Biomedical subjects

Xiaodong Yang

Publications and source records attributed to Xiaodong Yang.

At least 19 recordsLinked to original sources

PubMed2026

Intratumoral Sotigalimab with Pembrolizumab Induces Rapid Activation of Antigen-Presenting Cells and Drives Antitumor Responses in Non-injected Tumors in Metastatic Melanoma: A Phase I/II Study.

UNLABELLED: Immune checkpoint blockers (ICB) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 patients with ICB-naïve MM. Primary endpoints were safety and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase II dose, the ORR was 50%, and the disease control rate was 92%, with ORRs of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed that sotigalimab effectively engaged the CD40 pathway, boosting infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. T-cell receptor sequencing showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes but not with baseline features associated with response to anti-PD-1 monotherapy. SIGNIFICANCE: In this study, we provide compelling data that intratumoral sotigalimab combined with pembrolizumab is safe, activates antigen-presenting cells, and elicits broad innate and adaptive immune responses in both injected and non-injected tumors, supporting further randomized phase II trials to evaluate sotigalimab's potential to enhance anti-PD-1 therapy through "in situ" immunization.

Humans↗

PubMed2006

Cloning and expression of canine glucagon receptor and its use to evaluate glucagon receptor antagonists in vitro and in vivo.

Glucose homeostasis is maintained by the combined actions of insulin and glucagon. Hyperglucagonemia and/or elevation of glucagon/insulin ratio have been reported in diabetic patients and in animal models of diabetes. Therefore, antagonizing glucagon receptor function has long been considered a useful approach to lower hyperglycemia. Dogs serve as an excellent model for studying glycemic control and various aspects of glucagon biology in vivo; however, the amino acid sequence of the dog glucagon receptor has not been reported. To better understand the pharmacology of the dog glucagon receptor and to characterize glucagon receptor antagonists, we cloned a cDNA corresponding to the glucagon receptor from dog liver RNA. The dog glucagon receptor shares a significant (>75%) homology at both nucleotide and amino acid levels with the glucagon receptor from human, monkey, mouse, and rat. The protein is highly conserved among all species in areas corresponding to the 7 trans-membrane domains. However, it shows significant divergence at the carboxy terminus such that the receptor from dog has the longest cytoplasmic tail among all species examined. When expressed in chinese hamster ovary cells, the dog glucagon receptor bound [125I]Glucagon with a K(d) of 477+/-106 pM. Glucagon stimulated the rise of intracellular cAMP levels in these cells with an EC(50) of 9.6+/-1.7 nM and such effects could be blocked by known peptidyl and non-peptidyl small molecule antagonists. In addition we show that a small molecule glucagon receptor antagonist with significant activity in cell based assays also blocked the ability of glucagon to induce elevation in blood glucose in beagle dogs. These data demonstrate that the cloned cDNA encodes a functional dog glucagon receptor. The availability of the dog cDNA will facilitate the understanding of glucagon pharmacology and aid in the characterization of novel glucagon antagonists that may serve as anti-hyperglycemic treatment for type 2 diabetes mellitus.

Amino Acid Sequence↗

PubMed2006

Confirmation and prevention of intestinal barrier dysfunction and bacterial translocation caused by methotrexate.

When intestinal barrier function is damaged bacterial translocation (BT) can occur. The injury to intestinal barrier function caused by chemotherapy has been investigated in some studies, however, definitive evidence of BT caused by chemotherapy is lacking. The aim of this study was to investigate small intestinal barrier dysfunction and BT and to evaluate the preventive effect of granulocyte colony-stimulating factor (G-CSF) on intestinal barrier dysfunction and BT in a rat model of chemotherapy. Sprague-Dawley rats were treated with methotrexate (MTX; 3.5 mg/kg) for 3 days to induce intestinal barrier dysfunction and BT, gavaged Escherichia coli TG1 labeled with green fluorescent protein for 2 days to track BT, and G-CSF (10 microg/kg) for 4 days to prevent intestinal barrier dysfunction and BT. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following administration by gavage. Representative tissue specimens from the mesenteric lymph nodes, spleen, liver, and kidney were aseptically harvested for bacteria culture in ampicillin-supplemented medium. Light microscopy was performed on intestinal samples. MTX induced significant mucosal and villous atrophy in ileum and significantly increased intestinal permeability. MTX also induced noticeable BT. G-CSF significantly increased the mucosal thickness and villous height of the ileum and decreased intestinal permeability and BT. In conclusion, MTX caused intestinal barrier dysfunction and BT, and G-CSF prevented intestinal barrier dysfunction and BT.

