tbuckley/cabot-search huggingface dataset:
Scalable generation of functional human iPSC-derived CAR-macrophages that efficiently eradicate CD19-positive leukemia
Authors: Shifaa M. Abdin, Daniela Paasch, Arnold Kloos, Marco Carvalho Oliveira, Mi-Sun Jang, Mania Ackermann, Andriana Stamopoulou, Philipp J Mroch, Christine S Falk, Constantin S von Kaisenberg, Axel Schambach, Michael Heuser, Thomas Moritz, Gesine Hansen, Michael Morgan, Nico Lachmann
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Macrophages have recently become attractive therapeutics in cancer immunotherapy. The potential of macrophages to infiltrate and influence solid malignancies makes them promising targets for the chimeric antigen receptor (CAR) technology to redirect their stage of polarization, thus enhancing their anticancer capacities. Given the emerging interest for CAR-macrophages, generation of such cells so far mainly depends on peripheral blood monocytes, which are isolated from the respective donor prior to genetic manipulation. This procedure is time-intensive and cost-intensive, while, in some cases, insufficient monocyte amounts can be recovered from the donor, thus hampering the broad applicability of this technology. Hence, we demonstrate the generation and effectiveness of CAR-macrophages from various stem cell sources using also modern upscaling technologies for next generation immune cell farming. Methods Primary human hematopoietic stem and progenitor cells and induced pluripotent stem cells were used to derive anti-CD19 CAR-macrophages. Anticancer activity of the cells was demonstrated in co-culture systems, including primary material from patients with leukemia. Generation of CAR-macrophages was facilitated by bioreactor technologies and single-cell RNA (scRNA) sequencing was used to characterize in-depth response and behavior of CAR-macrophages. Results Irrespective of the stem-cell source, CAR-macrophages exhibited enhanced and antigen-dependent phagocytosis of CD19 + target cancer cells with increased pro-inflammatory responses. Phagocytic capacity of CAR-macrophages was dependent on target cell CD19 expression levels with superior function of CAR-macrophages against CD19 + cancer cell lines and patient-derived acute lymphocytic leukemia cancer cells. scRNA sequencing revealed CAR-macrophages to be distinct from eGFP control cells after co-culture with target cells, which includes the activation of pro-inflammatory pathways and upregulation of chemokines and cytokines associated with adaptive immune cell recruitment, favoring the repolarization of CAR-macrophages to a pro-inflammatory state. Taken together, the data highlight the unique features of CAR-macrophages in combination with the successful upscaling of the production pipeline using a three-dimensional differentiation protocol and intermediate scale bioreactors. Conclusion In summary, our work provides insights into the seminal use and behavior of CAR-macrophages which are derived from various sources of stem cells, while introducing a unique technology for CAR-macrophage manufacturing, all dedicated to the clinical translation of CAR-macrophages within the field of anticancer immunotherapies.
Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation–induced surfactant secretion
Authors: Gui-Lan Chen, Jing-Yi Li, Xin Chen, Jia-Wei Liu, Qian Zhang, Jie-Yu Liu, Jing Wen, Na Wang, Ming Lei, Jun-Peng Wei, Li Yi, Jia-Jia Li, Yu-Peng Ling, He-Qiang Yi, Zhenying Hu, Jingjing Duan, Jin Zhang, Bo Zeng
Journal: Journal of Clinical Investigation (2024)

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and also children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated for this process. Here we show that loss of mechanosensitive channels TMEM63A and TMEM63B resulted in atelectasis and respiratory failure in mice due to deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of lamellar body, a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated release of surfactant and ATP from lamellar bodies fused with the plasma membrane. The released ATP evoked Ca2+ signaling in AT2 cells and potentiated exocytic fusion of more lamellar bodies. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels, which makes the lung ready for the first breath at birth and maintains respiration through the life.
Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension
Authors: William R. Reay, Erin Clarke, Shaun Eslick, Carlos Riveros, Elizabeth G. Holliday, Mark A. McEvoy, Roseanne Peel, Stephen Hancock, Rodney J. Scott, John R. Attia, Clare E. Collins, Murray J. Cairns
Journal: Circulation (2024)

