Clinical Application of Mesenchymal Stem Cells in the Treatment and Prevention of Graft-versus-Host Disease

Mesenchymal stem cells (MSCs) represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair by in vitro and animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT), multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD) and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting

The Kanarra fold-thrust structure - the leading edge of the Sevier fold-thrust belt, southwestern Utah: Geology of the Intermountain West

The multiple origins proposed for the Kanarra anticline in southwestern Utah as a drag-fold along the Hurricane fault, a Laramide monocline, a Sevier fault-propagation fold, or a combination of these process­es, serve to muddy its tectonic significance. This in part reflects the structural complexity of the exposed eastern half of the fold. The fold evolved from open and up-right to overturned and tight, is cross-cut by multiple faults, and was subsequently dismembered by the Hurricane fault. The western half of the fold is obscured because of burial, along with the hanging wall of the Hurricane fault, beneath Neogene and younger sediments and volcanics. We present the results of detailed bedrock geologic mapping, and geo­logic cross sections restored to Late Cretaceous time (prior to Basin and Range extension), to demonstrate the Kanarra anticline is a compound anticline-syncline pair inextricably linked with concomitant thrust faulting that formed during the Sevier orogeny. We propose the name Kanarra fold-thrust structure to unambiguously identify the close spatial and temporal association of folding and thrusting in formation of this prominent geologic feature. We identify a previously unrecognized thrust, the Red Rock Trail thrust, as a forelimb shear thrust that was in a favorable orientation and position to have been soft-linked, and lo­cally hard-linked, with the thrust ramp of the basal detachment to form a break thrust. The east verging Red Rock Trail thrust is recognized by a distinctive cataclasite in the Lower Jurassic Navajo Sandstone. The hanging wall of the Red Rock Trail thrust is displaced eastward over the Middle Jurassic Carmel For­mation and Upper Cretaceous Formations and can be traced for at least 27 km and possibly farther. We contend the Kanarra fold-thrust structure unambiguously defines the leading edge of the Sevier fold-thrust belt in southwestern Utah. Stratigraphic relationships in the southern and northern part of the Kanarra fold-thrust structure constrain its development between the early and late Campanian (about 84 to 71 Ma) but possibly younger. In southwest Utah, initial movement along the Iron Springs thrust at about 100 Ma (Quick and others, 2020) and subsequent eastward advancement of the Sevier deformation front to the Red Rock Trail thrust at about 84 to 71 Ma coincided with well-documented magmatic flare ups in the Cordilleran arc in the hinterland of the Sevier fold-thrust belt. This temporal relationship between mag­matic flare ups and thrusting is consistent with a close correspondence between arc-related processes and episodic foreland deformation

Thrombocytosis: Diagnostic Evaluation, Thrombotic Risk Stratification, and Risk-Based Management Strategies

Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera

Mean Atlantic Meridional Overturning Circulation Across 26.5° N From Eddy-Resolving Simulations Compared to Observations

Observations along 26.5 degrees N are used to examine the time mean structure of the Atlantic meridional overturning circulation (AMOC) in eddy-resolving simulations with the Hybrid Coordinate Ocean Model (HYCOM). The model results yield a 5 year mean AMOC transport of 18.2 Sv, compared to 18.4 Sv based on data. The modeled northward limb of the AMOC has a vertical structure similar to observations. The southward limb is shallower than observed but deeper than other ocean general circulation models and includes a secondary transport maximum near 4000 m corresponding to Nordic Seas Overflow Water. The modeled flow through the Florida Strait and the deep western boundary current (DWBC) east of Abaco, Bahamas, are also approximately consistent with observations. The model results are used to clarify the sources of the northward AMOC transport and to explore the circulation pattern of the southward transport in the western subtropical North Atlantic in the range 18-33 degrees N. About 14.1 Sv of the modeled northward AMOC transport is through the Florida Strait and the remainder through the mid-ocean, primarily in the Ekman layer, but also below 600 m. The modeled AMOC transport is about 2/3 surface water and 1/3 Antarctic Intermediate Water with no contribution from the thermocline water in between. In the western subtropical North Atlantic the model results depict a complicated deep circulation pattern, associated with the complex bathymetry. The DWBC flows southward then eastward in both the upper and lower North Atlantic Deep Water (NADW) layers but with different offshore recirculation pathways, and there exists a second, more northern branch of eastward flow in the lower NADW layer

Identification of Burkholderia mallei and Burkholderia pseudomallei adhesins for human respiratory epithelial cells

