Individualized therapy for Cystic Fibrosis using artificial intelligence

Optimal clinical management of inherited chronic diseases, such as Cystic Fibrosis (CF), requires a dynamic approach which updates treatments to cope with the evolving course of illness and to tailor medicines and dosages for individual patients. The chronic progressive nature of CF and heterogeneity across patients lead to challenges of developing optimal regimens. An adaptive individualized therapy provides a solution and a means toward these goals. In this dissertation, we examine the problem of computing optimal adaptive individualized therapy for CF patients. A temporal difference reinforcement learning method called fitted Q-iteration is utilized to discover the optimal treatment regimen directly from clinical data. We propose multi-state discrete-time Markov process to model the disease dynamic for cystic fibrosis patients with Pseudomonas aeruginosa infection with the model parameters tuned and estimated from the published data in Wisconsin CF neonatal screening project. Our study results indicate that reinforcement learning and the clinical reinforcement trial framework can be an effective tool in discovering and developing personalized therapy which optimises the benefit-risk trade of in multi-stage decision making and improves long term outcomes in chronic diseases

Sample size estimation in educational intervention trials with subgroup heterogeneity in only one arm

We present closed form sample size and power formulas motivated by the study of a psycho-social intervention in which the experimental group has the intervention delivered in teaching subgroups while the control group receives usual care. This situation is different from the usual clustered randomized trial since subgroup heterogeneity only exists in one arm. We take this modification into consideration and present formulas for the situation in which we compare a continuous outcome at both a single point in time and longitudinally over time. In addition, we present the optimal combination of parameters such as the number of subgroups and number of time points for minimizing sample size and maximizing power subject to constraints such as the maximum number of measurements that can be taken (i.e. a proxy for cost)

Experimental study on sinomenine derivative modulating chemokine receptor in multiple myeloma cells

Background and purpose: The interaction of CXC motif chemokine receptor (CXCR) on the cell surface of multiple myeloma (MM) with chemokines in the bone marrow microenvironment is involved in proliferation, survival and extramedullary invasion of MM cells. Sinomenine derivative YL064 exerts its biological effects by targeting intracellular signaling regulators in MM cells. This study aimed to explore possible modulating and biological effects of sinomenine derivative YL064 on CXCR3 in MM cells. Methods: The MM cell lines H929 and MM1.S were used as in vitro models. H929-OE and MM1.S-OE cells with stable overexpression of CXCR3 were constructed with lentivirus vector. The effects of CXCR3 on clonal formation and migration of MM cells were detected by clone spot formation and transwell migration assay. Meanwhile, flow cytometry was used to analyze apoptotic rates of H929, H929-OE, MM1.S and MM1.S-OE cells treated with different concentrations of YL064. Furthermore, real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot assay were applied to detect expression levels of CXCR3 and its downstream signal regulators extracellular regulated protein kinase (ERK) and p-protein kinase B (p-AKT) in H929 and MM1.S cells before and after the treatment with YL064. Results: The clonal formation rates of H929-OE and MM1.S-OE cells with CXCR3 overexpression reached to 81.33%±5.79% and 73.00%±4.90%, which were significantly higher compared with H929 (58.33%±3.30%) and MM1.S cells (41.00%±3.14%). The migration proportion of H929-OE and MM1.S-OE cells were 7.90%±0.81% and 23.00%±1.63%, which were significantly higher compared with H929 (4.63%±0.37%) and MM1.S cells (14.63%±1.04%). After treatment with YL064, the apoptotic rates of H929-OE and MM1.S-OE cells were 29.80%±0.30% and 14.20%±0.26%, which were lower than those of H929 (33.40%±0.25%) and MM1.S cells (21.60%±0.21%). It was also shown that YL064 could reduce clonal formation and migration, inhibit CXCR3 gene transcription and downregulate expressions of CXCR3, ERK and AKT in H929 and MM1.S cells. Conclusions: CXCR3 might promote proliferation and invasion of MM cells. Sinomenine derivative YL064 could downregulate expressions of CXCR3 and its downstream signal regulators in MM cells, reduce abilities of clonal formation and migration, and induce apoptosis

PDGFRα reporter activity identifies periosteal progenitor cells critical for bone formation and fracture repair

The outer coverings of the skeleton, which is also known as the periosteum, are arranged in concentric layers and act as a reservoir for tissue-specific bone progenitors. The cellular heterogeneity within this tissue depot is being increasingly recognized. Here, inducible PDGFR alpha reporter animals were found to mark a population of cells within the periosteum that act as a stem cell reservoir for periosteal appositional bone formation and fracture repair. During these processes, PDGFR alpha reporter(+) progenitors give rise to Nestin(+) periosteal cells before becoming osteoblasts and osteocytes. The diphtheria toxin-mediated ablation of PDGFR alpha reporter(+) cells led to deficits in cortical bone formation during homeostasis and a diminutive hard callus during fracture repair. After ossicle transplantation, both mouse PDGFR alpha reporter(+) periosteal cells and human Pdgfr alpha(+) periosteal progenitors expand, ossify, and recruit marrow to a greater extent than their counterpart periosteal cells, whereas PDGFR alpha reporter(-) periosteal cells exhibit a predisposition to chondrogenesis in vitro. Total RNA sequencing identified enrichment of the secreted factors Fermt3 and Ptpn6 within PDGFR alpha reporter(+) periosteal cells, which partly underlie the osteoblastogenic features of this cell population

