investigation (2021)

Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteinases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-β1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.
A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer
Authors: Ivan de Kouchkovsky, Arpit Rao, Benedito A. Carneiro, Li Zhang, Catriona Lewis, Audrey Phone, Eric J. Small, Terence Friedlander, Lawrence Fong, Pamela L. Paris, Charles J. Ryan, Russell Z. Szmulewitz, Rahul Aggarwal
Journal: Clinical Cancer Research (2022)

Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC). Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled. Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1-4 and 8-15 with filgrastim on days 5-7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%-85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0-10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052). The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.
A Malaria Vaccine for Africa — An Important Step in a Century-Long Quest
Authors: Pedro L. Alonso, Katherine L. O’Brien
Journal: New England Journal of Medicine (2022)

Malaria continues to devastate people's health and livelihoods worldwide. In October 2021, the WHO for the first time recommended the large-scale use of a malaria vaccine for children living in areas with moderate-to-high malaria transmission.
MDP SPECT/CT Demonstration of Baastrup Disease
Authors: Yu Zhang, Huipan Liu, Wei Zhang, Yue Chen
Journal: Clinical Nuclear Medicine (2021)

We report the MDP SPECT/CT findings of Baastrup disease in the interspinal region of L4 to L5 in a 76-year-old woman with a history of lung cancer. Baastrup disease, also known as "kissing" spine, is characterized by close contact of adjacent spinous processes with resultant enlargement, flattening, and reactive sclerosis of apposing interspinous surfaces. Knowledge regarding the appearance of Baastrup disease on 99mTc-MDP SPECT/CT is important to distinguish it from spinal bone metastasis.
First-in-Class Anti-immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors
Authors: Lillian L. Siu, Ding Wang, John Hilton, Ravit Geva, Drew Rasco, Ruth Perets, Anson K. Abraham, Douglas C. Wilson, Julia F. Markensohn, Jared Lunceford, Leah Suttner, Shabana Siddiqi, Rachel A. Altura, Corinne Maurice-Dror
Journal: Clinical Cancer Research (2021)

Abstract Purpose: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab. Patients and Methods: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated. Results: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation. Conclusions: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.
Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice
Authors: Ana Casado-García, Marta Isidro-Hernández, Ninad Oak, Andrea Mayado, Christine Mann-Ran, Javier Raboso-Gallego, Silvia Alemán-Arteaga, Alexandra Buhles, Dario Sterker, Elena G. Sánchez, Jorge Martínez-Cano, Oscar Blanco, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, África González-Murillo, Francisco Javier García Criado, María Begoña García Cenador, Thomas Radimerski, Manuel Ramírez-Orellana, César Cobaleda, Jun J. Yang, Carolina Vicente-Dueñas, Andreas Weiss, Kim E. Nichols, Isidro Sánchez-García
Journal: Cancer Research (2022)

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development.
Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels
Authors: Chenfei Zhou, Wenfei Wei, Jing Ma, Yang Yang, Luojiao Liang, Yanmei Zhang, Zici Wang, Xiaojing Chen, Lei Huang, Wei Wang, Sha Wu
Journal: Molecular Therapy (2022)

(Molecular Therapy 29, 1512–1528; April 4 2021) In the originally published version of this paper, Figure 4 panel I had an erroneous upper left plot that was a duplicate of the bottom right plot. The corrected figure now appears below. The authors regret this error. Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vesselsZhou et al.Molecular TherapyDecember 31, 2020In BriefOur study elucidated a mechanistic model via which cervical cancer-secreted, exosome-encapsulated miR-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Moreover, clinical data revealed that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer patients. Full-Text PDF Open Access