A Bayesian adaptive marker‐stratified design for molecularly targeted agents with customized hierarchical modeling

It is well known that the treatment effect of a molecularly targeted agent (MTA) may vary dramatically, depending on each patient's biomarker profile. Therefore, for a clinical trial evaluating MTA, it is more reasonable to evaluate its treatment effect within different marker subgroups rather than evaluating the average treatment effect for the overall population. The marker‐stratified design (MSD) provides a useful tool to evaluate the subgroup treatment effects of MTAs. Under the Bayesian framework, the beta‐binomial model is conventionally used under the MSD to estimate the response rate and test the hypothesis. However, this conventional model ignores the fact that the biomarker used in the MSD is, in general, predictive only for the MTA. The response rates for the standard treatment can be approximately consistent across different subgroups stratified by the biomarker. In this paper, we proposed a Bayesian hierarchical model incorporating this biomarker information into consideration. The proposed model uses a hierarchical prior to borrow strength across different subgroups of patients receiving the standard treatment and, therefore, improve the efficiency of the design. Prior informativeness is determined by solving a “customized” equation reflecting the physician's professional opinion. We developed a Bayesian adaptive design based on the proposed hierarchical model to guide the treatment allocation and test the subgroup treatment effect as well as the predictive marker effect. Simulation studies and a real trial application demonstrate that the proposed design yields desirable operating characteristics and outperforms the existing designs

Effective adsorption of heavy metal ions in water by sulfhydryl modified nano titanium dioxide

Background: The monitoring and removal of heavy metal ions in wastewater will effectively improve the quality of water and promote the green and sustainable development of ecological environment. Using more efficient adsorption materials and more accurate detection means to treat heavy metal ions in water has always been a research focus and target of researchers.Method: A novel titania nanomaterial was modified with sulfhydryl group (nano TiO2-SH) for detection and adsorption of heavy metal ions in water, and accurately characterize the adsorption process using Surface-Enhanced Raman Spectroscopy (SERS) and other effective testing methods.Results: The maximum adsorption efficiency of nano TiO2-SH for the Hg2+, Cd2+, Pb2+ three heavy metal ions reached 98.3%, 98.4% and 98.4% respectively. And more importantly, after five cycles of adsorption and desorption, the adsorption efficiency of nano TiO2-SH for these three metal ions is still above 96%.Conclusion: These results proved the nano TiO2-SH adsorbent has great potential in practical water pollution purification

On the number of zeros of Abelian integrals for a kind of quadratic reversible centers

Hilbert$'$s 16th problem is extensively studied in mathematics and its applications. Arnold proposed a weakened version focusing on differential equations. While significant progress has been made for Hamiltonian systems, less attention has been given to integrable non-Hamiltonian systems. In recent years, investigating quadratic reversible systems in integrable non-Hamiltonian systems has gained widespread attention and shown promising advancements. In this academic context, our study is based on qualitative analysis theory. It explores the upper bound of the number of zeros of Abelian integrals for a specific class of quadratic reversible systems under perturbations with polynomial degrees of n. The Picard-Fuchs equation method and the Riccati equation method are employed in our investigation. The research findings indicate that when the degree of the perturbing polynomial is n ($n\geq5$), the upper bound for the number of zeros of Abelian integrals is determined to be $7n-12$. To achieve this, we first numerically transform the Hamiltonian function of the quadratic reversible system into a standard form. By applying a combination of the Picard-Fuchs equation method and the Riccati equation method, we derive the representation of the Abelian integrals. Using relevant theorems, we estimate the upper bound for the number of zeros of the Abelian integrals, which consequently provides an upper bound for the number of limit cycles in the system. The research results demonstrate that when the perturbation polynomial degree is high or equal to n, the Picard-Fuchs equation method and the Riccati equation method can be applied to estimate the upper bound of the number of zeros of the Abelian integrals

Characterization and potential of periosteum-derived cells: an overview

As a thin fibrous layer covering the bone surface, the periosteum plays a significant role in bone physiology during growth, development and remodeling. Over the past several decades, the periosteum has received considerable scientific attention as a source of mesenchymal stem cells (MSCs). Periosteum-derived cells (PDCs) have emerged as a promising strategy for tissue engineering due to their chondrogenic, osteogenic and adipogenic differentiation capacities. Starting from the history of PDCs, the present review provides an overview of their characterization and the procedures used for their isolation. This study also summarizes the chondrogenic, osteogenic, and adipogenic abilities of PDCs, serving as a reference about their potential therapeutic applications in various clinical scenarios, with particular emphasis on the comparison with other common sources of MSCs. As techniques continue to develop, a comprehensive analysis of the characterization and regulation of PDCs can be conducted, further demonstrating their role in tissue engineering. PDCs present promising potentials in terms of their osteogenic, chondrogenic, and adipogenic capacities. Further studies should focus on exploring their utility under multiple clinical scenarios to confirm their comparative benefit over other commonly used sources of MSCs

