Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Methodology/Principal Findings Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. Trial Registration ClinicalTrials.gov NCT0060723

CBLUE: A Chinese Biomedical Language Understanding Evaluation Benchmark

Artificial Intelligence (AI), along with the recent progress in biomedical language understanding, is gradually changing medical practice. With the development of biomedical language understanding benchmarks, AI applications are widely used in the medical field. However, most benchmarks are limited to English, which makes it challenging to replicate many of the successes in English for other languages. To facilitate research in this direction, we collect real-world biomedical data and present the first Chinese Biomedical Language Understanding Evaluation (CBLUE) benchmark: a collection of natural language understanding tasks including named entity recognition, information extraction, clinical diagnosis normalization, single-sentence/sentence-pair classification, and an associated online platform for model evaluation, comparison, and analysis. To establish evaluation on these tasks, we report empirical results with the current 11 pre-trained Chinese models, and experimental results show that state-of-the-art neural models perform by far worse than the human ceiling. Our benchmark is released at \url{https://tianchi.aliyun.com/dataset/dataDetail?dataId=95414&lang=en-us}

Dynamic Modeling and Comparison Study of Control Strategies of a Small-Scale Organic Rankine Cycle

The control strategy is crucial for the effective and safe operation of the ORC system. A transient model of the ORC system was developed in the present work and validated by the experimental data of a 4 kW ORC prototype. Then, the effect of heat source temperature on the dynamic response and operation characteristics of the ORC system were analyzed. Five control strategies were compared: the constant working fluid mass flow rate mode, constant vapor superheat mode, constant vapor temperature mode, constant evaporation pressure mode and constant output power load mode. Under the constraint that the working fluid at the expander inlet should be superheated, we found that the constant vapor superheat mode enabled the safe operation with the largest range of heat source temperature, while the other four modes were only available for a certain temperature range. Apart from the constant output power mode, the constant evaporation pressure mode can also provide a relatively stable performance for the ORC unit. The variation of the thermal efficiency was limited when the heat source temperature was higher than 125 °C, except for the constant vapor temperature mode. Considering the high performance and stable operation of the ORC system, it is necessary to have different operation modes combined in the control strategy according to the specific working scenarios

Multi-Objective Optimization of the Basic and Regenerative ORC Integrated with Working Fluid Selection

A multi-objective optimization based on the non-dominated sorting genetic algorithm (NSGA-II) is carried out in the present work for the basic organic Rankine cycle (BORC) and regenerative ORC (RORC) systems. The selection of working fluids is integrated into multi-objective optimization by parameterizing the pure working fluids into a two-dimensional array. Two sets of decision indicators, exergy efficiency vs. thermal efficiency and exergy efficiency vs. levelized energy cost (LEC), are adopted and examined. Five decision variables including the turbine inlet temperature, vapor superheat degree, the evaporator and condenser pinch temperature differences, and the mass fraction of the mixture are optimized. It is found that the turbine inlet temperature is the most effective factor for both the BORC and RORC systems. Compared to the reverse variation of exergy efficiency and thermal efficiency, only a weak conflict exists between the exergy efficiency and LEC which tends to make the binary objective optimization be a single objective optimization. The RORC provides higher thermal efficiency than BORC at the same exergy efficiency while the LEC of RORC also becomes higher because the bare module cost of buying one more heat exchange is higher than the cost reduction due to the reduced heat transfer area. Under the heat source temperature of 423.15 K, the final obtained exergy and thermal efficiencies are 45.6% and 16.6% for BORC, and 38.6% and 20.7% for RORC, respectively

Improved gene therapy for MFRP deficiency-mediated retinal degeneration by knocking down endogenous bicistronic Mfrp and Ctrp5 transcript

The membrane frizzled-related protein (Mfrp) and C1-tumor necrosis factor related protein 5 (Ctrp5) genes are transcribed as a bicistronic unit and dysregulation of either gene is associated with retinal degeneration in the retinal pigment epithelium (RPE) cells. However, the mechanisms that regulate the expression of the bicistronic transcript remain controversial. Here, we identified a microRNA-based negative feedback loop that helps maintain a normal expression level of the bicistronic Mfrp and Ctrp5 transcript. Specifically, miR-149-3p, a conserved microRNA, binds to the 3′UTR of the Mfrp gene. In MFRP-deficient rd6 mice, the miR-149-3p levels were compromised compared with those in WT mice, resulting in an increase in the bicistronic transcript. We also report a capsid-modified rAAVDJ-3M vector that is capable of robustly and specifically transducing RPE cells following subretinal delivery. Compared with the parental vector, the modified vector elicited similar levels of serum anti-rAAV antibodies, but recruited fewer microglial infiltrations. Most significantly, we also demonstrate that simultaneous overexpressing of MFRP and knockdown of the bicistronic transcript was more effective in rescuing vision than MFRP overexpression alone. Our findings offer new insights into the function of MFRP and provide a promising therapeutic strategy for the treatment of MFRP-associated ocular diseases

Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

<div><h3>Background</h3><p>No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.</p> <h3>Methodology/Principal Findings</h3><p>Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95^th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.</p> <h3>Conclusions/Significance</h3><p>We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00607230?term=NCT00607230&rank=1">NCT00607230</a></p> </div