tbuckley/cabot-search huggingface dataset:
Improved Small Extracellular Vesicle Secretion of Rat Adipose‐Derived Stem Cells by Microgrooved Substrates through Upregulation of the ESCRT‐III‐Associated Protein Alix
Authors: Yurong Ji, Weiju Han, Xiaoling Fu, Jing Li, Qi Wu, Yingjun Wang
Journal: Advanced Healthcare Materials (2021)

Abstract Mesenchymal stem cell‐derived small extracellular vesicles (MSC‐sEVs) hold great potential for regenerative therapies and have received considerable research attention in recent years. However, the use of MSC‐sEVs is limited by very low yield in routine culture conditions and suboptimal potency for certain diseases. Thus, strategies that enable the production of sufficient quantities of sEVs with desired therapeutic cargo in a facile and inexpensive way are in high demand. This study finds that the microgrooved substrates stimulate rat adipose‐derived mesenchymal stem cells (rASCs) to produce a larger quantity of sEVs than the flat substrates. Further investigation suggests that the ESCRT‐III‐associated protein Alix may be involved in mediating the elevated sEV production of rASCs on the microgrooved substrates. Besides, the cargo of sEVs is altered. SEVs secreted by rASCs on the microgrooved substrates carry higher levels of proangiogenic miRNAs and growth factors than those secreted by rASCs on the flat substrates. Functional assessments demonstrate that sEVs from rASCs on microgrooved substrates enhance the angiogenic properties of Human umbilical vein endothelial cells. The findings demonstrate that substrate topography is an effective regulator of the sEVs secretion by rASCs and highlight the potential of using microgrooved substrates as a platform to produce rASC‐sEVs rich in pro‐angiogenic factors.
Stress-Mediated Reprogramming of Prostate Cancer One-Carbon Cycle Drives Disease Progression
Authors: Nora Pällmann, Ke Deng, Marte Livgård, Martina Tesikova, Yixin Jin, Nicolai Sebastian Frengen, Nermin Kahraman, Hamada M. Mokhlis, Bulent Ozpolat, Wanja Kildal, Havard Emil Danielsen, Ladan Fazli, Paul S. Rennie, Partha P. Banerjee, Aykut Üren, Yang Jin, Omer F. Kuzu, Fahri Saatcioglu
Journal: Cancer Research (2021)

One-carbon (1C) metabolism has a key role in metabolic programming with both mitochondrial (m1C) and cytoplasmic (c1C) components. Here we show that activating transcription factor 4 (ATF4) exclusively activates gene expression involved in m1C, but not the c1C cycle in prostate cancer cells. This includes activation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression, the central player in the m1C cycle. Consistent with the key role of m1C cycle in prostate cancer, MTHFD2 knockdown inhibited prostate cancer cell growth, prostatosphere formation, and growth of patient-derived xenograft organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in preclinical prostate cancer mouse models. Consistently, MTHFD2 expression is significantly increased in human prostate cancer, and a gene expression signature based on the m1C cycle has significant prognostic value. Furthermore, MTHFD2 expression is coordinately regulated by ATF4 and the oncoprotein c-MYC, which has been implicated in prostate cancer. These data suggest that the m1C cycle is essential for prostate cancer progression and may serve as a novel biomarker and therapeutic target. SIGNIFICANCE: These findings demonstrate that the mitochondrial, but not cytoplasmic, one-carbon cycle has a key role in prostate cancer cell growth and survival and may serve as a biomarker and/or therapeutic target.
A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
Authors: Stephen Salloway, Martin Farlow, Eric McDade, David B. Clifford, Guoqiao Wang, Jorge J. Llibre-Guerra, Janice M. Hitchcock, Susan L. Mills, Anna M. Santacruz, Andrew J. Aschenbrenner, Jason Hassenstab, Tammie L. S. Benzinger, Brian A. Gordon, Anne M. Fagan, Kelley A. Coalier, Carlos Cruchaga, Alison A. Goate, Richard J. Perrin, Chengjie Xiong, Yan Li, John C. Morris, B. Joy Snider, Catherine Mummery, G. Mustafa Surti, Didier Hannequin, David Wallon, Sarah B. Berman, James J. Lah, Ivonne Z. Jimenez-Velazquez, Erik D. Roberson, Christopher H. van Dyck, Lawrence S. Honig, Raquel Sánchez-Valle, William S. Brooks, Serge Gauthier, Douglas R. Galasko, Colin L. Masters, Jared R. Brosch, Ging-Yuek Robin Hsiung, Suman Jayadev, Maité Formaglio, Mario Masellis, Roger Clarnette, Jérémie Pariente, Bruno Dubois, Florence Pasquier, Clifford R. Jack, Robert Koeppe, Peter J. Snyder, Paul S. Aisen, Ronald G. Thomas, Scott M. Berry, Barbara A. Wendelberger, Scott W. Andersen, Karen C. Holdridge, Mark A. Mintun, Roy Yaari, John R. Sims, Monika Baudler, Paul Delmar, Rachelle S. Doody, Paulo Fontoura, Caroline Giacobino, Geoffrey A. Kerchner, Randall J. Bateman, Maité Formaglio, Susan L. Mills, Jérémie Pariente, Christopher H. van Dyck
Journal: Nature Medicine (2021)
Abstract 20673: Mutations in TTN Coexisting With Others in Genes Encoding Functional, Structural and Ion Channels Components of the Cardiomyocytes Cause Severe Dilated Cardiomyopathy in Children
Authors: Norma Balderrabano-Saucedo, Karla Cano-Hernández, Dan Hu, Ryan Pfeiffer, Adriana Sánchez-Boiso, Yuesheng Wu, Tabitha Carrier, José Enrique Zamora-Mejía, Julio Erdmenger-Orellana, Santiago Nava, Keneth G Magaña, Ricardo F Albarracín-Ceballos, Rosario Becerra-Becerra, Begoña Segura-Stanford, Tania Tamayo-Espinosa, Ana Cruz-Miranda, Esteban Suárez-Delgado, Héctor Barajas Martínez
Journal: Circulation (2016)