Animals↗

PubMed2006

In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation.

The ATP-driven drug export pump, P-glycoprotein, is a primary gatekeeper of the blood-brain barrier and a major impediment to central nervous system (CNS) pharmacotherapy. Reducing P-glycoprotein activity dramatically increases penetration of many therapeutic drugs into the CNS. Previous studies in rat showed that brain capillary P-glycoprotein was transcriptionally up-regulated by the pregnane X receptor (PXR), a xenobiotic-activated nuclear receptor. Here we used a transgenic mouse expressing human PXR (hPXR) to determine the consequences of increased blood-brain barrier P-glycoprotein activity. P-glycoprotein expression and transport activity in brain capillaries from transgenic mice was significantly increased when capillaries were exposed to the hPXR ligands, rifampin and hyperforin, in vitro and when the mice were dosed with rifampin in vivo. Plasma rifampin levels in induced mice were comparable with literature values for patients. We also administered methadone, a CNS-acting, P-glycoprotein substrate, to control and rifampin-induced transgenic mice and measured the drug's antinociceptive effect. In rifampin-induced mice, the methadone effect was reduced by approximately 70%, even though plasma methadone levels were similar to those found in transgenic controls not exposed to rifampin. Thus, hPXR activation in vivo increased P-glycoprotein activity and tightened the blood-brain barrier to methadone, reducing the drug's CNS efficacy. This is the first demonstration of the ability of blood-brain barrier PXR to alter the efficacy of a CNS-acting drug.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Enhanced stimulated Raman scattering in slow-light photonic crystal waveguides.

We investigate for the first time, to our knowledge, the enhancement of the stimulated Raman scattering in slow-light silicon-on-insulator (SOI) photonic crystal line defect waveguides. By applying the Bloch-Floquet formalism to the guided modes in a planar photonic crystal, we develop a formalism that relates the intensity of the downshifted Stokes signal to the pump intensity and the modal group velocities. The formalism is then applied to two prospective schemes for enhanced stimulated Raman generation in slow-light photonic crystal waveguides. The results demonstrate a maximum factor of 104(66,000) enhancement with respect to SOI channel waveguides.

Journal Article↗

PubMed2006

Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells.

Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.

Apoptosis↗

PubMed2006

High-power and high-quality, green-beam generation by employing a thermally near-unstable resonator design.

We have obtained green-beam quality of M2 = 6.2 at an average output power of 120 W by intracavity frequency doubling of a diode-side-pumped, Q-switched Nd:YAG rod laser with a repetition rate of 10 kHz and an optical-to-optical conversion efficiency of 15.2%. To achieve high-beam quality at high average power, the laser employs a thermally near-unstable resonator design with two-rod birefringence compensation in an L-shaped flat-flat cavity. The output power fluctuation of the green laser remains less than 0.9% in 4 h.

Journal Article↗

PubMed2006

16S rRNA gene analyses of bacterial community structures in the soils of evergreen broad-leaved forests in south-west China.

Bacterial community structure was studied in humus and mineral soils of evergreen broad-leaved forests in Ailaoshan and Xishuangbanna, representing subtropical and tropical ecosystems, respectively, in south-west China using sequence analysis and terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA genes. Clone sequences affiliated to Acidobacteria were retrieved as the predominant bacterial phylum in both forest soils, followed by those affiliated to members of the Proteobacteria, Planctomycete and Verrucomicrobia. Despite higher floristic richness at the Xishuangbanna forest than at the Ailaoshan forest, soil at Xishuangbanna harbored a distinctly high relative abundance of Acidobacteria-affiliated sequences (80% of the total clones), which led to a lower overall bacterial diversity than at Ailaoshan. Bacterial communities in humus and mineral soils of the two forests appeared to be well differentiated, based on 16S rRNA gene phylogeny, and correlations were found between the bacterial T-RFLP community patterns and the organic carbon and nutrient contents of the soil samples. The data reveal that Acidobacteria dominate soil bacterial communities in the evergreen broad-leaved forests studied here and suggest that bacterial diversity may be influenced by soil carbon and nutrient levels, but is not related to floristic richness along the climatic gradient from subtropical to tropical forests in south-west China.

