Notes

Genetics associated with Osteoporotic Vertebral Breaks.
Epoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil.

A 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart cars without reported adverse effects.In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. selleck chemical Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.Cellular therapy with regulatory T cells (Tregs) has shown promising results for suppressing graft-versus-host disease (GVHD) while preserving graft vs tumor effects in animal models and phase 1/2 clinical trials. However, a paucity of Tregs in the peripheral blood makes it difficult to acquire sufficient numbers of cells and hampers further clinical application. Invariant natural killer T (iNKT) cells constitute another compartment of regulatory cells that ameliorate GVHD through activation of Tregs after their own activation with α-galactosylceramide (α-GalCer) or adoptive transfer. We demonstrate here that a single administration of α-GalCer liposome (α-GalCer-lipo) enhanced the in vivo expansion of Tregs after adoptive transfer in a murine GVHD model and improved therapeutic efficacy of Treg therapy even after injection of otherwise suboptimal cell numbers. Host iNKT cells rather than donor iNKT cells were required for GVHD suppression because the survival benefit of α-GalCer-lipo administration was not shown in the transplantation of cells from wild-type (WT) C57BL/6 mice into Jα18-/- iNKT cell-deficient BALB/c mice, whereas it was observed from Jα18-/- C57BL/6 donor mice into WT BALB/c recipient mice. The combination of iNKT cell activation and Treg adoptive therapy may make Treg therapy more feasible and safer by enhancing the efficacy and reducing the number of Tregs required.Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases.The clinicopathologic features of DNA methyltransferase 3A (DNMT3A)-mutated de novo acute myeloid leukemia (AML), and the significance of variant type, variant allele frequency (VAF), and multiple concomitant DNMT3A mutations, remain poorly defined. We examined 104 DNMT3A-mutated de novo AML patients from 2 major centers. Most (82%) had normal karyotype (NK); R882H variants were frequent(38%). The most commonly comutated genes included nucleophosmin (NPM1; 53%), Fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (25%), IDH1 (23%), IDH2 (23%), and TET2 (21%). Patients with high DNMT3A VAF at diagnosis (≥44%; DNMT3AHIGH) had more significant leukocytosis and higher blast counts in peripheral blood and bone marrow. DNMT3AHIGH cases were associated with much shorter event-free survival (EFS; 14.1 vs 56.8 months) and overall survival (OS; 18.3 months vs not reached) compared with cases of patients with low DNMT3A (DNMT3ALOW). Thirteen patients had 2 DNMT3A variants and similar VAFs at diagnosis that tracked together at multiple time points after chemotherapy and/or stem cell transplantation (SCT). In multivariable analyses performed in NK patients who received standard induction chemotherapy, presence of 2 DNMT3A mutations (hazard ratio [HR] = 3.192; P = .038) and SCT in first complete remission (HR = 0.295; P = .001) independently affected EFS; increasing marrow blast percentage (HR = 1.026; P = .025), high DNMT3A VAF (HR = 3.003; P = .010), and 2 DNMT3A mutations (HR = 4.816; P = .020) had independent effects on OS. These data support the adverse prognostic significance of DNMT3AHIGH reveal a novel association between 2 concomitant DNMT3A mutations and inferior outcome in DNMT3A-mutated de novo AML with a NK.Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lymphoma at our clinic. Median peak CAR-T-cell count was 16.14 CAR-T cells/µL. Patients with 16.14/μL or higher peak CAR-T cells (strong expanders) had more day-30 objective responses (91% vs 40%, P = .02). In univariate analysis, peak CAR-T cell ≥ 16.14 (P less then .001), normal platelet counts at start of lymphodepletion (P less then .001), no prior stem cell transplant (P = .04), and peak CAR-T cells as continuous variable (P = .03) were associated with better progression-free survival (PFS). After adjusting for platelet counts and prior stem cell transplantation, peak CAR-T cells below median was still associated with shorter PFS (relative risk, 0.15, 95% confidence interval, 0.04-0.59, P = .007). Low platelet counts also maintained significant impact on PFS. Our data demonstrate association of axi-cel levels and outcome in a nontrial setting and for the first time use a cutoff to segregate weak and strong expanders with respective outcomes.Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.Narrow distribution patterns of tropical Drosophila species are limited by lower resistance to cold or drought. In the invasive tropical Drosophila kikkawai, we tested whether developmental and adult acclimations at cooler temperatures could enhance its stress resistance level. Adult acclimation of winter collected body color morphs revealed a significant increase in the level of cold resistance. For light morph, its abundance during winter is not consistent with thermal-melanism hypothesis. However, higher cold acclimation capacity, as well as storage of energy metabolites could support its winter survival. In the wild-caught light and intermediate morphs, there is a lack of trade-off between cold and heat resistance but not in the case of dark morph. Developmental plasticity (15°C) resulted in the fivefold increase of cold survival at 0°C; and a twofold increase in desiccation resistance but a modest reduction (∼28-35%) in heat resistance as compared to morph strains reared at 25°C. Drought acclimation changes were significantly higher as compared with cold or heat pretreatment. We observed a trade-off between basal resistance and acclimation capacity for cold, heat, or drought resistance. For homeostatic energy balance, adult acclimation responses (cold versus drought; heat versus drought) caused compensatory plastic changes in the levels of proline or trehalose (shared patterns) but different patterns for total body lipids. In contrast, rapid cold or heat hardening-induced changes in energy metabolites were different as compared to acclimation. The ability of D. kikkawai to significantly increase stress tolerance through plasticity is likely to support its invasion potential.Secreted proteins are transported along intracellular route from the endoplasmic reticulum through the Golgi before reaching the plasma membrane. Small GTPase Rab and their effectors play a key role in membrane trafficking. Using confocal microscopy, we showed that MICAL-L1 was associated with tubulo-vesicular structures and exhibited a significant colocalization with markers of the Golgi apparatus and recycling endosomes. Super resolution STORM microscopy suggested at the molecular level, a very close association of MICAL-L1 and microdomains in the Golgi cisternae. Using a synchronized secretion assay, we report that the shRNA-mediated depletion of MICAL-L1 impaired the delivery of a subset of cargo proteins to the cell surface. The process of membrane tubulation was monitored in vitro, and we observe that recombinant MICAL-L1-RBD domain may contribute to promote PACSINs-mediated membrane tubulation. Interestingly, two hydrophobic residues at the C-terminus of MICAL-L1 appeared to be important for phosphatidic acid binding, and for association with membrane tubules.
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