Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients.

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

Xylosyltransferase 2 deficiency and organ homeostasis.

In this paper we characterize the function of Xylosyltransferase 2 (XylT2) in different tissues to investigate the role XylT2 has in the proteoglycan (PG) biochemistry of multiple organs. The results show that in all organs examined there is a widespread and significant decrease in total XylT activity in Xylt2 knock out mice (Xylt2-/-). This decrease results in increased organ weight differences in lung, heart, and spleen. These findings, in addition to our previous findings of increased liver and kidney weight with loss of serum XylT activity, suggest systemic changes in organ function due to loss of XylT2 activity. The Xylt2-/- mice have splenomegaly due to enlargement of the red pulp area and enhanced pulmonary response to bacterial liposaccharide. Tissue glycosaminoglycan composition changes are also found. These results demonstrate a role of XylT2 activity in multiple organs and their PG content. Because the residual XylT activity in the Xylt2-/- is due to xylosyltransferase 1 (XylT1), these studies indicate that both XylT1 and XylT2 have important roles in PG biosynthesis and organ homeostasis.

Xylosyltransferase II is a significant contributor of circulating xylosyltransferase levels and platelets constitute an important source of xylosyltransferase in serum.

Circulating glycosyltransferases including xylosyltransferases I (XylT1) and II (XylT2) are potential serum biomarkers for various diseases. Understanding what influences the serum activity of these enzymes as well as the sources of these enzymes is important to interpreting the significance of alterations in enzyme activity during disease. This article demonstrates that in the mouse and human the predominant XylT in serum is XylT2. Furthermore, that total XylT levels in human serum are approximately 200% higher than those in plasma due in part to XylT released by platelets during blood clotting in vitro. In addition, the data from Xylt2 knock-out mice and mice with liver neoplasia show that liver is a significant source of serum XylT2 activity. The data presented suggest that serum XylT levels may be an informative biomarker in patients who suffer from diseases affecting platelet and/or liver homeostasis.

One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders.

Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger's syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B(12) and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and sex-matched controls (n= 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine (P= 0.01 and P= 0.03, respectively) and alpha-aminobutyrate were observed (P= 0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P= 0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B(12) and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs.

[The genetic polymorphism of MTHFR gene in schizophrenia]. / Polimorfismul genetic al genei MTHFR in schizofrenie.

UNLABELLED: The 677C > T polymorphism of the MTHFR gene, resulting in hyperhomocysteinemia, has been shown to be implicated in the aetiology of schizophrenia. Previous studies showed that A1298 C polymorphism seems not to be related to schizophrenia. AIM OF THE STUDY: To analyze two genetic polymorphisms of the MTHFR gene, 677C > T and A1298 C in 44 patients with schizophrenia and evaluate its relationship with the risk of schizophrenia and with some clinical aspects. MATERIAL AND METHOD: We determined the presence of the 677C > T and A1298 C mutations of the MTHFR gene in 44 inpatients with schizophrenia and in 35 normal controls. The patients were assessed by psychiatric examination and scalar evaluation. RESULTS: 28 (66,7%) of the patient group had the T allele of the 677C > T genetic polymorphism, compared to 11 (34,3%) subjects of the control group. The intensity of the positive, negative and general symptoms was slightly higher in the patients presenting the T allele. The A1298C missense mutation was more frequent between control subjects (57,5%) compared to the patient group (39%). The intensity of the positive symptoms was slightly increased in the patients with the missense mutation in the position 1298, but the intensity of the negative and general symptoms did not differ. CONCLUSIONS: Our study confirms the role of the 677C > T genetic polymorphism in the susceptibility for schizophrenia. The relationship between A1298C genetic polymorphism and schizophrenia was not demonstrated in our study.

STR data for the 15 AmpFlSTR identifiler loci in the Western Romanian population.

Allele frequencies for the 15 tetranucleotide short tandem repeat loci contained in the AmpFlSTR Identifiler kit were obtained from a population sample of 219 unrelated individuals born in the western part of Romania.