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ABSTRACT: Objectives: The pharmacokinetics of vancomycin and meropenem in patients treated with continuous online hemodiafiltration (OL-HDF) are not well understood. Case: We evaluated dialytic clearance and serum concentrations of vancomycin and meropenem by OL-HDF in a critically ill patient with soft tissue infection. The mean clearance of OL-HDF and mean serum concentrations during continuous OL-HDF were 155.2 mL/min and 23.1 µg/mL for vancomycin and 145.6 mL/min and 22.7 µg/mL for meropenem. Conclusion: Vancomycin and meropenem showed high clearance rates during continuous OL-HDF. However, continuous infusion of these agents at high doses maintained therapeutic serum concentrations.

Background/Aim: Data on metastasis-directed radiotherapy (MDRT) are limited, particularly regarding its association with the prostate-specific antigen (PSA) doubling time (PSADT). The present study evaluated the oncological outcomes of MDRT on the basis of the PSADT in oligorecurrent prostate cancer patients. Patients and Methods: We retrospectively reviewed clinical data of 35 MDRTs for 29 patients at the Kitasato University Hospital, targeting oligometastatic prostate cancer developed after radical treatment for non-metastatic prostate cancer. Thirty-five MDRTs were classified into the PSADT >3 months (n=25) or PSADT =3 months group (n=10). Statistical analyses were performed to compare associations between the two PSADT groups and oncological outcomes such as progression-free survival (PFS) and PSA response after MDRT. Results: There were no significant differences between the two groups in terms of the clinicopathological features. Kaplan-Meier analysis showed that PFS was significantly better in the PSADT >3 months group than in the PSADT =3 months group [median: 13.3 versus (vs.) 2.6 months, p=0.046]. Regarding castration sensitivity, the predictive role of PSADT >3 months was maintained in 21 patients who received MDRT without prior salvage hormone therapy (median PFS: 12.7 vs. 2.6 months, p=0.024). In the castration-resistant setting (n=14), the frequency of a decrease in serum PSA levels after MDRT by 90% was 54.5% (median PFS: 23.1 months). Conclusion: MDRT can provide benefit especially for patients with PSADT =3 months who had oligo-recurrence after the radical treatment for non-metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aimed to analyze the early mortality rates and patterns of relapse after stereotactic body radiotherapy (SBRT) as an initial metastasis‐directed therapy. Methods Patients with pulmonary oligometastases initially treated with SBRT were included in this retrospective multicenter study. SBRT was performed between 2004 and 2015, and the primary lesion was controlled at the time of SBRT. Multivariate logistic regression was used for early mortality analyses. Results A total of 720 patients with 793 oligometastatic tumors for whom the median follow‐up period was 24.6 months were enrolled. The median overall survival period was 53.2 months. The 90‐, 180‐, and 360‐day mortality rates were 1.1% (8 deaths), 2.4% (17 deaths), and 10.8% (71 deaths), respectively. During follow up, 422 patients relapsed. Over 329 patients had single‐site relapse, the most frequent site was the lung in 176; 49 had local failure; and 42 had lymph node metastases. The maximum tumor diameter was significantly related to 90‐day mortality. Maximum tumor diameter, biological effective dose, and performance status were significantly related to 180‐day mortality, whereas maximum tumor diameter, performance status, and pathology were significantly related to 360‐day mortality. Conclusion Our results showed good survival outcomes and low rates of early mortality after SBRT. The patterns of relapse and factors affecting early mortality were revealed.

Induced pluripotent stem cells (iPSCs) offer an unlimited source for cartilage regeneration as they can generate a wide spectrum of cell types. Here, we established a tetracycline (tet) controlled bone morphogenetic protein-4 ( BMP-4 ) expressing iPSC (iPSC- Tet/BMP-4 ) line in which transcriptional activation of BMP-4 was associated with enhanced chondrogenesis. Moreover, we developed an efficient and simple approach for directly guiding iPSC- Tet/BMP-4 differentiation into chondrocytes in scaffold-free cartilaginous pellets using a combination of transcriptional activation of BMP-4 and a 3D shaking suspension culture system. In chondrogenic induction medium, shaking culture alone significantly upregulated the chondrogenic markers Sox9, Col2a1 , and Aggrecan in iPSCs- Tet/BMP-4 by day 21. Of note, transcriptional activation of BMP-4 by addition of tet (doxycycline) greatly enhanced the expression of these genes. The cartilaginous pellets derived from iPSCs- Tet/BMP-4 showed an oval morphology and white smooth appearance by day 21. After day 21, the cells presented a typical round morphology and the extracellular matrix was stained intensively with Safranin O, alcian blue, and type II collagen. In addition, the homogenous cartilaginous pellets derived from iPSCs- Tet/BMP-4 with 28 days of induction repaired joint osteochondral defects in immunosuppressed rats and integrated well with the adjacent host cartilage. The regenerated cartilage expressed the neomycin resistance gene, indicating that the newly formed cartilage was generated by the transplanted iPSCs- Tet/BMP-4 . Thus, our culture system could be a useful tool for further investigation of the mechanism of BMP-4 in regulating iPSC differentiation toward the chondrogenic lineage, and should facilitate research in cartilage development, repair, and osteoarthritis.