<p>Abstract</p> <p>Background</p> <p><it>Burkholderia pseudomallei </it>and <it>Burkholderia mallei </it>cause the diseases melioidosis and glanders, respectively. A well-studied aspect of pathogenesis by these closely-related bacteria is their ability to invade and multiply within eukaryotic cells. In contrast, the means by which <it>B. pseudomallei </it>and <it>B. mallei </it>adhere to cells are poorly defined. The purpose of this study was to identify adherence factors expressed by these organisms.</p> <p>Results</p> <p>Comparative sequence analyses identified a gene product in the published genome of <it>B. mallei </it>strain ATCC23344 (locus # BMAA0649) that resembles the well-characterized <it>Yersinia enterocolitica </it>autotransporter adhesin YadA. The gene encoding this <it>B. mallei </it>protein, designated <it>boaA</it>, was expressed in <it>Escherichia coli </it>and shown to significantly increase adherence to human epithelial cell lines, specifically HEp2 (laryngeal cells) and A549 (type II pneumocytes), as well as to cultures of normal human bronchial epithelium (NHBE). Consistent with these findings, disruption of the <it>boaA </it>gene in <it>B. mallei </it>ATCC23344 reduced adherence to all three cell types by ~50%. The genomes of the <it>B. pseudomallei </it>strains K96243 and DD503 were also found to contain <it>boaA </it>and inactivation of the gene in DD503 considerably decreased binding to monolayers of HEp2 and A549 cells and to NHBE cultures.</p> <p>A second YadA-like gene product highly similar to BoaA (65% identity) was identified in the published genomic sequence of <it>B. pseudomallei </it>strain K96243 (locus # BPSL1705). The gene specifying this protein, termed <it>boaB</it>, appears to be <it>B. pseudomallei</it>-specific. Quantitative attachment assays demonstrated that recombinant <it>E. coli </it>expressing BoaB displayed greater binding to A549 pneumocytes, HEp2 cells and NHBE cultures. Moreover, a <it>boaB </it>mutant of <it>B. pseudomallei </it>DD503 showed decreased adherence to these respiratory cells. Additionally, a <it>B. pseudomallei </it>strain lacking expression of both <it>boaA </it>and <it>boaB </it>was impaired in its ability to thrive inside J774A.1 murine macrophages, suggesting a possible role for these proteins in survival within professional phagocytic cells.</p> <p>Conclusions</p> <p>The <it>boaA </it>and <it>boaB </it>genes specify adhesins that mediate adherence to epithelial cells of the human respiratory tract. The <it>boaA </it>gene product is shared by <it>B. pseudomallei </it>and <it>B. mallei </it>whereas BoaB appears to be a <it>B. pseudomallei</it>-specific adherence factor.</p

Interleukin-15 Affects Patient Survival through Natural Killer Cell Recovery after Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphomas

Natural killer cells at day 15 (NK-15), after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT), is a prognostic factor for overall survival (OS) and progression-free survival (PFS) in non-Hodgkin lymphoma (NHL). The potential role of the immunologic (homeostatic) environment affecting NK-15 recovery and survival post-APHSCT has not been fully studied. Therefore, we evaluate prospectively the cytokine profile in 50 NHL patients treated with APHSCT. Patients with an interleukin-15 (IL-15) ≥ 76.5 pg/mL at day 15 post-APHSCT experienced superior OS and PFS compared with those who did not; median OS; not reached versus 19.2 months, P < .002; and median PFS; not reached versus 6.8 months, P < .002, respectively. IL-15 was found to correlate with (rs = 0.7, P < .0001) NK-15. Multivariate analysis showed only NK-15 as a prognostic factor for survival, suggesting that the survival benefit observed by IL-15 is most likely mediated by enhanced NK cell recovery post-APHSCT

Back reaction of a long range force on a Friedmann-Robertson-Walker background

It is possible that there may exist long-range forces in addition to gravity. In this paper we construct a simple model for such a force based on exchange of a massless scalar field and analyze its effect on the evolution of a homogeneous Friedmann-Robertson-Walker cosmology. The presence of such an interaction leads to an equation of state characterized by positive pressure and to resonant particle production similar to that observed in preheating scenarios.Comment: 14 pages, 6 color Postscript figures, LaTe

Aircraft accident report: NASA 712, Convair 990, N712NA, March Air Force Base, California, July 17, 1985, facts and analysis

On July 17, l985, at 1810 P.d.t., NASA 712, a Convair 990 aircraft, was destroyed by fire at March Air Force Base, California. The fire started during the rollout after the pilot rejected the takeoff on runway 32. The rejected takeoff was initiated during the takeoff roll because of blown tires on the right landing gear. During the rollout, fragments of either the blown tires or the wheel/brake assemblies penetrated a right-wing fuel tank forward of the right main landing gear. Leaking fuel ignited while the aircraft was rolling, and fire engulfed the right wing and the fuselage after the aircraft was stopped on the runway. The 4-man flightcrew and the 15 scientists and technicians seated in the cabin evacuated the aircraft without serious injury. The fire was not extinguished by crash/rescue efforts and the aircraft was destroyed

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5%(4-7%). Incidence in allogeneic-HSCT was 4%(2-6%) and in autologous-HSCT was 4%(1-15%). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35%(20-54%), whereas in acute GVHD it was 47%(32-62%). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population