iRGD-targeted delivery of a pro-apoptotic peptide activated by cathepsin B inhibits tumor growth and metastasis in mice.

The use of cytolytic peptides with potential therapeutic properties is a promising approach to cancer therapy due to their convenient automated synthesis and their capacity for modifications. However, the use of cytolytic peptides is limited due to their nonspecific cytolytic activity. In this study, we designed a tumor-targeting proapoptotic system based on an amphipathic D-amino acid-modified apoptotic peptide, KLA, a variant of (KLAKLAK)2, which is fused with a linear tumor-penetrating homing peptide iRGD through specific cathepsin B (CTSB) cleavage sequences that are overexpressed in many types of tumor tissues. Our data show that the procytotoxic peptide D(KLAKLAKKLAKLA)K-GG-iRGD (m(KLA)-iRGD) is internalized into cultured tumor cells through a neuropilin-1 (NRP1)-activated pathway by iRGD delivery. Once inside the cells, the peptide triggers rapid apoptosis through both the mitochondrial-induced apoptotic pathway and the death receptor pathway in NRP1+/αvß3/CTSB+ tumor cells. Furthermore, m(KLA)-iRGD spread extensively within the tumor tissue when it was injected into 4T1 tumor-bearing mice. The m(KLA)-iRGD peptide inhibited tumor growth to a certain degree, resulting in a significant reduction in tumor volume (P < 0.05) and the total inhibition of metastasis at the end of the treatment. These results suggest that m(KLA)-iRGD has the potential for development as a new antitumor drug.

Osteoblasts derived from induced pluripotent stem cells form calcified structures in scaffolds both in vitro and in vivo.

Reprogramming somatic cells into an ESC-like state, or induced pluripotent stem (iPS) cells, has emerged as a promising new venue for customized cell therapies. In this study, we performed directed differentiation to assess the ability of murine iPS cells to differentiate into bone, cartilage, and fat in vitro and to maintain an osteoblast phenotype on a scaffold in vitro and in vivo. Embryoid bodies derived from murine iPS cells were cultured in differentiation medium for 8­12 weeks. Differentiation was assessed by lineage-specific morphology, gene expression, histological stain, and immunostaining to detect matrix deposition. After 12 weeks of expansion, iPS-derived osteoblasts were seeded in a gelfoam matrix followed by subcutaneous implantation in syngenic imprinting control region (ICR) mice. Implants were harvested at 12 weeks, histological analyses of cell and mineral and matrix content were performed. Differentiation of iPS cells into mesenchymal lineages of bone, cartilage, and fat was confirmed by morphology and expression of lineage-specific genes. Isolated implants of iPS cell-derived osteoblasts expressed matrices characteristic of bone, including osteocalcin and bone sialoprotein. Implants were also stained with alizarin red and von Kossa, demonstrating mineralization and persistence of an osteoblast phenotype. Recruitment of vasculature and microvascularization of the implant was also detected. Taken together, these data demonstrate functional osteoblast differentiation from iPS cells both in vitro and in vivo and reveal a source of cells, which merit evaluation for their potential uses in orthopedic medicine and understanding of molecular mechanisms of orthopedic disease.

The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation.

Tissue-resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis, and tumor formation. Here, we define a population of resident lung MSCs (luMSCs) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin-induced loss of these endogenous luMSCs and elicited fibrosis (pulmonary fibrosis), inflammation, and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSCs attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T-cell proliferation in vitro. Global gene expression analysis indicated that the luMSCs are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and profibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity after injury; however, when endogenous MSCs are lost, this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury.

The correlation of the World Health Organization histologic classification of thymic epithelial tumors and its prognosis: a clinicopathologic study of 108 patients from China.

This study retrospectively reviewed the clinicopathological features of thymic epithelial tumors in 108 patients, and evaluated World Health Organization (WHO) histologic classification of thymic tumors. Other prognostic factors, including age, gender, clinical stage, and completeness of tumor resection were also analyzed. Seven type A tumors, 19 type AB, 23 type B1, 19 type B2, 27 type B3, and 13 thymic carcinomas were studied. The 5-year and 10-year survival rates were 100% after resection of tumor types A and AB; 93% and 81% for B1; 83% and 70% for B2; and 43% and 33% for B3. The overall 5-year and 10-year survival rates were 72.0% and 63.0%, respectively. Tumor classification was highly significant in predicting survival (P .001) and also reflected the clinical behavior of tumors. The Masaoka stage was the most important independent prognostic index in thymomas. The WHO histologic subtype and completeness of resection were also important prognostic factors.