The transcriptional regulation of induced pluripotent stem cells (iPSCs) holds promise for their directed differentiation into ameloblasts, which are usually lost after tooth eruption. Ameloblast differentiation is regulated by multiple signaling molecules, including bone morphogenetic proteins (BMPs). Epiprofin (Epfn), a transcription factor, is expressed in the dental epithelium, and epithelial Epfn overexpression results in ectopic ameloblast differentiation and enamel formation in mouse incisor, a striking phenotype resembling that of mice with deletion of follistatin (a BMP inhibitor). However, it remains unknown whether and how Epfn transcriptional activation promotes ameloblast induction from mouse iPSCs. Here, we generated doxycycline-inducible Epfn-expressing mouse iPSCs (Epfn-iPSCs). Ameloblasts, which are characterized by positive staining for keratin 14 and amelogenin and alizarin red S staining, were successfully derived from Epfn-iPSCs based on a stage-specific induction protocol, which involved the induction of the surface ectoderm, dental epithelial cells, and ameloblasts at stages 1, 2, and 3, respectively. Epfn activation by doxycycline at stages 2 and/or 3 decreased cell proliferation and promoted ameloblast differentiation, along with the upregulation of p-Smad1/5/8, a key regulator of the BMP-Smad signaling pathway. Gene analysis of the BMP-Smad signaling pathway-associated molecules revealed that Epfn activation decreased follistatin expression at stage 2, but increased BMP2/4/7 expression at stage 3. Perturbations in the ameloblast differentiation process were observed when the BMP-Smad signaling pathway was inhibited by a BMP receptor inhibitor (LDN-193189). Simultaneous LDN-193189 treatment and Epfn activation largely reversed the perturbations in ameloblast induction, with partial recovery of p-Smad1/5/8 expression, suggesting that Epfn activation promotes ameloblast induction from mouse iPSCs partially by upregulating BMP-Smad activity. These results reveal the potential regulatory networks between Epfn and the BMP-Smad pathway and suggest that Epfn is a promising target for inducing the differentiation of ameloblasts, which can be used in enamel and tooth regeneration.

Abstract Background Successful local therapy for oligometastases may lead to longer survival. The purpose of this multicentre retrospective study was to investigate factors affecting the local control (LC) of pulmonary oligometastases treated by stereotactic body radiotherapy (SBRT) and to investigate the impact of LC on survival. Methods The inclusion criteria included 1 to 5 metastases, the primary lesion and other extrathoracic metastases were controlled before SBRT, and the biological effective dose (BED10) of the SBRT was 75 Gy or more. The Cox proportional hazards model was used for analyses. Results Data of 1378 patients with 1547 tumours from 68 institutions were analysed. The median follow-up period was 24.2 months. The one-year, 3-year and 5-year LC rates were 92.1, 81.3 and 78.6%, respectively, and the 1-year, 3-year and 5-year overall survival rates were 90.1, 60.3 and 45.5%, respectively. Multivariate analysis for LC showed that increased maximum tumour diameter (p = 0.011), type A dose calculation algorithm (p = 0.005), shorter overall treatment time of SBRT (p = 0.035) and colorectal primary origin (p

