Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNAseq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated efficacy in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat with histone demethylase inhibitor GSKJ4 revealed synergy. Together, these data suggest a promising therapeutic strategy for DIPG.

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Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-α and -β-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of α-fodrin in the salivary glands and anti-α-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.

Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.

We use characteristic functions to construct α-multistable measures and integrals, where the measures behave locally like stable measures, but with the stability index α(x) varying with x. This enables us to construct α-multistable processes on R, that is processes whose scaling limit at time t is an α(t)-stable process. We present several examples of such multistable processes and examine their localisability.

Purpose: CD19 chimeric antigen receptor (CAR)-T therapy has shown impactful results in treatment of B-cell malignancies. However, immune recognition of the murine scFv may render subsequent infusion(s) ineffective. Also, nonselective expansion of both CAR-transduced and nontransduced T cells during the production stage affects the yield and purity of final products. Here, we aim to develop a humanized selective (hs) CD19 CAR to solve the above problems.Experimental Design: A CD19 hsCAR was designed, which incorporated a short selective domain between the humanized heavy chain and light chain. The CAR was examined for its property, and then trialed in 5 highly treated B-ALL patients.Results: hsCAR possessed around 6-fold higher affinity to CD19 versus murine CAR (mCAR). Incubation with selective domain-specific mAbs (SmAb) selectively expanded CAR-transduced T cells, and led to a higher proportion of central memory T cells in the final products. SmAb-stimulated CD19 hsCAR-T cells exhibited superior antitumor cytotoxic functions in vitro and in vivo. Autologous (n ¼ 2) and allogeneic donor (n ¼ 3, with hematopoietic stem cell transplantation) hsCAR-T cells were infused into 5 patients who had relapsed after receiving mCAR-T treatments. Two patients received mCAR-T treatments twice previously but the second treatments were ineffective. In contrast, subsequent hsCAR-T treatments proved effective in all 5 patients and achieved complete molecular remission in four, including one with extramedullary disease with central nervous system involvement.Conclusions: hsCD19 CAR-T treatment shows efficacy in highly treated B-ALL patients who have relapsed after receiving CD19 mCAR-T therapies.

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Long noncoding RNAs (lncRNAs) have recently emerged as important biological regulators, and the aberrant expression of lncRNAs has been reported in numerous diseases. However, the expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) has not been well documented. We applied a microarray analysis to profile the lncRNA and mRNA expression in 3 pairs of samples. Each sample was mixed with equivalent PBMCs from 9 female RA patients and 9 corresponding healthy controls, and the data were validated via qPCR using another cohort that comprised 36 RA patients and 24 healthy controls. A bioinformatic analysis was performed to investigate the potential functions of differentially expressed genes. Overall, 2,099 lncRNAs and 2,307 mRNAs were differentially expressed between the RA patients and healthy controls. The bioinformatic analysis indicated that the differentially expressed lncRNAs regulated the abnormally expressed mRNAs, which were involved in the pathogenesis of RA through several different pathways. The qPCR results showed that the expression levels of ENST00000456270 and NR_002838 were significantly increased in the RA patients, whereas the expression levels of NR_026812 and uc001zwf.1 were significantly decreased. Furthermore, the expression level of ENST00000456270 was strongly associated with the serum levels of IL-6 and TNF-a and the Simplified Disease Activity Index (SDAI) of the RA patients. Our data provided comprehensive evidence regarding the differential expression of lncRNAs in PBMCs of RA patients, which shed light on the understanding of the molecular mechanisms of lncRNAs in the pathogenesis of RA.