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47–mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97–mm Hg systolic BP increase in the lowest 10% ( P =1.95×10 −3 ). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.
Inhibition of protein-protein interactions using biodegradable depsipeptide nanoassemblies
Authors: Se-Hwan Choi, Hyun-seok Hwang, Seongryeong Han, Hohyeon Eom, Jun Shik Choi, Sanghun Han, Donghyun Lee, Soo Yeon Lee, Heebeom Koo, Ho Jeong Kwon, Yong-beom Lim
Journal: Journal of Controlled Release (2023)
Epidemiology, pathophysiology, diagnosis and management of chronic right‐sided heart failure and tricuspid regurgitation. A clinical consensus statement of the Heart Failure Association (<scp>HFA</scp>) and the European Association of Percutaneous Cardiovascular Interventions (<scp>EAPCI</scp>) of the ESC
Authors: Marianna Adamo, Ovidiu Chioncel, Matteo Pagnesi, Antoni Bayes‐Genis, Magdy Abdelhamid, Stefan D. Anker, Elena‐Laura Antohi, Luigi Badano, Tuvia Ben Gal, Michael Böhm, Victoria Delgado, Julien Dreyfus, Francesco F. Faletra, Dimitrios Farmakis, Gerasimos Filippatos, Julia Grapsa, Finn Gustafsson, Jörg Hausleiter, Tiny Jaarsma, Nicole Karam, Lars Lund, Philipp Lurz, Francesco Maisano, Brenda Moura, Wilfred Mullens, Fabien Praz, Anna Sannino, Gianluigi Savarese, Carlo Gabriele Tocchetti, Vanessa P.M. van Empel, Ralph Stephan von Bardeleben, Mehmet Birhan Yilmaz, José Luis Zamorano, Piotr Ponikowski, Emanuele Barbato, Giuseppe M.C. Rosano, Marco Metra
Journal: European Journal of Heart Failure (2023)

Right‐sided heart failure and tricuspid regurgitation are common and strongly associated with poor quality of life and an increased risk of heart failure hospitalizations and death. While medical therapy for right‐sided heart failure is limited, treatment options for tricuspid regurgitation include surgery and, based on recent developments, several transcatheter interventions. However, the patients who might benefit from tricuspid valve interventions are yet unknown, as is the ideal time for these treatments given the paucity of clinical evidence. In this context, it is crucial to elucidate aetiology and pathophysiological mechanisms leading to right‐sided heart failure and tricuspid regurgitation in order to recognize when tricuspid regurgitation is a mere bystander and when it can cause or contribute to heart failure progression. Notably, early identification of right heart failure and tricuspid regurgitation may be crucial and optimal management requires knowledge about the different mechanisms and causes, clinical course and presentation, as well as possible treatment options. The aim of this clinical consensus statement is to summarize current knowledge about epidemiology, pathophysiology and treatment of tricuspid regurgitation in right‐sided heart failure providing practical suggestions for patient identification and management.
Stability of ranibizumab during continuous delivery from the Port Delivery Platform
Authors: Aaron R. Hieb, Judit Horvath, Jennifer Rea, Tammy Tam, Debby P. Chang, Isabella de Jong, Kai Zheng, Stefan T. Yohe, Shrirang V. Ranade
Journal: Journal of Controlled Release (2023)

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system that has the potential to reduce treatment burden in patients with retinovascular diseases. The Port Delivery Platform (PD-P) implant is a permanent, indwelling device that can be refilled in situ through a self-sealing septum and is designed to continuously deliver ranibizumab by passive diffusion through a porous titanium release control element. We present results for the studies carried out to characterize the stability of ranibizumab for use with the PD-P. Simulated administration, in vitro release studies, and modeling studies were performed to evaluate the compatibility of ranibizumab with the PD-P administration components, and degradation and photostability in the implant. Simulated administration studies demonstrated that ranibizumab was highly compatible with the PD-P administration components (initial fill and refill needles) and commercially available administration components (syringe, transfer needle, syringe closure). Subsequent simulated in vitro release studies examining continuous delivery for up to 12 months in phosphate buffered saline, a surrogate for human vitreous, showed that the primary degradation products of ranibizumab were acidic variants. The presence of these variants increased over time and potency remained high. The stability attributes of ranibizumab were consistent across multiple implant refill-exchanges. Despite some degradation within the implant, the absolute mass of variants released daily from the implant was low due to the continuous release mechanism of the implant. Simulated light exposure within the implant resulted in small increases in the relative amount of ranibizumab degradants compared with those seen over 6 months.
Oral TNF-α siRNA delivery via milk-derived exosomes for effective treatment of inflammatory bowel disease
Authors: Geonhee Han, Hyosuk Kim, Hochung Jang, Eun Sun Kim, Sun Hwa Kim, Yoosoo Yang
Journal: Bioactive Materials (2023)

Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon, making it an ideal approach for treating patients with inflammatory bowel disease. However, multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract. Herein, we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha (TNF-α) siRNA completely. The remarkable structural stability of milk-derived exosomes (M-Exos), as opposed to those from HEK293T cells, makes them exceptional siRNA carriers. Results demonstrate that milk exosomes loaded with TNF-α siRNA (M-Exo/siR) can effectively inhibit the expression of TNF-α-related inflammatory cytokines. Moreover, given that milk exosomes are composed of unique lipids with high bioavailability, orally administered M-Exo/siR effectively reach colonic tissues, leading to decreased TNF-α expression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model. Hence, milk-derived exosomes carrying TNF-α siRNA can be effectively employed to treat inflammatory bowel disease. Indeed, using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery, including siRNA.
The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis
Authors: Magali A de Sauvage, Consuelo Torrini, Edwin Nieblas-Bedolla, Elizabeth J Summers, Emily Sullivan, Britney S Zhang, Emily Batchelor, Braxton Marion, Erika Yamazawa, Samuel C Markson, Hiroaki Wakimoto, Naema Nayyar, Priscilla K Brastianos
Journal: Neuro-Oncology (2023)

Abstract Background Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM. Methods We used immunotypical mouse models of BM bearing dual extracranial/intracranial tumors to evaluate the efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-programmed death receptor 1 (PD-1) antibody. We verified target inhibition and drug delivery, then investigated treatment effects on T-cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays, and T-cell receptor profiling. Results We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in 2 BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood–brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T-cell receptor repertoire in the extracranial tumor, enriches T-cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors. Conclusions Despite the limited BBB permeability of LY321, combined LY321 and anti-PD-1 treatment can improve intracranial disease control by amplifying extracranial immune responses, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.
Effect of age and season on respiratory mucosal immune marker profiles
Authors: Esther van Woudenbergh, Debbie M. van Rooijen, Janine J. Veldman-Wolf, Mioara A. Nicolaie, Martijn A. Huynen, Fiona R.M. van der Klis, Marien I. de Jonge, Gerco den Hartog
Journal: Journal of Allergy and Clinical Immunology (2023)
Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD
Authors: Juan Carlos Bórquez, Francisco Díaz-Castro, Francisco Pino-de La Fuente, Karla Espinoza, Ana María Figueroa, Inma Martínez-Ruíz, Vanessa Hernández, Iliana López-Soldado, Raúl Ventura, Joan Carles Domingo, Marta Bosch, Alba Fajardo, David Sebastián, Alejandra Espinosa, Albert Pol, Antonio Zorzano, Víctor Cortés, María Isabel Hernández-Alvarez, Rodrigo Troncoso
Journal: Metabolism (2023)
Global spread characteristics of CTX-M-type extended-spectrum β-lactamases: A genomic epidemiology analysis
Authors: Keyi Yu, Zhenzhou Huang, Yue Xiao, He Gao, Xuemei Bai, Duochun Wang
Journal: Drug Resistance Updates (2023)

Extended-spectrum β-lactamases (ESBLs) producing bacteria have spread worldwide and become a global public health concern. Plasmid-mediated transfer of ESBLs is an important route for resistance acquisition.
Management of sporadic intracanalicular vestibular schwannomas: A critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines
Authors: Anne Balossier, Arjun Sahgal, Rupesh Kotecha, Laura Fariselli, Alessandra Gorgulho, Marc Levivier, Lijun Ma, Ian Paddick, Bruce E Pollock, Jason P Sheehan, John H Suh, Shoji Yomo, Zhenwei Zhang, Jean Regis
Journal: Neuro-Oncology (2023)

