Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a Toll-like receptor 2-mediated cell-penetrating peptide.

Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In our study, enhanced expression of toll-like receptor 2 (TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding peptide motif, Pep2. We show that the TLR2-binding peptide motif targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2 expression (TLR2(high)) but not in chronic myeloid leukemia (CML) cells with low TLR2 expression (TLR2(low)). The antileukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2(high) AML compared to TLR2(low) CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2 is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.

[Mycelium of Hirsutella hepiali Chen et Shen activates autophagy and protects against metabolic syndrome in mice fed with high fat diet].

To investigate the protective effects and possible mechanism of Mycelium of Hirsutella hepiali Chen et Shen (MHCS) on metabolic syndromes, free fatty acid and MHCS-treated hepatocytes were used for detecting autophagy-related LC3, p62 and lipid accumulation. Moreover, high fat diet fed mice were used to establish metabolic syndromes model. 50-weeks age mice were randomly divided into: control group, model group and MHCS group. At 80-weeks age, 15 mice were randomly chosen from each group separately for examining oral glucose tolerance, serum insulin, insulin-like growth factor 1 (IGF-1), hepatic LC3, p62, p-NF-kappaB p65, NF-kappaB p65, IL-6 and CXCL-8. Moreover, insulin resistance index (IRI) was calculated. Hepatic pathological changes, including vacuoles, lipids accumulation and fibrosis were observed. Remaining mice were fed with diet separately to 110 weeks-age for statistics of mortality. MHCS promoted autophagy of free fatty acid treated hepatocytes. Mice fed with high fat plus MHCS diet exhibited improved oral glucose tolerance, insulin resistance, hepatic pathology, inflammation, mortality and activated autophagy. The protective effects of MHCS against metabolic syndroms might be through the activation of hepatic autophagy.

CT and MRI Findings of Renal Angiomyolipoma With Lung Metastasis: A Case Report and Literature Review.

Renal angiomyolipoma has two histological variants: classical and epithelioid. Epithelioid angiomyolipoma is considered as a potential malignant tumor, often leading to recurrence and metastasis, with rapid progression in most of the cases. The lung is one of the most commonly reported sites of metastasis, and pulmonary metastasis of renal angiomyolipoma is usually diagnostic by computed tomography (CT) scans. Here, we report for the first time renal angiomyolipoma with lung metastasis by combining CT and magnetic resonance imaging (MRI).

Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice.

AIM: Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis. METHODS: Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined. RESULTS: Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice. CONCLUSION: The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.

Piecewise Developable Modeling Via Implicit Neural Deformation and Feature-Guided Cutting.

We propose a novel and automatic method to model shapes using a small set of discrete developable patches. Central to our approach is using implicit neural shape representation that makes our algorithm independent of tessellation and allows us to obtain the Gaussian curvature of each point analytically. With this powerful representation, we first deform the input shape to be an almost developable shape with clear and sparse salient feature curves. Then, we convert the deformed implicit field to a triangle mesh, which is further cut to disk topology along parts of the sparse feature curves. Finally, we achieve the resulting piecewise developable mesh by alternatingly optimizing discrete developability, enforcing manufacturability constraints, and merging patches. The feasibility and practicability of our method are demonstrated over various shapes. Compared to the state-of-the-art methods, our method achieves a better tradeoff between the number of developable patches and the approximation error.

Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report.

Hereditary spastic paraplegias (HSP) are inherited neurodegenerative disorders characterized by progressive paraplegia and spasticity in the lower limbs. SPG48 represents a rare genotype characterized by mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking. This study describes a case of a 53-year-old male patient with SPG48 presenting spastic paraplegia, infertility, hearing impairment, cognitive abnormalities and peripheral neuropathy. The Sanger sequencing revealed a homozygous deletion in the chr 7:4785904-4786677 region causing a premature stop codon in exon 10. The patient's brother was heterozygous for the mutation. The brain magnetic resonance imaging found a mild brain atrophy and white matter lesions. In the analysis of the auditory thresholds, we found a significant hearing decrease in both ears.

Robust Coarse Cage Construction with Small Approximation Errors.