Introduction: Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure (HF). It has been shown rare variations in more than 40 genes related to DCM, most of which encode str...
Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models
Authors: Yao-Xin Lin, Yi Wang, Jianxun Ding, Aiping Jiang, Jie Wang, Mian Yu, Sara Blake, Shuaishuai Liu, Charles J. Bieberich, Omid C. Farokhzad, Lin Mei, Hao Wang, Jinjun Shi
Journal: Science Translational Medicine (2021)

The restoration of tumor suppressor PTEN by synthetic mRNA nanoparticles sensitizes Pten -null or mutated tumors to immune checkpoint blockade therapy.
Controlling one’s world: Identification of sub-regions of primate PFC underlying goal-directed behavior
Authors: Lisa Y. Duan, Nicole K. Horst, Stacey A.W. Cranmore, Naotaka Horiguchi, Rudolf N. Cardinal, Angela C. Roberts, Trevor W. Robbins
Journal: Neuron (2021)

Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and overactivated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC), and 14-25 (caudal ventromedial PFC) and the anteromedial caudate to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmoset monkeys. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32, or 14-25 had no effect. Overactivation of areas 11 and 24 impaired this response. These findings demonstrate the distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders, including obsessive-compulsive disorder.
A practical guide to promote informatics-driven efficient biotopographic material development
Authors: Yuanlong Guo, Jiaomei Mi, Chen Ye, Yong Ao, Mengru Shi, Zhengjie Shan, Bingzhi Li, Zetao Chen, Zhuofan Chen, Krasimir Vasilev, Yin Xiao
Journal: Bioactive Materials (2021)

Micro/nano topographic structures have shown great utility in many biomedical areas including cell therapies, tissue engineering, and implantable devices. Computer-assisted informatics methods hold great promise for the design of topographic structures with targeted properties for a specific medical application. To benefit from these methods, researchers and engineers require a highly reusable "one structural parameter – one set of cell responses" database. However, existing confounding factors in topographic cell culture devices seriously impede the acquisition of this kind of data. Through carefully dissecting the confounding factors and their possible reasons for emergence, we developed corresponding guideline requirements for topographic cell culture device development to remove or control the influence of such factors. Based on these requirements, we then suggested potential strategies to meet them. In this work, we also experimentally demonstrated a topographic cell culture device with controlled confounding factors based on these guideline requirements and corresponding strategies. A "guideline for the development of topographic cell culture devices" was summarized to instruct researchers to develop topographic cell culture devices with the confounding factors removed or well controlled. This guideline aims to promote the establishment of a highly reusable "one structural parameter – one set of cell responses" database that could facilitate the application of informatics methods, such as artificial intelligence, in the rational design of future biotopographic structures with high efficacy.
Bim Regulates the Survival and Suppressive Capability of CD8+ Foxp3+ Regulatory T Cells during Graft Versus Host Disease
Authors: Benjamin G. Vincent, Kimberle A. Agle, Ludovic Belle, Vivan Zhou, Clint Piper, Warren D Shlomchik, Jonathan S Serody, William R. Drobyski
Journal: Blood (2017)
Abstract 223: Parkin is Critical for the Clearance of Damaged Mitochondria via an Autophagy-independent Pathway
Authors: Babette C Hammerling, Melissa Q Cortez, Rita H Najor, Åsa B Gustafsson
Journal: Circulation Research (2016)