Dermal papilla cells (DPCs) play crucial roles in hair regeneration, but they readily lose their hair‐forming ability during in vitro culture. Although the formation of spheroids partially restores the ability, shrinkage of the spheroids makes it difficult to maintain cellular viability. To address this problem, we stimulated DPCs with factors known to induce adipogenic and/or osteogenic differentiation, because DPCs share unique gene expression profiles with adipocytes and osteocytes. We isolated DPCs from versican (vcan)–GFP mice, in which GFP is expressed under the control of a vcan promoter, which is strongly active in DPCs of anagen hair follicles. GFP fluorescence was most intense when the spheroids were made from DPCs cultured in a half‐diluted combination of adipogenic and osteogenic media (CAO1/2), a Dulbecco’s modified Eagle’s medium‐based medium that contains 10% FBS, 275 nm dexamethasone, 2.5 mm β‐glycerol phosphate, 12.5 µg·mL−1 ascorbic acid, 0.125 µm isobutylmethylxanthine and 2.5 ng·mL−1 insulin. The dose of each additive used was less than the optimal dose for adipogenic or osteogenic differentiation, and shrinkage of the spheroids was avoided through the addition of fibroblast growth factor 2 and platelet‐derived growth factor‐AA to CAO1/2. In addition, the gene and protein expression of vcan, osteopontin, alkaline phosphatase and α‐smooth muscle actin in the spheroids were augmented to levels similar to those of the intact dermal papillae, which exhibited restored hair‐forming activity. In conclusion, a combination of certain adipogenic and osteogenic inducers, together with fibroblast growth factor 2 and platelet‐derived growth factor‐AA, can promote differentiation toward the DPC lineage.

Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence suggests the existence of an intermediate, or oligometastatic, state when metastases are limited in number and/or location. In addition, following initial curative therapy, many patients present with limited metastatic disease, or oligo-recurrence. Metastasis-directed, anti-cancer therapies may benefit these patients. A growing evidence-base supports the use of hypofractionated, image-guided radiotherapy (HIGRT) for a variety of malignant conditions including inoperable stage I NSCLC and many metastatic sites. When surgical resection is not possible, HIGRT offers an effective alternative for local treatment of limited metastatic disease. Early studies have produced promising results when HIGRT was delivered to all known sites of disease in patients with oligometastatic/oligo-recurrent NSCLC. In a population of patients formerly considered rapidly terminal, these studies report five year overall survival rates of 13-22%. HIGRT for metastatic NSCLC warrants further study. We call for large, intergroup, and even international randomized trials incorporating HIGRT and other metastasis-directed therapies into the treatment of patients with oligometastatic/oligo-recurrent NSCLC.

Mesenchymal stromal/stem cells (MSCs), which generally expand into adherent monolayers, readily lose their proliferative and multilineage potential following repeated passages. Floating culture systems can be used to generate MSC spheroids, which are expected to overcome limitations associated with conventional adherent cultures while facilitating scaffold-free cell transplantation. However, the phenotypic characteristics of spheroids after long-term culture are unknown. In addition, regenerative therapies require new culture systems to maintain their undifferentiated state. In this study, we established a novel culture method employing three-dimensional (3D) “shaking” to generate MSC spheroids using bone marrow derived MSCs. Floating 3D cultures of mouse or human MSCs formed spheroids after shaking (85–95 rpm), within 1 month. These spheroids maintained their osteogenic-, adipogenic-, and chondrogenic-differentiation capacity. The adipogenic-differentiation capacity of adherent cultured mouse and human MSCs, which is lost following several passages, was remarkedly restored by shaking-culture. Notably, human MSC spheroids exhibited a renewable “undifferentiated MSC-pool” property, wherein undifferentiated MSCs grew from spheroids seeded repeatedly on a plastic culture dish. These data suggest that the shaking-culture method maintains and restores multipotency that is lost following monolayer expansion and thereby shows potential as a promising strategy for regenerative therapies with mesenchymal tissues.

Stem cell-based developmental engineering has been considered as a promising strategy for tissue/organ regeneration. Tooth is formed by sequential reciprocal interactions between epithelium derived from surface ectoderm and mesenchymal cells derived from cranial neural crest. The neural crest cell is an appealing cell source for tooth development and regeneration research. In this study, we investigated the odontogenic differentiation and dentin-pulp complex regeneration potential of neural crest cells. Our results showed that neural crest cells (O9-1 mouse cranial neural crest cell line) can sequentially differentiate into dentin matrix acidic phosphoprotein 1 (DMP-1)-positive odontoblasts within a developing tooth germ in vitro. Moreover, O9-1 cells and induced pluripotent stem cell (iPSC)-derived neural crest-like cells (iNCLCs) can form well-organized vascularized dentin-pulp complex when transplanted in vivo with tooth scaffold. Furthermore, both O9-1 cells and iNCLCs can be differentiated into odontoblast-like cells, positive staining with odontogenic-related markers DMP-1 and dentin sialophosphoprotein (DSPP), under odontogenic induction with the administration of bone morphogenetic protein 4 (BMP-4). These results demonstrated that neural crest cells, especially the unlimited iNCLCs, are a promising cell source for tooth development and dental tissue/tooth organ regeneration studies.

