Improving stability of human three dimensional skin equivalents using plasma surface treatment.

In developing three-dimensional (3D) human skin equivalents (HSEs), preventing dermis and epidermis layer distortion due to the contraction of hydrogels by fibroblasts is a challenging issue. Previously, a fabrication method of HSEs was tested using a modified solid scaffold or a hydrogel matrix in combination with the natural polymer coated onto the tissue culture surface, but the obtained HSEs exhibited skin layer contraction and loss of the skin integrity and barrier functions. In this study, we investigated the method of HSE fabrication that enhances the stability of the skin model by using surface plasma treatment. The results showed that plasma treatment of the tissue culture surface prevented dermal layer shrinkage of HSEs, in contrast to the HSE fabrication using fibronectin coating. The HSEs from plasma-treated surface showed significantly higher transepithelial electrical resistance compared to the fibronectin-coated model. They also expressed markers of epidermal differentiation (keratin 10, keratin 14 and loricrin), epidermal tight junctions (claudin 1 and zonula occludens-1), and extracellular matrix proteins (collagen IV), and exhibited morphological characteristics of the primary human skins. Taken together, the use of plasma surface treatment significantly improves the stability of 3D HSEs with well-defined dermis and epidermis layers and enhanced skin integrity and the barrier functions.

Design, synthesis, and biological evaluation of phenylcyclopropylamine-entinostat conjugates that selectively target cancer cells.

Small molecule-based selective cancer cell-targeting can be a desirable anticancer therapeutic strategy. Aiming to discover such small molecules, we previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) that selectively release anticancer agents in cancer cells where lysine-specific demethylase 1 (LSD1) is overexpressed. In this work, we designed PCPA-entinostat conjugates for selective cancer cell targeting. PCPA-entinostat conjugate 12 with a 4-oxybenzyl group linker released entinostat in the presence of LSD1 in in vitro assays and selectively inhibited the growth of cancer cells in preference to normal cells, suggesting the potential of PCPA-entinostat conjugates as novel anticancer drug delivery small molecules.

Multivariate Analysis of Risk Factors for Complications in Pediatric Tissue Expansion.

BACKGROUND: Tissue expanders represent one of the main surgical options for skin reconstruction in cases of tumors, traumalike burn injury, scar contracture, and alopecia. However, the tissue expander device is also associated with complications such as infection and extrusion. The aim of this study was to analyze risk factors for major complications of use of tissue expanders in pediatric patients using multivariate analysis. METHODS: A retrospective, single-center observational study was performed over 10 years in pediatric patients who were treated with tissue expanders for tumors, nevus, scars, burn reconstruction, and alopecia from April 2012 to March 2022. The primary outcome was overall complications per operation and expander, including infection and extrusion. Ten predictor variables were included as risk factors based on previous studies and as new factors considered important from clinical experience. Univariate and multivariate logistic regression analyses were performed to identify risk factors for major complications such as expander infection or extrusion. RESULTS: The study included 44 patients who underwent 92 operations using 238 tissue expanders. The overall complication rate per expander was 14.3%. Univariate logistic regression analysis identified associations of younger age, number of expanders used per operation, history of infection, and tissue expander locations with a higher complication rate. In multivariate logistic regression analysis, younger age (odds ratio, 1.14; P = 0.043) was associated with a high likelihood of expander complications. CONCLUSIONS: Younger age is an independent risk factor for tissue expander complications in pediatric patients. This factor should be considered in preoperative planning and discussions with the patient's family.

Characteristics and distribution of chronic pain after mastectomy and breast reconstruction: a long-term prospective cohort study.

PURPOSE: Chronic pain following breast surgery is a concern for breast cancer survivors; however, few studies have investigated the localization of persistent postoperative pain. We conducted this study to identify the location of pain following breast reconstruction. METHODS: A total of 213 Japanese women undergoing mastectomy only or breast reconstruction with a tissue expander/implant (TE/Imp) or a deep inferior epigastric perforator (DIEP) flap were enrolled in the study. Questionnaires related to pain location were sent to patients at the end of postoperative year (POY) 1 and POY 5. Multiple comparisons of the types of operation and cross-tabulation were made between the two time points. RESULTS: Surveys were completed by 107 of the women. Severe pain in the upper medial breast was significantly more common in POY 1 after DIEP reconstruction than after mastectomy only (P = 0.01), whereas abdominal pain was worse in POY 5 after DIEP reconstruction than after mastectomy only (P = 0.04). Pain in the medial arm and axilla had resolved better after TE/Imp (P = 0.03) and DIEP reconstruction (P = 0.01) than after mastectomy only by POY 5, but the difference between TE/Imp and DIEP reconstruction was not significant. CONCLUSIONS: These results show that localization of prolonged postoperative pain following breast reconstruction differs depending on the surgical strategy.

Patient-Reported Outcomes After Autologous Fat Grafting in Prosthetic Breast Reconstruction: Prospective Cohort Study Using a Multivariate Analysis.

INTRODUCTION: There is widespread recognition of the importance of assessment of patient satisfaction and well-being after breast reconstruction. However, few studies of fat grafting performed simultaneously with implant-based breast reconstruction (IBBR) have accounted for confounding factors, such as patient background and information bias. The aim of this study was to examine patient satisfaction and well-being using multivariate analysis of BREAST-Q scores in patients treated with IBBR combined with fat grafting. METHODS: Seventy-one consecutive patients who underwent IBBR with silicone breast implants were enrolled for a prospective cohort study. Among these patients, 56 responded to the BREAST-Q questionnaire, including 24 who underwent fat grafting at the same time as IBBR (FAT+ group) and 32 who underwent IBBR alone (FAT- group). The BREAST-Q questionnaire was completed 1 year after surgery. Statistical analysis was performed using descriptive and summary statistics to identify differences between the 2 groups. RESULTS: Logistic regression analysis showed that the FAT+ group was significantly more likely than the FAT- group to have satisfaction with breasts (P = 0.0201) and satisfaction with outcome (P = 0.0364). CONCLUSIONS: Multivariate analysis with consideration of confounding factors indicated that addition of fat grafting to IBBR improves outcomes of breast reconstruction. These results suggest that a minor surgical procedure of fat grafting can improve patient satisfaction and outcomes after breast reconstruction.

Induction of MYCN-amplified neuroblastoma differentiation through NMYC suppression using PPAR-γ antagonist.

Neuroblastomas are the most common extracranial solid tumors in children and have a unique feature of neuronal differentiation. Peroxisome proliferator-activated receptor (PPAR)-γ is reported to have neuroprotective effects in addition to having antitumor effects in various cancers. Thus, we aimed to clarify the role of PPAR-γ agonist and antagonist in malignant neuroblastomas, which also possess neuronal features. In MYCN-amplified neuroblastoma CHP212 cells, treatment with the PPAR-γ antagonist GW9662 induced growth inhibition in a dose-dependent manner. In addition, the PPAR-γ antagonist treatment changed cell morphology with increasing expression of the neuronal differentiation marker tubulin beta 3 (TUBB3) and induced G1 phase arrest and apoptosis in MYCN-amplified neuroblastoma. Notably, the PPAR-γ antagonist treatment significantly decreased expression of NMYC, B-cell lymphoma 2 (BCL2) and bromodomain-containing protein 4 (BRD4). It is implied that BRD4, NMYC, BCL2 suppression by the PPAR-γ antagonist resulted in cell growth inhibition, differentiation, and apoptosis induction. In our in vivo study, the PPAR-γ antagonist treatment induced CHP212 cells differentiation and resultant tumor growth inhibition. Our results provide a deeper understanding of the mechanisms of tumor cell differentiation and suggest that PPAR-γ antagonist is a new therapeutic and prevention option for neuroblastomas.

Localization of Chronic Pain in Postmastectomy Patients: A Prospective Comparison Between Patients With and Without Breast Reconstruction.

BACKGROUND: After breast surgery with or without immediate reconstruction, chronic pain can be a major problem for patients. However, few studies have examined the details of the sites of long-lasting postoperative pain. In this study, we specified the postoperative pain location after breast surgery, including reconstruction, to find ways to improve surgical procedures or provide effective pain relief. METHODS: The subjects were 205 Japanese women undergoing mastectomy or breast reconstruction with a tissue expander (TE)/implant or a deep inferior epigastric perforator (DIEP) flap. Patients were asked whether they had pain in different parts of the body at 1 year after surgery. Differences were assessed by cross-tabulation and χ2 statistics. RESULTS: Surveys were completed by 157 subjects. Deep inferior epigastric perforator flap cases had significantly more pain and TE/Imp cases had significantly less pain in the medial breast, upper breast, breast upper medial quadrant, and abdomen (P = 0.006, P = 0.006, P < 0.001, P < 0.001, respectively). In the neck area, pain in TE/Imp cases was significantly worse than that in all other patients (P = 0.025). There was no significant difference in chronic pain in any other body regions among the mastectomy only, TE/Imp, and DIEP flap groups. CONCLUSIONS: The results of the present study revealed that the localization of prolonged postoperative pain after breast surgery differs depending on the surgical procedure. In DIEP flap reconstruction, there was a marked tendency for pain in the inner and upper chest and in the abdomen, whereas TE/IMP surgery resulted in pain around the neck of the affected side. These findings may help improve surgical methods and establish effective pain relief that focuses on the identified pain areas.

Three-Dimensional Culture of Cartilage Tissue on Nanogel-Cross-Linked Porous Freeze-Dried Gel Scaffold for Regenerative Cartilage Therapy: A Vibrational Spectroscopy Evaluation.

This study presents a set of vibrational characterizations on a nanogel-cross-linked porous freeze-dried gel (NanoCliP-FD gel) scaffold for tissue engineering and regenerative therapy. This scaffold is designed for the in vitro culture of high-quality cartilage tissue to be then transplanted in vivo to enable recovery from congenital malformations in the maxillofacial area or crippling jaw disease. The three-dimensional scaffold for in-plate culture is designed with interface chemistry capable of stimulating cartilage formation and maintaining its structure through counteracting the dedifferentiation of mesenchymal stem cells (MSCs) during the formation of cartilage tissue. The developed interface chemistry enabled high efficiency in both growth rate and tissue quality, thus satisfying the requirements of large volumes, high matrix quality, and superior mechanical properties needed in cartilage transplants. We characterized the cartilage tissue in vitro grown on a NanoCliP-FD gel scaffold by human periodontal ligament-derived stem cells (a type of MSC) with cartilage grown by the same cells and under the same conditions on a conventional (porous) atelocollagen scaffold. The cartilage tissues produced by the MSCs on different scaffolds were comparatively evaluated by immunohistochemical and spectroscopic analyses. Cartilage differentiation occurred at a higher rate when MSCs were cultured on the NanoCliP-FD gel scaffold compared to the atelocollagen scaffold, and produced a tissue richer in cartilage matrix. In situ spectroscopic analyses revealed the cell/scaffold interactive mechanisms by which the NanoCliP-FD gel scaffold stimulated such increased efficiency in cartilage matrix formation. In addition to demonstrating the high potential of human periodontal ligament-derived stem cell cultures on NanoCliP-FD gel scaffolds in regenerative cartilage therapy, the present study also highlights the novelty of Raman spectroscopy as a non-destructive method for the concurrent evaluation of matrix quality and cell metabolic response. In situ Raman analyses on living cells unveiled for the first time the underlying physiological mechanisms behind such improved chondrocyte performance.

A Medical Tattooing Technique for Enhancing the Three-Dimensional Appearance of the Nipple-Areola Complex After Flap-Based Nipple Reconstruction.

INTRODUCTION: Medical tattooing is a critical reconstructive component in the surgical process for good esthetic outcomes and improved patient satisfaction. There are many nipple reconstruction methods that use a local flap, but reduced post-operative nipple projection is a common problem. Here, we report a modified tattooing method (3D-E tattoo) that enhances the three-dimensional appearance of the nipple-areola complex (NAC), including Montgomery glands, after flap-based nipple reconstruction. METHODS: The subjects were 110 consecutive patients who underwent nipple reconstruction using the C-V flap technique between April 2017 and June 2019. Of these patients, 49 received traditional medical tattooing (Group T) and 61 underwent 3D-E tattoo (Group 3D). A 10-point subjective evaluation of the 3D appearance of the reconstructed NAC was performed, and the scores were compared between the groups. RESULTS: The procedure time for 3D-E tattoo was about 5 minutes longer than that for traditional tattooing. The average score in Group 3D of 7.8/10 was significantly higher than that of 6.4/10 in Group T. CONCLUSION: Application of 3D techniques or "realism" in tattoo artistry has significant potential to improve the esthetic outcomes of reconstructive surgery. Adoption of simple technical skills to produce a more realistic 3D NAC permitted a symmetrical appearance to be reconstructed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS-mutated ovarian cancer cells with high AXL expression.

KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS-MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target-based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY-T30 and OVCAR-5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST-8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS-mutated ovarian cancer with high expression of AXL.