Comparative transcriptomic analyses of two sugarcane Saccharum L. cultivars differing in drought tolerance

Sugarcane (Saccharum spp.) is an important cash crop, and drought is an important factors limiting its yield. To study the drought resistance mechanism of sugarcane, the transcriptomes of two sugarcane varieties with different levels of drought resistance were compared under different water shortage levels. The results showed that the transcriptomes of the two varieties were significantly different. The differentially expressed genes were enriched in starch and sucrose metabolism, linoleic acid metabolism, glycolysis/gluconeogenesis, and glyoxylate and dicarboxylate metabolic pathways. Unique trend genes of the variety with strong drought resistance (F172) were significantly enriched in photosynthesis, mitogen-activated protein kinases signaling pathway, biosynthesis of various plant secondary metabolites, and cyanoamino acid metabolism pathways. Weighted correlation network analysis indicated that the blue4 and plum1 modules correlated with drought conditions, whereas the tan and salmon4 modules correlated with variety. The unique trend genes expressed in F172 and mapped to the blue4 module were enriched in photosynthesis, purine metabolism, starch and sucrose metabolism, beta-alanine metabolism, photosynthesis-antenna proteins, and plant hormone signal transduction pathways. The expression of genes involved in the photosynthesis-antenna protein and photosynthesis pathways decreased in response to water deficit, indicating that reducing photosynthesis might be a means for sugarcane to respond to drought stress. The results of this study provide insights into drought resistance mechanisms in plants, and the related genes and metabolic pathways identified may be helpful for sugarcane breeding in the future

Long-Term Protection from SARS-CoV-2 Variants in Mice by a Phase II Clinically Evaluated Original mRNA Vaccine Booster

The global coronavirus disease 2019 (COVID-19) pandemic was caused by SARS-CoV-2. The authors developed an mRNA vaccine (LVRNA009) that encoded the S protein of the Wuhan-Hu-1 strain and evaluated the long-term protection potential against SARS-CoV-2 variants. Mice were initially vaccinated with 2 doses of LVRNA009, then boosted 8 months later. The virus neutralization titers against SARS-CoV-2 variants and antigen-specific T cell responses of the mice were determined. These animals were also tested using viral challenge experiments. Moreover, a phase II clinical study was carried out in 420 healthy adults. LVRNA009 vaccination induced neutralization antibodies and protected mice from SARS-CoV-2 original and Omicron BA.1.1 challenge 8 months post-boosting. A second booster dose of LVRNA009 further enhanced VNTs against Omicron variants. Clinical studies showed that LVRNA009 has good safety and immunogenicity profiles in humans. LVRNA009 could provide long-term protection against SARS-CoV-2 variants and confer better protection with a booster dose. These findings indicate that LVRNA009, a vaccine designed based on the original virus, might be effective in management of the COVID-19 pandemic

Measurements of the observed cross sections for exclusive light hadron production in e^+e^- annihilation at \sqrt{s}= 3.773 and 3.650 GeV

By analyzing the data sets of 17.3 pb$^{-1}$ taken at $\sqrt{s}=3.773$ GeV and 6.5 pb$^{-1}$ taken at $\sqrt{s}=3.650$ GeV with the BESII detector at the BEPC collider, we have measured the observed cross sections for 12 exclusive light hadron final states produced in $e^+e^-$ annihilation at the two energy points. We have also set the upper limits on the observed cross sections and the branching fractions for $\psi(3770)$ decay to these final states at 90% C.L.Comment: 8 pages, 5 figur

Measurements of the Mass and Full-Width of the ηc\eta_c Meson

In a sample of 58 million $J/\psi$ events collected with the BES II detector, the process J/$\psi\to\gamma\eta_c$ is observed in five different decay channels: $\gamma K^+K^-\pi^+\pi^-$, $\gamma\pi^+\pi^-\pi^+\pi^-$, $\gamma K^\pm K^0_S \pi^\mp$ (with $K^0_S\to\pi^+\pi^-$), $\gamma \phi\phi$ (with $\phi\to K^+K^-$) and $\gamma p\bar{p}$. From a combined fit of all five channels, we determine the mass and full-width of $\eta_c$ to be $m_{\eta_c}=2977.5\pm1.0 ({stat.})\pm1.2 ({syst.})$ MeV/$c^2$ and $\Gamma_{\eta_c} = 17.0\pm3.7 ({stat.})\pm7.4 ({syst.})$ MeV/$c^2$.Comment: 9 pages, 2 figures and 4 table. Submitted to Phys. Lett.

Search for the Rare Decays J/Psi --> Ds- e+ nu_e, J/Psi --> D- e+ nu_e, and J/Psi --> D0bar e+ e-

We report on a search for the decays J/Psi --> Ds- e+ nu_e + c.c., J/Psi --> D- e+ nu_e + c.c., and J/Psi --> D0bar e+ e- + c.c. in a sample of 5.8 * 10^7 J/Psi events collected with the BESII detector at the BEPC. No excess of signal above background is observed, and 90% confidence level upper limits on the branching fractions are set: B(J/Psi --> Ds- e+ nu_e + c.c.)<4.8*10^-5, B(J/Psi --> D- e+ nu_e + c.c.) D0bar e+ e- + c.c.)<1.1*10^-5Comment: 10 pages, 4 figure