Functional mitochondria are essential for highly metabolic organs such as the heart. When mitochondria are damaged they can release pro-death factors and reactive oxygen species which in turn can result in cell death. The E3 ubiquitin ligase Parkin plays an important role in clearing damaged mitochondria via the autophagy pathway to protect cells against unnecessary cell death. Interestingly, we have found that Parkin can mediate clearance of damaged mitochondria via an autophagy-independent pathway. In fact, Parkin promotes clearance of depolarized mitochondria at the same rate in both wild-type (WT) and autophagy deficient Atg5-/- mouse embryonic fibroblasts (MEFs) in response to the mitochondrial uncoupler FCCP. We also found that Parkin-mediated ubiquitination is critical for this process as disease associated mutants of Parkin were incapable of inducing mitochondrial clearance in Atg5-/- MEFs. Upon further investigation, we observed a significant increase in the number of Rab5+ early- and Rab7+ late endosomes in both WT and Atg5-/- MEFs after depolarization of mitochondria with FCCP or valinomycin, indicating activation of the endosomal-lysosomal degradation pathway. We did not observe activation of the endosomal pathway after exposure to actinomycin D, an inhibitor RNA synthesis and activator of apoptosis, confirming that mitochondrial damage specifically activates the endosomal degradation pathway. We also observed activation of the endosomal pathway in neonatal myocytes in response to FCCP treatment or after exposure to simulated ischemia/reperfusion (sI/R). Overexpression of the dominant negative Rab5S34N significantly enhanced sI/R-mediated cell death, suggesting that this is a protective pathway activated by cells in response to stress. Moreover, Beclin1 is well known to regulate activation of autophagy. Here, we found that knockdown of Beclin1 inhibited both the number of Rab5+ early endosomes and their colocalization with mitochondria in response to either FCCP or sI/R in myocytes, suggesting that Beclin1 is a critical upstream regulator of the endosomal degradation pathway. Thus, our data suggest that Parkin mediates clearance of damaged mitochondria via both the autophagy and endosomal pathways in cells.
FLOT versus ECF/ECX peri-operative regimens in real life setting for patients with resectable gastric adenocarcinoma
Authors: J. Graça, M. Pinto, D. Alberca, P. Chitonho, A. Matos, J. Barata, M. Neves, F. Alves, A. Martins
Journal: Annals of Oncology (2019)
Diamond in the Rough: Toward Improved Materials for the Bone−Implant Interface
Authors: Jessica S. L. Fong, Marsilea A. Booth, Aaqil Rifai, Kate Fox, Amy Gelmi
Journal: Advanced Healthcare Materials (2021)

Abstract The ability of an orthopedic implant to integrate successfully with the surrounding bone tissue is imperative for optimal patient outcomes. Here, the recent advances and future prospects for diamond‐based coatings of conventional osteo‐implant materials (primarily titanium) are explored. The ability of these diamond coatings to enhance integration into existing bone, improved implant mechanical properties, facilitate surface chemical functionalization, and provide anti‐microbial properties are discussed in context of orthopedic implants. These diamond‐based materials may have the additional benefit of providing an osteo‐inductive effect, enabling better integration into existing bone via stem cell recruitment and bone regeneration. Current and timely research is highlighted to support the discussion and suggestions in further improving implant integration via an osseoinductive effect from the diamond composite materials.
DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis
Authors: Linea N. Toksvang, Kathrine Grell, Jacob Nersting, Matilda Degn, Stine N. Nielsen, Jonas Abrahamsson, Bendik Lund, Jukka Kanerva, Ólafur G. Jónsson, Kristi Lepik, Goda Vaitkevičienė, Laimonas Griškevičius, Petter Quist-Paulsen, Ajay Vora, Anthony V. Moorman, Daniel Murdy, Martin Zimmermann, Anja Möricke, Bruce Bostrom, Jaitri Joshi, Lisa L. Hjalgrim, Kim P. Dalhoff, Bodil Als-Nielsen, Kjeld Schmiegelow
Journal: Leukemia (2021)
Abstract 1196: BALF liquid biopsy provides a novel platform for speedy and accurate EGFR mutation testing in advanced NSCLC patients
Authors: In Ae Kim, Jae Young Hur, Hee Joung Kim, Wan Seop Kim, Kye Young Lee
Journal: Cancer Research (2021)