Does an In-House Computer-Aided Design/Computer-Aided Manufacturing Approach Contribute to Accuracy and Time Shortening in Mandibular Reconstruction?

Mandibular reconstruction using computer-aided design and computer-assisted manufacturing (CAD/CAM) techniques has received recent attention. This technique has theoretical advantages, although this approach can be commercially used in the limited area of the world.The aim is to describe our experience using in-house CAD/CAM guides and the situations in which CAD/CAM may present benefit in the region where commercial guides are unavailable.The authors developed our In-house CAD/CAM approach for mandibular reconstructions with a free fibular flap. Patients were divided into 2 group; CAD/CAM and conventional groups. In the CAD/CAM group, reconstructions were planned virtually using CAD/CAM; these CAD/CAM guides were used in the surgery. In the conventional group, free-hand cutting and fitting of the fibular segments were performed as reconstructions. Later, the bone computed tomographic image was compared with the plan. The averaged deviations and the percentages of the points within 1 mm, 2 mm, and 3 mm deviations were recorded. Total and ischemic time were also recorded.Reconstruction points within 1 mm deviation were 59% of CAD/CAM group (n = 9) and 42% of conventional group (n = 10, P = 0.04), within 2 mm 82% and 69% (P = 0.03). Total time were 1012 and 911 minutes, while flap ischemic time were 147 and 175 minutes (P = 0.03), respectively.In-house CAD/CAM mandibular reconstruction also supported accuracy and shorter flap ischemic time. For a detailed accurate reconstruction, CAD/CAM showed superiority than conventional method. Use of the In-house CAD/CAM guides might be an option where commercial guides are not available.

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. METHODS: We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. RESULTS: The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. CONCLUSION: We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors.

Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

Using an In-House Approach to Computer-Assisted Design and Computer-Aided Manufacturing Reconstruction of the Maxilla.

PURPOSE: Computer-assisted design (CAD) and computer-aided manufacturing (CAM) techniques are in widespread use for maxillofacial reconstruction. However, CAD/CAM surgical guides are commercially available only in limited areas. To use this technology in areas where these commercial guides are not available, the authors developed a CAD/CAM technique in which all processes are performed by the surgeon (in-house approach). The authors describe their experience and the characteristics of their in-house CAD/CAM reconstruction of the maxilla. PATIENTS AND METHODS: This was a retrospective study of maxillary reconstruction with a free osteocutaneous flap. Free CAD software was used for virtual surgery and to design the cutting guides (maxilla and fibula), which were printed by a 3-dimensional printer. After the model surgery and pre-bending of the titanium plates, the actual reconstructions were performed. The authors compared the clinical information, preoperative plan, and postoperative reconstruction data. The reconstruction was judged as accurate if more than 80% of the reconstructed points were within a deviation of 2 mm. RESULTS: Although on-site adjustment was necessary in particular cases, all 4 reconstructions were judged as accurate. In total, 3 days were needed before the surgery for planning, printing, and pre-bending of plates. The average ischemic time was 134 minutes (flap suturing and bone fixation, 70 minutes; vascular anastomoses, 64 minutes). The mean deviation after reconstruction was 0.44 mm (standard deviation, 0.97). The deviations were 67.8% for 1 mm, 93.8% for 2 mm, and 98.6% for 3 mm. The disadvantages of the regular use of CAD/CAM reconstruction are the intraoperative changes in defect size and local tissue scarring. CONCLUSION: Good accuracy was obtained for CAD/CAM-guided reconstructions based on an in-house approach. The theoretical advantage of computer simulation contributes to the accuracy. An in-house approach could be an option for maxillary reconstruction.

Molecular-targeting therapies against quantitative abnormalities in gene expression with malignant tumors.

Genetic mutations in exons of oncogenes and tumor-suppressor genes causing qualitative abnormalities result in activation of the oncogenes and inactivation of the tumor-suppressor genes, thereby causing cancer. In contrast, we have previously demonstrated that decreases in the RB promoter activity by genetic or epigenetic abnormalities can also cause carcinogenesis. In addition, activation and inactivation of a variety of oncogenes and tumor-suppressor genes finally cause quantitative abnormalities in gene expression. Interestingly, we discovered effective molecular-targeting agents, such as a novel MEK inhibitor, trametinib, by screening for agents upregulating the expression of cyclin-dependent kinase inhibitors. In the present review, we focused on the quantitative abnormalities in gene expression with carcinogenesis, and discuss the importance of normalizing the quantitative abnormalities in gene expression with several molecular-targeting agents.