Enhanced photocatalytic activity of rutile-based TiO2 materials under general lighting is practically desired. O2 plasma-assisted annealing (PAA) effects on Pt-doped rutile TiO2 nanoparticles were clarified along with its visible-light-driven photocatalytic activity enhancement. The PAA-treated samples were mainly analyzed using optical spectroscopy and x-ray photoelectron spectroscopy (XPS). The photocatalytic activity was assessed by decomposing methylene blue dye and inactivating Bacillus subtilis under general lighting. The PAA treatment changed the O 1s, Ti 2p, and Pt 4f spectra of XPS from those of the pristine sample. This change indicated that the PAA treatment introduced more oxygen deficiency or oxygen vacancies and more oxygen groups adsorbed on the surface. The introduced oxygen vacancies and adsorbed oxygen groups would change the band structure, which primarily narrowed the bandgap energy or broadened the valence band edge, increased the number of electron-trapping sites from the shallow to midgap levels, and enhanced the upward band-bending at the surface. The PAA-induced change in the band structure enhanced the decomposition and bacterial inactivation because it facilitated the separation and concentration of photoexcited carriers. The findings provide a new perspective on enhancing the photocatalytic activities of rutile-based TiO2 nanoparticles under general lighting. [ABSTRACT FROM AUTHOR]

Simple Summary: Oligo-recurrence and oligo-progression in oncology refer to scenarios in which five or fewer metastases develop after the primary lesions and other metastases have been treated using radical surgery or controlled using systemic therapy. Such scenarios are now considered favorable indications for metastasis-directed treatment (MDT), where a curative approach is possible. The primary strategy for recurrence and metastases in renal cell carcinoma (RCC) is systemic therapy, which includes immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors. However, MDTs such as stereotactic body radiation therapy, which involves larger doses administered over fewer fractions than conventional radiation therapy, have shown the potential to improve outcomes for selected patients with RCC experiencing oligo-recurrence and oligo-progression. Combining MDT with ICIs may yield better results owing to their synergistic effects. In this review, we provide an overview of the current evidence related to the management of oligo-recurrent and -progressive RCC. One-third of renal cell carcinomas (RCCs) without metastases develop metastatic disease after extirpative surgery for the primary tumors. The majority of metastatic RCC cases, along with treated primary lesions, involve limited lesions termed "oligo-recurrent" disease. The role of metastasis-directed therapy (MDT), including stereotactic body radiation therapy (SBRT) and metastasectomy, in the treatment of oligo-recurrent RCC has evolved. Although the surgical resection of all lesions alone can have a curative intent, SBRT is a valuable treatment option, especially for patients concurrently receiving systemic therapy. Contemporary immune checkpoint inhibitor (ICI) combination therapies remain central to the management of metastatic RCC. However, one objective of MDT is to delay the initiation of systemic therapies, thereby sparing patients from potentially unnecessary burdens. Undertaking MDT for cases showing progression under systemic therapies, known as "oligo-progression", can be complex in considering the treatment approach. Its efficacy may be diminished compared to patients with stable disease. SBRT combined with ICI can be a promising treatment for these cases because radiation therapy has been shown to affect the tumor microenvironment and areas beyond the irradiated sites. This may enhance the efficacy of ICIs, although their efficacy has only been demonstrated in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy. Methods We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients. Results Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with α/β = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3-year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage. Conclusions Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but unsatisfactory.

Effective regenerative treatments for periodontal tissue defects have recently been demonstrated using mesenchymal stromal/stem cells (MSCs). Furthermore, current bioengineering techniques have enabled de novo fabrication of tooth-perio dental units in mice. These cutting-edge technologies are expected to address unmet needs within regenerative dentistry. However, to achieve efficient and stable treatment outcomes, preparation of an appropriate stem cell source is essential. Many researchers are investigating the use of adult stem cells for regenerative dentistry; bone marrow-derived MSCs (BM-MSCs) are particularly promising and presently used clinically. However, current BM-MSC isolation techniques result in a heterogeneous, non-reproducible cell population because of a lack of identified distinct BM-MSC surface markers. Recently, specific subsets of cell surface markers for BM-MSCs have been reported in mice (PDGFRα+ and Sca-1+) and humans (LNGFR+, THY-1+ and VCAM-1+), facilitating the isolation of unique enriched BM-MSCs (so-called “purified MSCs”). Notably, the enriched BM-MSC population contains neural crest-derived cells, which can differentiate into cells of neural crest- and mesenchymal lineages. In this review, characteristics of the enriched BM-MSCs are outlined with a focus on their potential application within future regenerative dentistry.