Tissue‐Engineered Tracheal Reconstruction Using Three‐Dimensionally Printed Artificial Tracheal Graft: Preliminary Report

Three‐dimensional printing has come into the spotlight in the realm of tissue engineering. We intended to evaluate the plausibility of 3D‐printed (3DP) scaffold coated with mesenchymal stem cells (MSCs) seeded in fibrin for the repair of partial tracheal defects. MSCs from rabbit bone marrow were expanded and cultured. A half‐pipe‐shaped 3DP polycaprolactone scaffold was coated with the MSCs seeded in fibrin. The half‐pipe tracheal graft was implanted on a 10 × 10‐mm artificial tracheal defect in four rabbits. Four and eight weeks after the operation, the reconstructed sites were evaluated bronchoscopically, radiologically, histologically, and functionally. None of the four rabbits showed any sign of respiratory distress. Endoscopic examination and computed tomography showed successful reconstruction of trachea without any collapse or blockage. The replaced tracheas were completely covered with regenerated respiratory mucosa. Histologic analysis showed that the implanted 3DP tracheal grafts were successfully integrated with the adjacent trachea without disruption or granulation tissue formation. Neo‐cartilage formation inside the implanted graft was sufficient to maintain the patency of the reconstructed trachea. Scanning electron microscope examination confirmed the regeneration of the cilia, and beating frequency of regenerated cilia was not different from those of the normal adjacent mucosa. The shape and function of reconstructed trachea using 3DP scaffold coated with MSCs seeded in fibrin were restored successfully without any graft rejection.     

A Case of Nonalcoholic Steatohepatitis and Small Intestinal Bacterial Overgrowth with Peripheral Edema Caused by Intestinal Bypass Surgery and Relieved by Repair

Intestinal bypass surgery, particularly jejuno-ileal bypass surgery, performed for the purpose of weight reduction may cause an unexpected exacerbation of nonalcoholic steatohepatitis (NASH). Here, we report a case of NASH caused by small intestinal bacterial overgrowth, which developed after jejuno-colic bypass surgery and resolved dramatically after surgical correction.     

A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer

Background MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC.Methods This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS).Results A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively.Conclusion Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC.ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT03332498","term_id":"NCT03332498"}}NCT03332498.Subject terms: Cancer immunotherapy, Colorectal cancer     

Three‐Dimensional Contrast Echocardiography in Assessing Left Ventricular Diverticulum

Congenital left ventricular (LV) diverticulum is a rare malformation that can be alone or in association with other congenital abnormalities. Since the several complications have been reported in association with LV diverticulum, as cardiac rupture, heart failure, and endocarditis, patients with LV diverticulum who are managed with conservative treatment would require regular checkups to ascertain the absence of such complications. We report a case of LV diverticulum in a 47‐year‐old man. He took the serial three‐dimensional contrast echocardiography, which was reliable and readily available tool for defining LV diverticulum and monitoring the presence of complications.     

Combination of a chemopreventive agent and paclitaxel in CD44-targeted hybrid nanoparticles for breast cancer treatment

The CD44 receptor, which is upregulated in many cancer cells, provides a selective cellular surface for targeted drug delivery systems. We developed a hybrid nanocarrier for the CD44-targeted delivery of ibuprofen (IBU) and paclitaxel (PTX). The solid lipid nanoparticles (SLNs) were prepared by a hot-melt oil/water emulsion technique and then coated with hyaluronic acid (HA) by electrostatic interactions. The final SLN were spherical with a hydrodynamic diameter (Z) of 72.16 ± 2.9 nm, polydispersity index (PDI) of 0.276 ± 0.009, and zeta potential (ZP) of 28.20 ± 0.69 mV. Similarly, SLN coated with HA (SLN-HA) exhibited acceptable physical properties (Z 169.3 ± 0.55 nm, PDI 0.285 ± 0.004, and ZP ? 10.5 ± 0.15 mV). Cell viability assays showed that the combination of IBU, a chemopreventive agent, and PTX exerted a synergistic inhibitory effect on the proliferation of cancer cells (CI < 1.0). Additionally, our observations indicated that both SLN and SLN-HA enhanced apoptosis and cellular uptake compared to the cocktail of free drugs. HA indicated its affinity for cancer cells through the improvement of cellular uptake and induction of apoptosis. These results clearly indicated that these nanoparticle systems hold great promise for drug delivery in breast cancer treatment.     

Acarbose treatments improve arterial stiffness in patients with type 2 diabetes mellitus

Aims/Introduction: Although the improvement of postprandial hyperglycemia by an alpha‐glucosidase inhibitor (α‐GI) has been associated with a risk reduction of cardiovascular events, the relationship between postprandial hyperglycemia and arterial stiffness has not been well understood. We therefore examined whether ameliorating the postprandial state by α‐GI leads to an improvement in arterial stiffness. Materials and Methods: A total of 22 patients with type 2 diabetes mellitus were treated with acarbose. Cardio‐ankle vascular index (CAVI) as the arterial stiffness was measured by using a VaSera CAVI instrument before and 12 months after acarbose treatment. Serum high‐sensitivity C‐reactive protein (hs‐CRP), pentraxin‐3 (PTX3) and matrix metalloproteinase (MMP) ‐2, ‐9 were measured at the same time points. Furthermore, circulating peripheral blood mononuclear cells were examined for the frequencies of CD14 positive cells expressing membrane type‐1 MMP (MT1‐MMP) at the single cell level using flow cytometry. Results: After acarbose treatment, postprandial glucose and glycosylated hemoglobin (HbA_1c) were significantly decreased. Serum levels of hs‐CRP, PTX3, MMP‐2 and MMP‐9 were significantly decreased. CAVI showed a significant reduction, although the changes were not significant in blood pressure and heart rate. MT1‐MMP expression was significantly decreased by acarbose treatment. In multivariate analysis, improvement of blood glucose, decrease of PTX3 levels and MT1‐MMP expression were independent predictors of beneficial change in CAVI. Conclusions: The present study showed that the beneficial effects of acarbose on arterial stiffness are mediated by an improvement of postprandial hyperglycemia and vascular remodeling markers. In conclusion, acarbose treatment might reduce the risk of cardiovascular diseases by altering the arterial stiffness in postprandial hyperglycemic status. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00079.x , 2010)