Secondary Maxillary and Orbital Floor Reconstruction With a Free Scapular Flap Using Cutting and Fixation Guides Created by Computer-Aided Design/Computer-Aided Manufacturing.

Computer-aided design/computer-aided manufacturing (CAD/CAM) guides are now widely used in maxillofacial reconstruction. However, there are few reports of CAD/CAM guides being used for scapular flaps. The authors performed the secondary maxillary and orbital floor reconstruction using a free latissimus dorsi muscle, cutaneous tissue, and scapular flap designed using CAD/CAM techniques in a 72-year-old man who had undergone partial maxillectomy four years previously. The patient had diplopia, the vertical dystopia of eye position, and a large oral-nasal-cutaneous fistula. After the operation, the authors confirmed that the deviation between the postoperative and preoperative planning three-dimensional images was less than 2 mm. Because scapular guides require 3 cutting surfaces, the shape of the scapular guide is more complex than that of a conventional fibular guide. In orbital floor reconstruction, the use of a CAM technique such as that used to manufacture the authors' fixation guide is as necessary for accurate, safe, and easy reconstruction as is preoperative CAD planning. The production of a fixation guide as well as a cutting guide is particularly useful because it is difficult to determine the angle for reconstructing the orbital floor by freehand techniques. In this case, the orbital floor was reconstructed based on a mirror image of the healthy side to avoid overcompression of the orbital tissue. Although the patient's vertical dystopia of eye position was improved, diplopia was not improved because, for greater safety, the authors did not plan overcorrection of the orbital volume.

Inverted Nipple Correction with Selective Dissection of Lactiferous Ducts Using an Operative Microscope and a Traction Technique.

BACKGROUND: An inverted nipple is a common congenital condition in young women that may cause breastfeeding difficulty, psychological distress, repeated inflammation, and loss of sensation. Various surgical techniques have been reported for correction of inverted nipples, and all have advantages and disadvantages. Here, we report a new technique for correction of an inverted nipple using an operative microscope and traction that results in low recurrence and preserves lactation function and sensation. METHODS: Between January 2010 and January 2013, we treated eight inverted nipples in seven patients with selective lactiferous duct dissection using an operative microscope. An opposite Z-plasty was added at the junction of the nipple and areola. Postoperatively, traction was applied through an apparatus made from a rubber gasket attached to a sterile syringe. Patients were followed up for 15-48 months. RESULTS: Adequate projection was achieved in all patients, and there was no wound dehiscence or complications such as infection. Three patients had successful pregnancies and subsequent breastfeeding that was not adversely affected by the treatment. There was no loss of sensation in any patient during the postoperative period. CONCLUSION: Our technique for treating an inverted nipple is effective and preserves lactation function and nipple sensation. The method maintains traction for a longer period, which we believe increases the success rate of the surgery for correction of severely inverted nipples. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Generation of Directly Converted Human Osteoblasts That Are Free of Exogenous Gene and Xenogenic Protein.

Generation of osteoblasts from human somatic cells may be applicable in an effective transplantation therapy against bone diseases. Recently we established a procedure to directly convert human fibroblasts into osteoblasts by transducing some transcription factor genes via retroviral vectors. However, retroviral vector-mediated transduction may potentially cause tumor formation from the infected cells, thus a non-viral gene transfection method may be more preferable for preparation of osteoblasts to be used for transplantation therapy. Here, we constructed a plasmid vector encoding Oct4, Osterix, and L-Myc that were an appropriate combination of transcription factors for this purpose. Osteoblast-like phenotypes including high alkaline phosphatase (ALP) activity, bone matrix production and osteoblast-specific gene expression were induced in normal human fibroblasts that were transfected with the plasmid followed by culturing in osteogenic medium. The plasmid-driven directly converted osteoblasts (p-dOBs) were obtained even in the absence of a xenogenic protein. The plasmid vector sequence had fallen out of the p-dOBs. The cells formed deposition of calcified bodies in situ after transplantation into mice. These results strongly suggest that p-dOBs can be put into practical use for a novel cell-based therapy against bone diseases. J. Cell. Biochem. 117: 2538-2545, 2016. © 2016 Wiley Periodicals, Inc.

C-H activation enables a rapid structure-activity relationship study of arylcyclopropyl amines for potent and selective LSD1 inhibitors.

We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.