β-tricalcium Phosphate/Collagen Composites Improve Bone Regeneration in Rat Calvarial Bone Defects

Autogenous bone grafting is the most widely accepted approach for repairing bone defects, yet limitations in the donor site and subsequent morbidity associated with harvesting bone from other sites remain as major concerns. Consequently, synthetic bone-like biocomposites have drawn much attention as a novel regenerative strategy. This study evaluated the regenerative properties of our prototype β-TCP/collagen composite in an animal model. We prepared the original β-TCP/collagen composite by mixing an acidic atelocollagen gel and alkaline colloidal β-TCP, and Raman microspectroscopy of the composite revealed the typical spectral features attributable to bone after manual mixing. We then transplanted either the composite or collagen alone into a full-thickness trephine defect made in the calvarial bone of rats. At 8 weeks after implantation, the elastic modulus of regenerated bone that developed alongside the composite was comparable to that of native cortical bone. Decalcification and processing of the calvarial bones for histological observation revealed that the β-TCP/collagen enabled better bone regenerative properties compared to collagen alone. Our newly developed β-TCP/collagen composite imitates the structural properties of bone, and thus provides a potentially useful scaffold material to support the mechanical integrity of regenerated bone

Before-after (1998 and 2008) trend analyses on regional clustering of clinical dentist-to-population ratio in all 1,976 municipalities of Japan

Purpose: The main purpose of this study was to obtain geographic clustering information in order to identify shortages (“cold spots”) and surpluses (“hot spots”) of dentists in all municipalities of Japan. Methods: Pretreatment steps were conducted to recover the lost comparability between pre-1998 and post-2008 data due to the large-scale merging of municipalities (42.1% reduction) in the Heisei era. Moran’s I, LISA and spatial multiple regression analyses with AIC were performed to verify regional clustering. Dependent variables of the regression analyses were the clinical dentist-to-population ratio in 2008 (Model 1) and the difference between 1998 and 2008 (Model 2). Results: The R2 was 0.8379 (p<0.0001) for Model 1 and 0.5832 (p<0.0001) for Model 2. The initial dentist-to-population ratio in 1998 showed the highest significance in both models. However, the coefficient of Model 2 was negative, which was exactly the opposite of that of Model 1. Furthermore, indices relating to urbanization and hospital dentist-to-population ratio in 1998 were also highly significant (p<0.01) after adjustment for confounding factors. High- High clustered municipalities are located in most urbanized areas, whereas Low-Low clustered municipalities are located in remote areas far from urbanized areas. This study revealed that factors which attract dental clinics are urbanization and hospitals with dental care capabilities. Conclusion: Clinical dentist-topopulation ratios have improved only in municipalities in urbanized areas in the past ten years. On the contrary, accessibility of dental treatment has not improved in remote/isolated areas

Postoperative recurrence and the role of adjuvant chemotherapy in patients with pulmonary large-cell neuroendocrine carcinoma

ObjectivesThe prognosis for patients with large-cell neuroendocrine carcinoma is generally very poor. In this study, we describe the clinical features of recurrent tumors of large-cell neuroendocrine carcinoma and discuss the role of adjuvant chemotherapy and management of recurrence in patients with large-cell neuroendocrine carcinoma.MethodsWe retrospectively analyzed clinical data from 79 patients and evaluated the prognosis of patients with platinum-based adjuvant chemotherapy, recurrence patterns, patient response to chemotherapy or radiation therapy, and prognosis in patients who experienced relapse.ResultsOf 72 patients, 36 had confirmed recurrent tumors upon follow-up examinations. Of those with recurrent tumors, 33 patients (91.7%) had their first recurrent tumors within 3 years. Patients who underwent platinum-based adjuvant chemotherapy had a significantly lower rate of tumor recurrence and a higher rate of disease-free survival than those who had non–platinum-based adjuvant chemotherapy or no adjuvant chemotherapy. Multivariate analyses revealed that platinum-based adjuvant chemotherapy, pathologic stage, and the presence of second cancer are independent prognostic factors. Three patients with limited resection of the primary tumor had poor prognosis with recurrence. Postoperatively, 11 of the 36 patients without recurrence (30.6%) had metachronous second primary cancers, of which 4 patients had more than 1 site.ConclusionsPatients with large-cell neuroendocrine carcinoma had frequent recurrence following resection of the primary tumor, and those without recurrence often developed metachronous second primary cancers. Platinum-based adjuvant chemotherapy after surgery may be useful for preventing recurrence in patients with large-cell neuroendocrine carcinoma

Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells

BackgroundPemetrexed (PEM) is an anti-cancer agent targeting DNA and RNA synthesis, and clinically in use for mesothelioma and non-small cell lung carcinoma. A mechanism of resistance to PEM is associated with elevated activities of several enzymes involved in nucleic acid metabolism.MethodsWe established two kinds of PEM-resistant mesothelioma cells which did not show any increase of the relevant enzyme activities. We screened genes enhanced in the PEM-resistant cells with a microarray analysis and confirmed the expression levels with Western blot analysis. A possible involvement of the candidates in the PEM-resistance was examined with a WST assay after knocking down the expression with si-RNA. We also analyzed a mechanism of the up-regulated expression with agents influencing AMP-activated protein kinase (AMPK) and p53.ResultsWe found that expression of cardiac ankyrin repeat protein (CARP) was elevated in the PEM-resistant cells with a microarray and Western blot analysis. Down-regulation of CARP expression with si-RNA did not however influence the PEM resistance. Parent and PEM-resistant cells treated with PEM increased expression of CARP, AMPK, p53 and histone H2AX. The CARP up-regulation was however irrelevant to the p53 genotypes and not induced by an AMPK activator. Augmented p53 levels with nutlin-3a, an inhibitor for p53 degradation, and DNA damages were not always associated with the enhanced CARP expression.ConclusionsThese data collectively suggest that up-regulated CARP expression is a potential marker for development of PEM-resistance in mesothelioma and that the PEM-mediated enhanced expression is not directly linked with immediate cellular responses to PEM

Human artificial chromosome with a conditional centromere for gene delivery and gene expression.

Human artificial chromosomes (HACs), which carry a fully functional centromere and are maintained as a single-copy episome, are not associated with random mutagenesis and offer greater control over expression of ectopic genes on the HAC. Recently, we generated a HAC with a conditional centromere, which includes the tetracycline operator (tet-O) sequence embedded in the alphoid DNA array. This conditional centromere can be inactivated, loss of the alphoid(tet-O) (tet-O HAC) by expression of tet-repressor fusion proteins. In this report, we describe adaptation of the tet-O HAC vector for gene delivery and gene expression in human cells. A loxP cassette was inserted into the tet-O HAC by homologous recombination in chicken DT40 cells following a microcell-mediated chromosome transfer (MMCT). The tet-O HAC with the loxP cassette was then transferred into Chinese hamster ovary cells, and EGFP transgene was efficiently and accurately incorporated into the tet-O HAC vector. The EGFP transgene was stably expressed in human cells after transfer via MMCT. Because the transgenes inserted on the tet-O HAC can be eliminated from cells by HAC loss due to centromere inactivation, this HAC vector system provides important novel features and has potential applications for gene expression studies and gene therapy

Potential Activity of Amrubicin as a Salvage Therapy for Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin with an aggressive clinical course. Although anthracycline- and platinum-based regimens are empirically used as first-line treatments for metastatic or unresectable cases, no salvage therapy has been established. A 73-year-old man with platinum-refractory recurrent MCC was treated with amrubicin. The symptoms improved soon, and a partial response was achieved. A total of nine cycles of amrubicin were administered in nine months with manageable adverse events until disease progression was finally observed. The present findings suggest the potential of amrubicin monotherapy as a second-line therapy for patients with advanced/recurrent MCC

Prognosis of Good syndrome : mortality and morbidity of thymoma associated immunodeficiency in perspective

Good syndrome (GS) or thymoma-associated immunodeficiency, is a rare condition that has only been studied in retrospective case series. General consensus was that GS has a worse prognosis than other humoral immunodeficiencies. In this study, physicians of GS patients completed two questionnaires with a two year interval with data on 47 patients, 499 patient years in total. Results on epidemiology, disease characteristics, and outcome are presented. Mean age at diagnosis was 60 years and median follow-up from onset of symptoms was 9 years. There was a high frequency of respiratory tract infections due to encapsulated bacteria. Median survival was 14 years. Survival was reduced compared to age-matched population controls (5-year survival: 82% versus 95%, p = 0.008). In this cohort survival was not associated with gender (HR 0.9, 95% CI 0.3-3.0), autoimmune diseases (HR 2.9, 95% CI 0.8-10.1) or immunosuppressive use (HR 0.3, 95% CI: 0.1-1.2). (C) 2016 The Authors. Published by Elsevier Inc.Peer reviewe

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients