Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow— stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. SIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.</p

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Abdominal wall endometrioma mimicking an incarcerated hernia: a case report

Christos Simoglou,1 Paul Zarogoulidis,2 Nikolaos Machairiotis,3 Konstantinos Porpodis,2 Lambros Simoglou,4 Alexandros Mitrakas,5 Agisilaos Esebidis,5 Eirini Sarika,6 George Kouklakis,7 Alkis Iordanidis,8 Nikolaos Katsikogiannis31Cardiothoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Greece; 2Pulmonary Department, &amp;quot;G Papanikolaou&amp;quot; General Hospital, Aristotle University of Thessaloniki, Greece; 3Surgery Department (NHS), University General Hospital of Alexandroupolis, Greece; 4Surgical Clinic (NHS), Komotini General Hospital, Thrace, Greece; 51st University Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Greece; 6Biopathology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Greece; 7Gastrointestinal Endoscopy Unit, University General Hospital of Alexandroupolis, Democritus University of Thrace, 8Radiology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, GreeceAbstract: The case of a tender, isolated abdominal wall tumor within a Pfannenstiel incision due to a seeding deposit of endometrial tissue secondary to a previous obstetric operation (caesarean section) in a 39-year-old female without previously reported pelvic endometriosis is presented. The lesion clinically mimicked the appearance of an incarcerated incisional hernia at the outer corner of the healed Pfannenstiel incision. The preoperative differential diagnosis also included that of a locally forming post-operative tender granuloma and the remote possibility of an incisional endometrioma (although no link to menstruation could be made). Local malignancy was not taken as a serious possibility. Definitive diagnosis of the excised lesion was made at histology. The pre-operative diagnostic dilemma is presented, along with a short review of the literature.Keywords: endometrioma, seeding endometriosis, abdominal wall tumo

Dynamic modelling of the voltage response of direct methanol fuel cells and stacks: Part I: Model development and validation.

Abstract The feasibility of using empirical state space models such as canonical variates analysis (CVA) models for the scale-up and scale-down of direct methanol fuel cells (DMFC) is explored. The development of such models to predict voltage responses of DMFCs has been previously investigated with a small-scale single cell and a three-cell stack assembly. Each system was subjected to a range of varying dynamic loads and operating conditions. A model was developed for each of the two systems for varying cell operating conditions, and these models were then validated against the other &quot;unseen&quot; data sets collected from the two cells. The models developed were found to give acceptable inferential estimates and one-step-ahead predictions. One outcome of that study was the possibility of using such models to aid cell scale-up and scale-down. This paper addresses the feasibility of using a dynamic state space canonical variates analysis (CVA) model of the small-scale single cell to predict the voltage responses of the scaled up three-cell stack system. In addition the feasibility of using the three-cell system model to predict the dynamic behaviour of the small system is also studied (scale-down). The results achieved are encouraging and indicate the potential of using a CVA state space representations as an aid to cell scale-up and scale-down.

First report of the root-knot nematode, Meloidogyne hispanica, infecting sunflower in Greece

Severe plant stunting, chlorosis, and extensive root galling were observed on sunflower (Helianthus annus Pioneer Hi-bred PR64LE19, Dupont) in a commercial field at Agios Athanasios, Drama Province, northeastern Greece at the end of May 2013. Disease symptoms were observed about 1.5 months after planting, and were distributed in patches that covered approximately 2% of the whole cultivated area. Examination of the soil and root samples from selected infected plants revealed the presence of abundant root-knot nematodes. Juveniles, males, and females were extracted by sieving, decanting, and root dissection for identification using morphological traits. Nematode population densities ranging from 100 to 150 J2s per 100 cm3 of soil, and 150 to 3,000 eggs per g of fresh sunflower roots were observed. Identification was confirmed by perineal patterns of females and by sequencing of the D2-D3 expansion segments of 28S ribosomal RNA gene (1,3,4). All identification methods were consistent with typical Meloidogyne hispanica. Morphology of perineal patterns of females and measurements of the second-stage juveniles (J2s) matched those of the original description of M. hispanica (3). Alignment indicated that the D2-D3 sequence (GenBank Accession No. KF501128) was 99% homologous to other sequences of M. hispanica deposited in GenBank from Brazil, Portugal, and Spain (EU443606, EU443608, and GQ375158, respectively), differing in only one nucleotide. Phylogenetic analyses using maximum likelihood of this sequence placed the Meloidogyne sp. in a highly supported (100%) clade that included all M. hispanica sequences available from the GenBank database (4). Root-knot nematodes in general have been reported to cause economic losses in sunflower in Europe (2), but there are no reports of M. hispanica. M. hispanica was first found in Seville Province, southern Spain, infecting rootstocks of Prunus spp. (3). Its distribution has been confirmed worldwide on different agricultural crops. However, to our knowledge, this is the first report of M. hispanica infecting sunflower in Europe and the first report of this species on any crop for Greece. The identification of M. hispanica in sunflower is relevant because it may represent a threat for sunflower production in Greece. Research to develop sunflower varieties resistant to root-knot nematodes should now also consider M. hispanica along with other species of Meloidogyne.Peer Reviewe