A Novel PEGylated Liposome-Encapsulated SANT75 Suppresses Tumor Growth through Inhibiting Hedgehog Signaling Pathway

The Hedgehog (Hh) pathway inhibitors have shown great promise in cancer therapeutics. SANT75, a novel compound we previously designed to specially inhibit the Smoothened (SMO) protein in the Hh pathway, has greater inhibitory potency than many of commonly used Hh inhibitors. However, preclinical studies of SANT75 revealed water insolubility and acute toxicity. To overcome these limitations, we developed a liposomal formulation of SANT75 and investigated its antitumor efficacy in vitro and in vivo. We encapsulated SANT75 into PEGylated liposome and the mean particle size distribution and zeta-potential (ZP) of liposomes were optimized. Using the Shh-light2 cell and Gli-GFP or Flk-GFP transgenic reporter zebrafish, we confirmed that liposome-encapsulated SANT75 inhibited Hh activity with similar potency as the original SANT75. SANT75 encapsulated into liposome exerted strong tumor growth-inhibiting effects in vitro and in vivo. In addition, the liposomal SANT75 therapy efficiently improved the survival time of tumor-bearing mice without obvious systemic toxicity. The pathological morphology and immunohistochemistry staining revealed that liposomal SANT75 induced tumor cell apoptosis, inhibited tumor angiogenesis as assessed by CD31 and down-regulated the expression of Hh target protein Gli-1 in tumor tissues. Our findings suggest that liposomal formulated SANT75 has improved solubility and bioavailability and should be further developed as a drug candidate for treating tumors with abnormally high Hh activity.     

Identification of a Potent Endothelium-Derived Angiogenic Factor

The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up₄U) from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up₄U was identified by MALDI-LIFT-fragment-mass-spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up₄U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up₄U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up₄U after stimulation with shear stress. Mean total plasma Up₄U concentrations of healthy subjects (N = 6) were sufficient to induce angiogenic and proliferative effects (1.34±0.26 nmol L^-1). In conclusion, Up₄U is a novel strong human endothelium-derived angiogenic factor.     

Dysfunction and Post-Traumatic Stress Disorder in Fracture Victims 50 Months after the Sichuan Earthquake

Background

This study aimed to evaluate the effectiveness of a rehabilitation intervention on physical dysfunction (PDF) and post-traumatic stress disorder (PTSD) in fracture victims 50 months after the Sichuan earthquake of 2008 and to identify risk factors for PTSD.

Methods

This is a retrospective cohort study. Four hundred and fifty-nine earthquake-related fracture victims from Mianzhu city, Sichuan Province who did not qualify for disability pension participated. Two hundred and forty-five subjects received regular rehabilitation and 214 did not. Muscle strength, joint range of motion (ROM),sensory function, and sit-to-stand balance capacity were evaluated to assess PDF. The PTSD Checklist-Civilian Version (PCL-C) was administered to screen for PTSD. An ordinary least square regression was used to predict PTSD, and a logistic regression was used to predict PDF. In addition a Least Angle Regression (LARS) was carried out for PTSD to study the effects of rehabilitation and PDF at the same time.

Results

Unadjusted and adjusted group differences in physical dysfunction (p<0.01) and PTSD prevalence (p<0.05) were significant in favor of the rehabilitation group. In addition, being female, average or above family income, having witnessed death and fearfulness were found risk factors for PTSD symptoms 50 months after the earthquake. Both PDF and rehabilitation were selected predictors by LARS demonstrating opposite effects.

Conclusion

PDF and PTSD were significantly reduced by the rehabilitation intervention. Future medical intervention strategies should consider rehabilitation in order to assist survivors in dealing with both physical and psychological effects of natural disaster.     

Two new endemic species of Ophiorrhiza L. (Rubiaceae: Ophiorrhizeae) from Davao Oriental,Philippines

Two new species of Ophiorrhiza collected from Mt Hamiguitan Range Wildlife Sanctuary in Davao Oriental, Philippines, are herein described and illustrated. Ophiorrhiza erythropilosa is the third Philippine species possessing involucral bracts and is further characterized by its predominantly villose stems that appear red due to strikingly red-violet trichomes, subpersistent bifid stipules, linear involucral bracts without prominent midrib, and 4 mm long urceolate corolla that is villose outside and lightly puberulous inside. Ophiorrhiza hamiguitanensis is characterized by its coriaceous, lanceolate leaves with attenuate apex and base, brochidodromous venation, subpersistent bilobed stipules with slightly recurved acute tips, presence of 1.5–2.5 mm long linear ensiform bracts, heterostylous flowers, clavate calyces and broadly obcordate capsules.     

Sexually selected male weapon is associated with lower inbreeding load but higher sex load in the bulb mite

Elaborate sexually selected ornaments and armaments are costly but increase the reproductive success of their bearers (usually males). It has been postulated that high-quality males can invest disproportionately more in such traits, making those traits honest signals of genetic quality. However, genes associated with such traits may have sexually antagonistic effects on fitness. Here, using a bulb mite Rhizoglyphus robini, a species in which a distinct dimorphism exists between males in the expression of a sexually selected weapon, we compare inbreeding and gender load between lines derived from armed fighters and unarmed scramblers. After four generations of sib-mating, inbreeding depression for female fitness was significantly lower in fighter-derived lines compared to scrambler-derived lines, suggesting that fighter males had significantly higher genetic quality. However, outbred females from fighter-derived lines had significantly lower fitness compared to outbred females from scrambler-derived lines, demonstrating significant gender load associated with the presence of a sexually selected male weapon. Our results imply that under outbreeding, genetic benefits of mating with bearers of elaborate sexually selected traits might be swamped by the costs of decreased fitness of female progeny due to sexually antagonistic effects.     

Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification (IBGC) is a rare neuropsychiatric disorder characterized by bilateral and symmetric cerebral calcifications. Recently, SLC20A2 was identified as a causative gene for familial IBGC, and three mutations were reported in a northern Chinese population. Here, we aimed to explore the mutation spectrum of SLC20A2 in a southern Chinese population. Sanger sequencing was employed to screen mutations within SLC20A2 in two IBGC families and 14 sporadic IBGC cases from a southern Han Chinese population. Four novel mutations (c.82G > A p.D28N, c.185T > C p.L62P, c.1470_1478delGCAGGTCCT p.Q491_L493del and c.935-1G > A) were identified in two families and two sporadic cases, respectively; none were detected in 200 unrelated controls. No mutation was found in the remaining 12 patients. Different mutations may result in varied phenotypes, including brain calcification and clinical manifestations. Our study supports the hypothesis that SLC20A2 is a causative gene of IBGC and expands the mutation spectrum of SLC20A2, which facilitates the understanding of the genotype–phenotype correlation of IBGC.