We propose a robust and automatic method to construct manifold cages for 3D triangular meshes. The cage contains hundreds of triangles to tightly enclose the input mesh without self-intersections. To generate such cages, our algorithm consists of two phases: (1) construct manifold cages satisfying the tightness, enclosing, and intersection-free requirements and (2) reduce mesh complexities and approximation errors without violating the enclosing and intersection-free requirements. To theoretically make the first stage have those properties, we combine the conformal tetrahedral meshing and tetrahedral mesh subdivision. The second step is a constrained remeshing process using explicit checks to ensure that the enclosing and intersection-free constraints are always satisfied. Both phases use a hybrid coordinate representation, i.e., rational numbers and floating point numbers, combined with exact arithmetic and floating point filtering techniques to guarantee the robustness of geometric predicates with a favorable speed. We extensively test our method on a data set of over 8500 models, demonstrating robustness and performance. Compared to other state-of-the-art methods, our method possesses much stronger robustness.

Practical Integer-Constrained Cone Construction for Conformal Parameterizations.

We propose a practical method to construct sparse integer-constrained cone singularities with low distortion constraints for conformal parameterizations. Our solution for this combinatorial problem is a two-stage procedure that first enhances sparsity for generating an initialization and then optimizes to reduce the number of cones and the parameterization distortion. Central to the first stage is a progressive process to determine the combinatorial variables, i.e., numbers, locations, and angles of cones. The second stage iteratively conducts adaptive cone relocations and merges close cones for optimization. We extensively test our method on a data set containing 3885 models, demonstrating practical robustness and performance. Our method achieves fewer cone singularities and lower parameterization distortion than state-of-the-art methods.

Survey on computational 3D visual optical art design.

Visual arts refer to art experienced primarily through vision. 3D visual optical art is one of them. Artists use their rich imagination and experience to combine light and objects to give viewers an unforgettable visual experience. However, the design process involves much trial and error; therefore, it is often very time-consuming. This has prompted many researchers to focus on proposing various algorithms to simplify the complicated design processes and help artists quickly realize the arts in their minds. To help computer graphics researchers interested in creating 3D visual optical art, we first classify and review relevant studies, then extract a general framework for solving 3D visual optical art design problems, and finally propose possible directions for future research.

Adult-onset Krabbe disease presenting with progressive myoclonic epilepsy and asymmetric occipital lesions: A case report.

Krabbe disease (KD), also known as globoid cell leukodystrophy, is a rare autosomal recessive condition caused by mutations in the galactocerebrosidase (GALC) gene. KD is more common in infants and young children than in adults. We reported the case of an adult-onset KD presenting with progressive myoclonic epilepsy (PME) and cortical lesions mimicking mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. The whole-exome sequencing (WES) identified a pathogenic homozygous missense mutation of the GALC gene. Parents of the patient were heterozygous for the mutation. The clinical, electrophysiological, and radiological data of the patient were retrospectively analyzed. The patient was a 24-year-old woman presenting with generalized seizures, progressive cognitive decline, psychiatric symptoms, gait ataxia, and action-induced myoclonus. The brain magnetic resonance imaging (MRI) revealed a right occipital cortical ribbon sign without any other damage. This single case expands the clinical phenotypes of adult-onset KD.

Voting for Distortion Points in Geometric Processing.

Low isometric distortion is often required for mesh parameterizations. A configuration of some vertices, where the distortion is concentrated, provides a way to mitigate isometric distortion, but determining the number and placement of these vertices is non-trivial. We call these vertices distortion points. We present a novel and automatic method to detect distortion points using a voting strategy. Our method integrates two components: candidate generation and candidate voting. Given a closed triangular mesh, we generate candidate distortion points by executing a three-step procedure repeatedly: (1) randomly cut an input to a disk topology; (2) compute a low conformal distortion parameterization; and (3) detect the distortion points. Finally, we count the candidate points and generate the final distortion points by voting. We demonstrate that our algorithm succeeds when employed on various closed meshes with a genus of zero or higher. The distortion points generated by our method are utilized in three applications, including planar parameterization, semi-automatic landmark correspondence, and isotropic remeshing. Compared to other state-of-the-art methods, our method demonstrates stronger practical robustness in distortion point detection.

Volume-Enhanced Compatible Remeshing of 3D Models.

Compatible remeshing provides meshes with common connectivity structures. The existing compatible remeshing methods usually suffer from high computational cost or poor quality. In this paper, we present a fast method for computing compatible meshes with high quality. Given two closed, oriented, and topologically equivalent surfaces and a sparse set of corresponding landmarks, we first compute a bijective inter-surface mapping, from which compatible meshes are generated. We then improve the remeshing quality by using a volume-enhanced optimization. In contrast to previous work, our method designs a fast volume-enhanced improvement procedure that directly reduces the isometric distortion of the map between the compatible meshes. Our method also tries to preserve the shapes of the input meshes by projecting the vertices of the compatible meshes onto the input surfaces. Central to this approach is the use of the monotone preconditioned conjugate gradient method, which minimizes the energies effectively and efficiently. Compared with state-of-the-art methods, our method performs about one order of magnitude faster with better remeshing quality. We demonstrate the efficiency and efficacy of our method using various model pairs.

Advanced Hierarchical Spherical Parameterizations.

Computing spherical parameterizations for genus-zero closed surfaces is a fundamental task for geometric processing and computer graphics. Existing methods usually suffer from a lack of practical robustness or poor quality. In this paper, we present a practically robust method to compute high-quality spherical parameterizations with bijection and low isometric distortion. Our method is based on the hierarchical scheme containing mesh decimation and parameterization refinement. The practical robustness of our method relies on two novel techniques. The first one is a flat-to-extrusive decimation strategy, which contains two decimation error metrics to alleviate the difficulty of further mesh refinement. The second is a flexible group refinement technique that consists of flexible vertex insertion and efficient volumetric distortion minimization to control the maximum distortion. We convert the task of volumetric distortion minimization to one of tetrahedral mesh improvement to make the vertices distribute uniformly for efficient refinement. Compared with state-of-the-art methods, our method is more practically robust and possesses better mapping qualities. We demonstrate the efficacy of our method in spherical parameterization computations on a data set containing over five thousand complex models.

Evaluation of urinary metal concentrations and sperm DNA damage in infertile men from an infertility clinic.

This study aimed to examine associations between urinary metal concentrations and sperm DNA damage. Thirteen metals [arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), molybdenum (Mo), mercury (Hg), nickel (Ni), selenium (Se), and zinc (Zn)] were detected in urine samples of 207 infertile men from an infertility clinic using inductively coupled plasma mass spectrometry, and also, sperm DNA damage (tail length, percent DNA tail, and tail distributed moment) were assessed using neutral comet assay. We found that urinary Hg and Ni were associated with increasing trends for tail length (both p for trend<0.05), and that urinary Mn was associated with increasing trend for tail distributed moment (p for trend=0.02). These associations did persist even when considering multiple metals. Our results suggest that environmental exposure to Hg, Mn, and Ni may be associated with increased sperm DNA damage.

Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

Timing is critical for an effective anti-metastatic immunotherapy: the decisive role of IFNγ/STAT1-mediated activation of autophagy.

BACKGROUND: Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown. METHODS AND FINDINGS: Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis. CONCLUSION AND SIGNIFICANCE: Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.

[Controlled clinical trials of initial observation on therapeutic effects of moxibustion for osteoarthritis of the knee: multi-center clinical effect].

OBJECTIVE: To compare therapeutic effects between moxibustion and infrared therapy for the treatment of knee osteoarthritis. METHODS: From January 2007 to June 2008 period, 65 patients with knee osteoarthritis were divided into treatment and control groups randomly uniform random number table generated from SAS statistical software. Among 35 patients in the treatment group, 17 patients were male and 18 patients were female, ranging in age from 45 to 75 years, with an average of (61.2+/-6.4) years; the course of disease ranged from 9 to 43 months, with a mean of (23.6+/-13.8) months; the preoperative Lysholm score ranged from 19 to 28 scores, averaged (24.3+/-3.3) scores. In the control group, there were 30 patients, including 13 males and 17 females, ranging in age from 47 to 79 years, with an average of (62.5+/-9.3) years; the course of disease ranged from 8 to 45 months, with a mean of (24.6+/-16.6) months; the preoperative Lysholm score ranged from 20 to 29 scores, averaged (25.9+/-3.0) scores. The patients in the treatment group were treated with moxibustion, and the patients in control group were treated with infrared therapy. All the patients were followed up for 4 weeks. The Lysholm scores were compared between the two groups. RESULTS: According to Lysholm score for clinical efficacy, treatment group got (87.5+/-5.6) scores and the control group were (85.9+/-3.5) scores, the Lysholm score of the treatment group was higher than that of the control group (P<0.05). Among pain score, joint flexion and extension score, joint stability score, and up and down stairs score, the pain and joint stability scores of patients in the treatment group were higher than those of control group (P<0.05). CONCLUSION: Compared with infrared therapy, moxibustion treatment for knee osteoarthritis can get better joint function, which is effect to alleviate the patient's pain, improve joint stability, improve the efficacy, and is valued to be promoted.