Tregs have the potential to establish long-term immune tolerance in patients recently diagnosed with type 1 diabetes (T1D) by preserving β cell function. Adoptive transfer of autologous thymic Tregs, ...although safe, exhibited limited efficacy in previous T1D clinical trials, likely reflecting a lack of tissue specificity, limited IL-2 signaling support, and in vivo plasticity of Tregs. Here, we report a cell engineering strategy using bulk CD4+ T cells to generate a Treg cell therapy (GNTI-122) that stably expresses FOXP3, targets the pancreas and draining lymph nodes, and incorporates a chemically inducible signaling complex (CISC). GNTI-122 cells maintained an expression profile consistent with Treg phenotype and function. Activation of CISC using rapamycin mediated concentration-dependent STAT5 phosphorylation and, in concert with T cell receptor engagement, promoted cell proliferation. In response to the cognate antigen, GNTI-122 exhibited direct and bystander suppression of polyclonal, islet-specific effector T cells from patients with T1D. In an adoptive transfer mouse model of T1D, a mouse engineered-Treg analog of GNTI-122 trafficked to the pancreas, decreased the severity of insulitis, and prevented progression to diabetes. Taken together, these findings demonstrate in vitro and in vivo activity and support further development of GNTI-122 as a potential treatment for T1D.
CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for ...minimal residual disease. High-grade toxic effects were frequent but treatable.
SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small ...molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.
The Excited Spin State of 1I/2017 U1 'Oumuamua Belton, Michael J. S.; Hainaut, Olivier R.; Meech, Karen J. ...
Astrophysical journal. Letters,
04/2018, Letnik:
856, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We show that 'Oumuamua's excited spin could be in a high-energy long axis mode (LAM) state, which implies that its shape could be far from the highly elongated shape found in previous studies. CLEAN ...and ANOVA algorithms are used to analyze 'Oumuamua's lightcurve using 818 observations over 29.3 days. Two fundamental periodicities are found at frequencies (2.77 0.11) and (6.42 0.18) cycles/day, corresponding to (8.67 0.34) hr and (3.74 0.11) hr, respectively. The phased data show that the lightcurve does not repeat in a simple manner, but approximately shows a double minimum at 2.77 cycles/day and a single minimum at 6.42 cycles/day. 'Oumuamua could be spinning in either the LAM or short axis mode (SAM). For both, the long axis precesses around the total angular momentum vector with an average period of (8.67 0.34) hr. For the three LAMs we have found, the possible rotation periods around the long axis are 6.58, 13.15, or 54.48 hr, with 54.48 hr being the most likely. 'Oumuamua may also be nutating with respective periods of half of these values. We have also found two possible SAM states where 'Oumuamua oscillates around the long axis with possible periods at 13.15 and 54.48 hr. In this case any nutation occurs with the same periods. Determination of the spin state, the amplitude of the nutation, the direction of the total angular momentum vector (TAMV), and the average total spin period may be possible with a direct model fit to the lightcurve. We find that 'Oumuamua is "cigar-shaped," if close to its lowest rotational energy, and an extremely oblate spheroid if close to its highest energy state.
Peripartum cardiomyopathy (PPCM) is a potentially life‐threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the ...months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre‐existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline‐directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress‐mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease‐specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter‐defibrillators, cardiac resynchronization therapy and implanted long‐term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate ...CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.
•Tisagenlecleucel (CTL019) has demonstrated clinical efficacy in relapsed/refractory B-cell ALL and CLL.•The cellular kinetic profile of tisagenlecleucel was consistent across the 2 diseases, with higher exposure in responding vs nonresponding patients.
The immune system of some genetically susceptible children can be triggered by certain environmental factors to produce islet autoantibodies (IA) against pancreatic β cells, which greatly increases ...their risk for Type-1 diabetes. An environmental factor under active investigation is the gut microbiome due to its important role in immune system education. Here, we study gut metagenomes that are de-novo-assembled in 887 at-risk children in the Environmental Determinants of Diabetes in the Young (TEDDY) project. Our results reveal a small set of core protein families, present in >50% of the subjects, which account for 64% of the sequencing reads. Time-series binning generates 21,536 high-quality metagenome-assembled genomes (MAGs) from 883 species, including 176 species that hitherto have no MAG representation in previous comprehensive human microbiome surveys. IA seroconversion is positively associated with 2373 MAGs and negatively with 1549 MAGs. Comparative genomics analysis identifies lipopolysaccharides biosynthesis in Bacteroides MAGs and sulfate reduction in Anaerostipes MAGs as functional signatures of MAGs with positive IA-association. The functional signatures in the MAGs with negative IA-association include carbohydrate degradation in lactic acid bacteria MAGs and nitrate reduction in Escherichia MAGs. Overall, our results show a distinct set of gut microorganisms associated with IA seroconversion and uncovered the functional genomics signatures of these IA-associated microorganisms.
Cystic fibrosis (CF) is an autosomal recessive disease characterized by abnormal airways secretions, chronic endobronchial infection, and progressive airway obstruction. The use of medications to ...slow the progression of lung disease has led to significant improvement in survival. An evidence review of chronic medications for CF lung disease was performed in 2007 to provide guidance to clinicians in evaluating and selecting appropriate treatment for individuals with this disease. We have undertaken a new review of the literature to update the recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. A multidisciplinary committee of experts in CF pulmonary care was established to review the evidence for use of chronic medications for CF lung disease and make treatment recommendations. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.
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