Bacteria↗

PubMed2006

Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes.

Tumor cells rely preferentially on anaerobic glycolysis rather than on respiration for ATP generation, a phenomenon known as the Warburg effect. We explored the effects of glucose withdrawal on glioblastoma multiforme-derived cell lines and their nontransformed counterparts, normal human astrocytes. We found that glucose withdrawal induces extensive apoptosis in glioblastoma multiforme cells but not in normal astrocytes. In all cells examined, ATP levels are sustained on glucose withdrawal due to elevation of fatty acid oxidation and ensuing respiration; however, we show that oxidative stress generated in the mitochondrial respiratory chain is the direct cause of cell death in glioblastoma multiforme cells. Oxidative stress that only occurs in glioblastoma multiforme cells underlies the selective susceptibility to glucose withdrawal-induced apoptosis documented in the malignant cells. This study implicates glycolysis as a potentially efficient and selective target for glioblastoma multiforme treatment.

Adenosine Triphosphate↗

PubMed2005

Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists.

A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.

Administration, Oral↗

PubMed2005

Efficient improvement of laser beam quality by coherent combining in an improved Michelson cavity.

The efficient improvement of laser beam quality is demonstrated by coherent combining of two Nd:YVO4 lasers in an improved Michelson cavity. When the two lasers are separately operated with beam qualities of M(x)2 = 1.74 and M(y)2 = 1.34 for laser 1 and M(x)2 = 1.53 and M(y)2 = 1.39 for laser 2, by coherent combining of the two lasers, a single beam output exceeding 2 W with a nearly perfect TEM00 mode (M(x)2 = 1.08, M(y)2 = 1.04) is obtained. Moreover, it can withstand environmental perturbations with no change in beam quality or output power and has the potential for scaling to much higher output power with high beam quality by coherent addition of multiple lasers in this configuration.

Journal Article↗

PubMed2005

Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.

A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).

Humans↗

PubMed2005

Limb regeneration in higher vertebrates: developing a roadmap.

We review what is known about amphibian limb regeneration from the prospective of developing strategies for the induction of regeneration in adult mammals. Prominent in urodele amphibian limb regeneration is the formation of a blastema of undifferentiated cells that goes on to reform the limb. The blastema shares many properties with the developing limb bud; thus, the outgrowth phase of regeneration can be thought of as cells going through development again, i.e., redevelopment. Getting to a redevelopment phase in mammals would be a major breakthrough given our extensive understanding of limb development. The formation of the blastema itself represents a transition phase in which limb cells respond to injury by dedifferentiating to become embryonic limb progenitor cells that can undergo redevelopment. During this phase, rapid wound closure is followed by the dedifferentiation of limb cells to form the blastema. Thus, the regeneration process can be divided into a wound-healing/dedifferentiation phase and a redevelopment phase, and we propose that the interface between the wound-healing response and gaining access to developmentally regulated programs (dedifferentiation) lies at the heart of the regeneration problem in mammals. In urodele amphibians, dedifferentiation can occur in all of the tissues of the limb; however, numerous studies lead us to focus on the epidermis, the dermis, and muscle as key regulators of regeneration. Among higher vertebrates, the digit tip in mammals, including humans, is regeneration-competent and offers a unique mammalian model for regeneration. Recent genetic studies in mice identify the Msx1 gene as playing a critical role in the injury response leading to digit tip regeneration. The results from regeneration studies ranging from amphibians to mammals can be integrated to develop a roadmap for mammalian regeneration that has as its focus understanding the phenomenon of dedifferentiation.

Animals↗

PubMed2005

Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography.