Abstract Background The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). Methods Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. Results Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P &amp;lt; .001). Need for further treatment was reported in 1%, 2%, and 25% for SRS, MR, and CS, respectively (P = .001). Hearing preservation was reported in 67%, 68%, and 55% for SRS, MR, and CS, respectively (P = .21). Persistent facial nerve deficit was reported in 0.1% and 10% for SRS and MR series, respectively (P = .01). Conclusions SRS is a noninvasive treatment with at least equivalent rates of tumor control and hearing preservation as compared to MR, with the caveat of better facial nerve preservation. As compared to CS, upfront SRS is an effective treatment in achieving tumor control with similar rates of hearing preservation.
Whole tumor analysis reveals early origin of the <i>TERT</i> promoter mutation and intercellular heterogeneity in <i>TERT</i> expression
Authors: Christina L Appin, Chibo Hong, Abigail K Suwala, Stephanie Hilz, Radhika Mathur, David A Solomon, Ivan V Smirnov, Nicholas O Stevers, Anny Shai, Albert Wang, Mitchel S Berger, Susan M Chang, Joanna J Phillips, Joseph F Costello
Journal: Neuro-Oncology (2023)

Abstract Background The TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale. Methods We investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope. Results We detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor. Conclusions On a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.
Developing a computable phenotype for glioblastoma
Authors: Sandra Yan, Kaitlyn Melnick, Xing He, Tianchen Lyu, Rachel S F Moor, Megan E H Still, Duane A Mitchell, Elizabeth A Shenkman, Han Wang, Yi Guo, Jiang Bian, Ashley P Ghiaseddin
Journal: Neuro-Oncology (2023)

Glioblastoma is the most common malignant brain tumor, and thus it is important to be able to identify patients with this diagnosis for population studies. However, this can be challenging as diagnostic codes are nonspecific. The aim of this study was to create a computable phenotype (CP) for glioblastoma multiforme (GBM) from structured and unstructured data to identify patients with this condition in a large electronic health record (EHR).
Gastric peroral endoscopic myotomy versus botulinum toxin injection for the treatment of refractory gastroparesis: results of a double-blind randomized controlled study
Authors: Jean-Michel Gonzalez, François Mion, Mathieu Pioche, Victor Garbay, Karine Baumstarck, Mohamed Boucekine, Antoine Debourdeau, Jérôme Rivory, Marc Barthet, Véronique Vitton
Journal: Endoscopy (2023)

Abstract Introduction Gastric peroral endoscopic myotomy (G-POEM) is a promising technique for treating refractory gastroparesis. We present the first double-blind randomized study comparing the clinical efficacy of G-POEM versus pyloric botulinum toxin injection (BTI). Methods This randomized study, conducted in two expert centers, enrolled patients with refractory gastroparesis, medically managed for &gt;6 months and confirmed by gastric emptying scintigraphy (GES), into two groups, G-POEM versus BTI, with follow-up of 1 year. The primary end point was the 3-month clinical efficacy, defined as a &gt;1-point decrease in the mean Gastroparesis Cardinal Symptom Index (GCSI) score. Secondary end points were: 1-year efficacy, GES evolution, adverse events, and quality of life. Results 40 patients (22 women; mean age 48.1 [SD 17.4]), with mean symptom duration of 5.8 (SD 5.7) years, were randomized. Etiologies included idiopathic (n=18), diabetes (n=11), postoperative (n=6), and mixed (n=4). G-POEM showed a higher 3-month clinical success than BTI (65% vs. 40%, respectively; P=0.10), along with non-significantly higher 1-year clinical success (60% vs. 40%, respectively) on intention-to-treat analysis. The GCSI decreased in both groups at 3 months and 1 year. Only three minor adverse events occurred in the G-POEM group. The GES improvement rate was 72% in the G-POEM group versus 50% in the BTI group (non-significant). Conclusion G-POEM seems to have a higher clinically relevant success rate than BTI, but this was not statistically demonstrated. This study confirms the interest in treatments targeting the pylorus, either mechanically or chemically, for managing refractory gastroparesis.