OR-026 Exercise induces HIF-1α redistribution in the small intestine

Objective Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria, affected by reduced blood flow and tissue hypoxia. Exercise induces blood flow redistribution, leading to hypoperfusion and gastrointestinal (GI) compromise. The hypoxia-inducible factor (HIF) 1α is pivotal in the transcriptional response to oxygen flux. In this study, we hypothesized that exercise induces GI system hypoxia and accumulates HIF-1α. Methods (1) ROSA26 ODD-Luc/+ mouse model (ODD-Luc) was used to detect HIF-1α expression in the intestine (female, 8-week, n=6/group). ODD-Luc mice were randomized into 4 groups: stayed in 21% O2 as the normoxic control (C), exercise (E), injected HIF-1α inhibitor PX-478 before swimming (PS), placed in the chamber containing 9% O2 for 4 hours as the positive control (PC). (2) Exercise models were conducted by volume: Moderate Exercise (ME): mice voluntarily swam for 30 min; Heavy-intensity Exercise (HE): mice swam for 1.5 hours with 5% body weight loads attached to their tails; Long-time Exercise (LE): mice voluntarily swam for 3 hours or till fatigue. Results (1) Exercise increased HIF-1α in the abdominal area. The luciferase activities boosted after exercise, compared to the controls (ME v.s. C, P<0.05; HE v.s. C, P<0.05; LE v.s. C, P<0.05) but no differences among three exercise groups (ME v.s. HE, P>0.99; ME v.s. LE, P>0.99; HE v.s. LE, P>0.99); (2) Exercise altered HIF-1α distribution in the small intestine in a time-dependent manner. The expression of HIF-1α was significantly increased after exercise and gradually reduced to the rest level. The photons increased at the 0th hour after exercise compared to that of the normoxic control (P<0.01). The level of photons then reduced over time, while the 2nd, 4th and 6th hour post-exercise were still greater than that of the normoxic control  (2nd hour v.s. C, P<0.01; 4th hour v.s. C, P<0.01; 6th hour v.s. C, P<0.05), and returned to normal after 24 hours (24th hour v.s. C, P>0.99). Conclusions Exercise induced the distribution of HIF-1α in the small intestine. The expression of HIF-1α is shown in a time-dependent manner after exercise

PO-154 Exercise induced redistribution of oxygen in internal organs

Objective Exercise induces tissue blood flow redistribution, which decreases splanchnic circulation and leads to physiologic hypoxia in the gastrointestinal (GI) system and liver.  We hypothesized that the oxygen redistribution in the internal organs is affected by exercise. Methods Twenty–four female 8-10wk ROSA26 ODD-Luc/+ mice (n= 6 per group) were used in this study. Three exercise models were conducted: (1) Moderate Exercise (ME): mice voluntarily swam for 30 min. (2) Heavy-intensity Exercise (HE): mice swam for 1.5 hours with 5% body weight loads attached to their tails. (3) Long-time Exercise (LE): mice voluntarily swam for 3 hours or till fatigue. Sedentary mice (SED) were used as controls. A hypoxic marker pimonidazole HCl was applied to detect tissue hypoxia. Pimonidazole HCl forms protein adducts when PO2 is under 10 mmHg. An hour after intraperitoneal injection of pimonidazole HCl (60 mg/kg body weight), the mice were anesthetized with isoflurane then sacrificed. The small intestine, colon, skeletal muscle, heart, liver, spleen and kidney specimens were fixed in 4% paraformaldehyde and stained with a specific monoclonal antibody against the pimonidazole HCl protein adducts to observe the hypoxic level of internal organs. Results (1) The distributions of immunostaining intensity of pimonidazole HCl were different among the internal organs. In the kidney, the renal tubules demonstrated staining for hypoxia. In the liver, the positive staining was radiating outwards from central veins. In the small intestine and colon, there was the retention of pimonidazole HCl from the crypt to villus. (2) In the ME group, the extent of hypoxia in the kidney, liver and colon was increased compared with the SED. We found the small intestine is susceptible to exercise-induced tissue hypoxia distribution. Exercise resulted in a markedly increased staining in the crypts, whereas decreased staining in the villus. Intensified positive stains were observed in the nuclei of hypoxic cells, mostly in ME and HE groups. (3) The heart, skeletal muscle and spleen were not shown positive staining pre- and post-exercise. Conclusions This study presented evidences that exercise induces the oxygen redistribution in the small intestine, colon, liver and kidney. The small intestine is susceptible to exercise induced physiological hypoxia