BACKGROUND: Numerous knockout mouse studies have revealed that P-glycoprotein (P-gp) significantly limits drug distribution across the mouse blood-brain barrier (BBB). To determine the importance of P-gp at the human BBB, we developed a state-of-the-art, noninvasive, quantitative imaging technique to measure P-gp activity by use of carbon 11-labeled verapamil as the P-gp substrate and cyclosporine (INN, ciclosporin) as the P-gp inhibitor. METHODS: In brief, 11C-verapamil (approximately 0.2 mCi/kg) was administered to healthy volunteers (n = 12 [6 women and 6 men]) as an intravenous infusion over a period of approximately 1 minute before and after at least a 1-hour infusion of cyclosporine (2.5 mg x kg(-1) x h(-1)). Arterial blood samples and brain positron emission tomography images were obtained at frequent intervals for 45 minutes. Both blood and plasma radioactivity contents were determined in each verapamil sample. The content of verapamil and its metabolites in the 20- and 45-minute plasma samples was determined by a rapid solid-phase extraction method. The brain uptake of 11C-radioactivity (brain area under the curve [AUCbrain ]/blood area under the curve [AUCblood]) was determined in the presence and absence of cyclosporine. RESULTS: The AUCbrain/AUCblood ratio of 11C-radioactivity was increased by 88% +/- 20% (1.02 +/- 0.18 versus 0.55 +/- 0.10, P < .001) in the presence of cyclosporine (mean blood concentration, 2.8 +/- 0.4 micromol/L) without affecting 11C-verapamil metabolism or plasma protein binding. The corresponding increases for the brain white and gray matter were 84% +/- 13% and 84% +/- 18%, respectively. CONCLUSIONS: This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas.

Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate (AN-1), induced hyperacetylation, increased p21(Cip1) expression, inhibited proliferation, and enhanced apoptosis. Histone deacetylase inhibitor-induced apoptosis was mediated primarily by caspase-8. Treatment of cells with AN-1 or AN-9 for 24 hours before exposure to gamma-irradiation potentiated further caspase-8 activity and resultant apoptosis. Clonogenic survival curves revealed marked reductions in cell renewal capacity of U251 MG cells exposed to combinations of AN-1 and radiation. Preliminary in vivo experiments using human glioma cell lines grown as xenografts in mouse flanks suggest in vivo efficacy of AN-9. The data suggest that novel butyric acid prodrugs provide a promising treatment strategy for malignant gliomas as single agents and in combination with radiation therapy.

Antineoplastic Agents↗

PubMed2005

[Study on chemical constituents of Lagotis yunnanensis].

OBJECTIVE: To study the chemical constituents of Lagotis yunnanensis W. W. Smith. METHODS: Compounds were isolated from the ethanolic extract of the title herb by silicagel column chromatography and polyamide column chromatography, and their structures were identified by physical and chemical evidences and spectral methods. RESULTS: Six compounds were isolated and identified as quercetin-3-O-beta-D-glucoside (1), apigenin-7-methyl ether (2), E-cinnamic acid (3), Z-cinnamic acid (4), E-p-coumatic acid (5), Z-p-coumatic acid (6). CONCLUSION: All the compounds are isolated from this plant for the first time.

Flavonoids↗

PubMed2004

Growth hormone receptor expression in human colorectal cancer.

The purpose of this study was to determine whether human colorectal cancer (CRC) expresses growth hormone receptor (GHR) and whether growth hormone plays an important role in the development and progression of human CRC. We investigated 42 specimens of CRC and normal colorectal mucous membrane, taken from the colon or rectum in a group of patients with CRC. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) technique were used to demonstrate GHR expression. The relationship between expression of GHR and clinical or pathological factors was analyzed. Immunohistochemical analyses revealed that GHR was expressed in human CRC (35/42; 83.33%) and appeared to be up-regulated compared to normal mucous tissue (29/42; 69.05%; P < 0.001). Contrasting sharply with the mostly strongly positive tumors, corresponding normal colorectal mucous membrane was negative or weakly positive. A significant inverse correlation was found between GHR expression and tumor stage (P = 0.002) and tumor differentiation (P = 0.036). In RT-PCR, 33 of the 42 tumors expressed GHR mRNA, while only 22 of the 42 normal colorectal mucous membranes did so. Our data demonstrate that GHR is frequently expressed in human CRCs and appears to be up-regulated compared to normal mucous tissue, thus supporting a possible role for growth hormone in CRC physiology.

Adenocarcinoma↗

PubMed2004

Molecular recognition of biowarfare agents using micromechanical sensors.

Recent terrorist events have demonstrated that an urgent and widespread need exists for the development of novel sensors for threat detection, especially biowarfare agents. The advent of inexpensive, mass-produced microcantilever sensors promises to bring about a revolution in detection of terrorist threats. Extremely sensitive and highly selective sensors can be developed for using a microcantilever platform. Microcantilevers undergo bending when molecules are adsorbed on a single side. For biowarfare agent detection, specificity is achieved by immobilizing antibodies on one side of the cantilever. Antigen adsorption decreases surface energy and stress, resulting in cantilever deflection.

Antibodies, Bacterial↗