Postural Changes in Measures of Arterial Stiffness in Hypertensive Subjects on Antihypertensive Drug Therapy: A Prospective, Pilot Study.

Prospective study with a controlled arm to know if there are variations of measures of arterial stiffness with posture in subjects with hypertension on antihypertensive medications. We studied postural variations of measures of arterial stiffness in 21 subjects with diagnosed hypertension on antihypertensive medications and compared them with 21 normotensive subjects. All subjects underwent pulse-wave analysis on SphygmoCor in the morning between 8 am to 10 am initially in supine and then in sitting position after 3 minutes. Summary measures on demographics, and blood pressure characteristics at sitting and supine positions are obtained. Differences between characteristics at supine and sitting position are compared using nonparametric paired test of Wilcoxon signed-rank test. A value of p < 0.05 was accepted as statistically significant. Antihypertensive medications decreased the supine aortic augmentation pressure (AAP) and augmentation index (AI) but not significantly. When subgroups of patients with antihypertensive treatment were analyzed, it was noted that angiotensin-converting enzyme inhibitor and angiotensin receptor blocker group (12) decreased AAP and AI significantly in supine position compared with patients on other antihypertensive medications (9) (p-value 0.034 and 0.038, respectively). There was no significant difference in other groups of calcium channel blockers, ß-blockers, or diuretics. However, in normotensive control arm, there was an increase in AAP and AI in the supine position. In hypertensive subjects, on antihypertensive, there was reduction in AAP and AI in supine position compared with those of normotensives. The significance of the decrease in AAP and AI in supine position on antihypertensive needs to be studied further.

Crystallization and mechanical properties of reinforced PHBV composites using melt compounding: Effect of CNCs and CNFs.

Nanocellulose reinforced poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) composites were prepared using melt compounding. The effects of nanocellulose types (CNCs and CNFs) and nanocellulose content (1, 2, 3, 4, 5, 6 and 7wt%) on the crystallization, thermal and mechanical properties of PHBV composites were systematically compared in this study. The thermal stability of PHBV composites was improved by both CNCs and CNFs. CNFs with a higher thermal stability leaded to a higher thermal stability of PHBV composites. Both CNCs and CNFs induced a reduction in the crystalline size of PHBV spherulites. Furthermore, CNCs could act as a better nucleating agent for PHBV than did CNFs. CNCs and CNFs showed reinforcing effects in PHBV composites. At the equivalent content of nanocellulose, CNCs led to a higher tensile modulus of PHBV composites than did CNFs. 1wt% CNCs/PHBV composites exhibited the most optimum mechanical properties.

Development of a noninvasive electrical impedance probe for minimally invasive tumor localization.

Compared with traditional open surgery, minimally invasive surgery (MIS) improves the accuracy and dexterity of a surgeon and minimizes trauma to the patient. However, the lack of significant haptic feedback in MIS can make tumor localization difficult. A noninvasive electrical impedance probe (NEIP), consisting mainly of two spherical electrodes and a constant force generator, has been developed to gently touch or slide over tissue surface and at the same time record impedance values without prior registration of the surface. We prove that there is a linear relationship between the surgical margin width and the recorded conductance. Ex vivo experiments in ten human kidney specimens were performed to demonstrate the feasibility of NEIP. The experimental results verify the linear relationship and indicate that NEIP can provide accurate tumor location while sliding over the tissue surface.

An artificial neural network approach to the predictive modeling of tensile force during renal suturing.

Further understanding of the mechanical deformation and tear behavior of kidney during suturing helps to enhance surgical task execution that requires fine suture manipulation. This paper aims to develop a model to describe the relationship between the tensile force acting on suture line and the resulted kidney deformation in the tension of suture line. The tensile force was recorded during multiple suture procedures, filtered, and we extracted the force data between the beginnings of tensioning suture line and tearing renal remnant. The extracted data were interpolated to obtain the same data sample length for each suture procedure, and then used to train the back propagation (BP) neural network. In order to predict the tearing force, force data were collected in sequence and interpolated to be input into BP network. Suture processes were performed on in vitro porcine kidneys, and experimental results verified the effectiveness of predictive modeling and the accuracy of tearing force prediction. The relative error for tearing force prediction was about 15%. The predictive modeling method can be used to forecast the tearing force before the suture line tears through soft tissues.