Effects of Exercise on AMPK Signaling and Downstream Components to PI3K in Rat with Type 2 Diabetes

Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague-Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and downstream components of phosphatidylinositol 3-kinase (PI3K) signaling pathways in the soleus. As a result, blood glucose, triglyceride, total cholesterol, and free fatty acid were significantly increased, whereas insulin level progressively declined in diabetic rats. Interestingly, chronic and acute exercise reduced blood glucose, increased phosphorylation and expression of AMPKα1/2 and the isoforms AMPKα1 and AMPKα2, and decreased phosphorylation and expression of AMPK substrate, acetyl CoA carboxylase (ACC). Chronic exercise upregulated phosphorylation and expression of AMPK upstream kinase, LKB1. But acute exercise only increased LKB1 expression. In particular, exercise reversed the changes in protein kinase C (PKC)ζ/λ phosphorylation, and PKCζ phosphorylation and expression. Additionally, exercise also increased protein kinase B (PKB)/Akt1, Akt2 and GLUT4 expression, but AS160 protein expression was unchanged. Chronic exercise elevated Akt (Thr(308)) and (Ser(473)) and AS160 phosphorylation. Finally, we found that exercise increased peroxisome proliferator-activated receptor-γ coactivator 1 (PGC1) mRNA expression in the soleus of diabetic rats. These results indicate that both chronic and acute exercise influence the phosphorylation and expression of components of the AMPK and downstream to PIK3 (aPKC, Akt), and improve GLUT4 trafficking in skeletal muscle. These data help explain the mechanism how exercise regulates glucose homeostasis in diabetic rats

The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28

The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also independently ubiquitinates p53 as an E3 ligase activated by MAGE-C2. Moreover, MAGE-C2 is highly expressed in various cancers, but the detailed mechanisms of MAGE-C2 involved in MDM2/TRIM28-mediated p53 ubiquitination remain unknown. Here, we found that MAGE-C2 directly interacts with MDM2 through its conserved MHD domain to inhibit the activity of MDM2 on p53 ubiquitination. Furthermore, TRIM28 acts as an MAGE-C2 binding partner and directly competes with MAGE-C2 for MDM2 interaction, thus releasing the inhibitory role of MAGE-C2 and promoting p53 ubiquitination. MAGE-C2 suppresses cell proliferation in TRIM28-deficient cells, but the overexpression of TRIM28 antagonizes the inhibitory role of MAGE-C2 and accumulates p53 ubiquitination to promote cell proliferation. This study clarified the molecular link of MAGE-C2 in two major E3 systems MDM2 and TRIM28 on p53 ubiquitination. Our results revealed the molecular function of how MAGE-C2 and TRIM28 contribute to p53 ubiquitination and cell proliferation, in which MAGE-C2 acts as a potential inhibitor of MDM2 and TRIM28 is a vital regulator for MAGE-C2 function in p53 protein level and cell proliferation. This work would be helpful to understand the regulation mechanism of tumor suppressor p53

Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines

<p>Abstract</p> <p>Background</p> <p>Cancer stem cells (CSCs) are regarded as the cause of tumor formation and recurrence. The isolation and identification of CSCs could help to develop novel therapeutic strategies specifically targeting CSCs.</p> <p>Methods</p> <p>Human hepatoma cell lines were plated in stem cell conditioned culture system allowed for sphere forming. To evaluate the stemness characteristics of spheres, the self-renewal, proliferation, chemoresistance, tumorigenicity of the PLC/PRF/5 sphere-forming cells, and the expression levels of stem cell related proteins in the PLC/PRF/5 sphere-forming cells were assessed, comparing with the parental cells. The stem cell RT-PCR array was performed to further explore the biological properties of liver CSCs.</p> <p>Results</p> <p>The PLC/PRF/5, MHCC97H and HepG2 cells could form clonal nonadherent 3-D spheres and be serially passaged. The PLC/PRF/5 sphere-forming cells possessed a key criteria that define CSCs: persistent self-renewal, extensive proliferation, drug resistance, overexpression of liver CSCs related proteins (Oct3/4, OV6, EpCAM, CD133 and CD44). Even 500 sphere-forming cells were able to form tumors in NOD/SCID mice, and the tumor initiating capability was not decreased when spheres were passaged. Besides, downstream proteins DTX1 and Ep300 of the CSL (CBF1 in humans, Suppressor of hairless in Drosophila and LAG1 in C. elegans) -independent Notch signaling pathway were highly expressed in the spheres, and a gamma-secretase inhibitor MRK003 could significantly inhibit the sphere formation ability.</p> <p>Conclusions</p> <p>Nonadherent tumor spheres from hepatoma cell lines cultured in stem cell conditioned medium possess liver CSC properties, and the CSL-independent Notch signaling pathway may play a role in liver CSCs.</p