Abstract Background EGFR mutation testing is an essential step for the therapeutic decision in newly diagnosed advanced NSCLC patients and usually performed by using DNA extracted from biopsied tumor tissue with a turnaround time(TAT) of 2-3 weeks. Plasma liquid biopsy using ctDNA is minimally invasive and less time-consuming, but shows limited usefulness due to low sensitivity. We conducted a prospective study to demonstrate clinical usefulness of bronchoalveolar lavage fluid (BALF) liquid biopsy using extracellular vesicle(EV)-derived DNA in advanced NSCLC patients by comparing the sensitivity and TAT with conventional tissue biopsy and plasma liquid biopsy Methods The analysis set for liquid EGFR genotyping is 224 BALF samples and 110 plasma samples obtained from newly diagnosed 224 advanced non-squamous NSCLC patients. EGFR genotyping was done through peptide nucleic acid(PNA)-mediated real-time PCR after extracting BALF EV DNA and plasma cfDNA separately. The sensitivity, specificity, and concordance rate of BALF liquid biopsy were calculated in comparison to matched tissue genotyping and plasma liquid biopsy. In addition, TAT was compared between BALF liquid biopsy and tissue genotyping. Results Tissue genotyping revealed 93 EGFR mutant cases (41.5%) and 131 wild-type cases (58.5%). The sensitivity, specificity, positive predictive value, negative predictive value, and concordance rate of BALF liquid biopsy to tissue genotyping were 97.8%, 96.9%, 96.8%, 98.4%, and 97.7%, respectively. BALF liquid biopsy showed almost identical performance with standard tissue genotyping, while only 5 cases were mismatched each other. On the other hand, plasma liquid biopsy using cfDNA (n=110) revealed 48.5% sensitivity, 86.3% specificity, and 63.6% concordance rate in comparison to tissue genotyping. The mean turnaround times of BALF liquid biopsy was significantly shortened to 2.6±2.0 days in contrast to 13.9±12.4 days of tissue genotyping. (p&amp;lt;0.001). Conclusion BALF liquid biopsy can be developed as a novel platform for EGFR mutation testing in advanced NSCLC with almost identical performance with conventional tissue genotyping and significantly shorten TAT to 1-2 days. Citation Format: In Ae Kim, Jae Young Hur, Hee Joung Kim, Wan Seop Kim, Kye Young Lee. BALF liquid biopsy provides a novel platform for speedy and accurate EGFR mutation testing in advanced NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1196.
Evolutive diaphragmatic lesions causing recurrent catamenial pneumothorax
Authors: Céline Forster, Charles Bénière, Justine Lattion, Jean Yannis Perentes, Michel Christodoulou
Journal: Thorax (2021)

A 47-year-old woman was diagnosed with pelvic endometriosis during a caesarean at the age of 37 years. Two years later, she presented two episodes of spontaneous right-sided pneumothorax occurring 2 days after the onset of her menses. The first episode was treated with pleural drainage and the chest CT scan did not show parenchymal or diaphragmatic anomalies. A second episode occurred 1 month later and the patient underwent thoracoscopic exploration, wedge resection of the lung apex and mechanical pleurodesis. During this intervention, multiple dark elliptical nodules were identified on the tendinous part of the diaphragm (figure 1A …
Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains
Authors: Md Golam Sharoar, Sarah Palko, Yingying Ge, Takaomi C. Saido, Riqiang Yan
Journal: Molecular Neurodegeneration (2021)

Neuritic plaques in Alzheimer's disease (AD) brains refer to β-amyloid (Aβ) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APPNL-G-F), 5xFAD and APP/PS1ΔE9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround Aβ plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1+-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and Aβ oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.
Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification
Authors: Hector Martín Merinero, Yuzhou Zhang, Emilia Arjona, Guillermo del Angel, Renee Goodfellow, Elena Gomez-Rubio, Rui-Ru Ji, Malkoa Michelena, Richard J. H. Smith, Santiago Rodríguez de Córdoba
Journal: Blood (2021)
Acute promyelocytic leukemia current treatment algorithms
Authors: Musa Yilmaz, Hagop Kantarjian, Farhad Ravandi
Journal: Blood Cancer Journal (2021)

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a "rapid downhill course" characterized with a severe bleeding tendency. APL, accounting for 10-15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. The PML-RARA fusion oncoprotein induces leukemia by blocking normal myeloid differentiation. Before using anthracyclines in APL therapy in 1973, no effective treatment was available. In the mid-1980s, all-trans retinoic acid (ATRA) monotherapy was used with high response rates, but response durations were short. Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.
Corneal Confocal Microscopy Predicts the Development of Diabetic Neuropathy: A Longitudinal Diagnostic Multinational Consortium Study
Authors: Bruce A. Perkins, Leif Erik Lovblom, Evan J.H. Lewis, Vera Bril, Maryam Ferdousi, Andrej Orszag, Katie Edwards, Nicola Pritchard, Anthony Russell, Cirous Dehghani, Danièle Pacaud, Kenneth Romanchuk, Jean K. Mah, Maria Jeziorska, Andrew Marshall, Roni M. Shtein, Rodica Pop-Busui, Stephen I. Lentz, Mitra Tavakoli, Andrew J.M. Boulton, Nathan Efron, Rayaz A. Malik
Journal: Diabetes Care (2021)

OBJECTIVE Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2–7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1–5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70–5.11; P &amp;lt; 0.001) for new-onset DPN. CONCLUSIONS CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future.