Human resources are an important factor in establishing universal health coverage (UHC). We examined Japan's health policies related to development of human resources for health (HRH) toward establishing UHC, and tried to formulate a model for other countries wanting to introduce UHC through reviewing existing data and documents related to Japan’s history in developing HRH. In the results, there were four phases of HRH development in Japan: Phase 1 involved a shortage of HRH; Phase 2 was characterized by rapid production of less-educated HRH; Phase 3 involved introduction of quality improvement procedures such as upgrade education for nursing staff or licensing examination for physicians; Phase 4 was characterized by a predominance of formal health professionals. To encourage transition between these phrases, Japan utilized several procedures, including: (i) offering shorter professional education, (ii) fewer admission requirements for professional education, (iii) widespread location of schools, and (iv) the aforementioned quality improvement procedures. Japan was able to introduce UHC during Phase 3, and Japanese health indicators have improved gradually through these phases. Consequently, the government of Japan focused on increasing the quantity of HRH through relaxed admission requirements, shorter education periods, and increasing the numbers of educational facilities, before introducing UHC. Subsequently, the government began focusing on improving quality through procedures such as upgrade education or licensing examination programs to enable less-educated HRH to become fully educated professionals. For governments wanting to introduce UHC, the Japanese model can be a suitable option for HRH development, particularly in resource-poor countries.

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Associating liver partition and portal vein ligation (ALPPS) is introduced as a modified two-staged hepatectomy for advanced liver malignancies, which requires extended hepatectomy with very small future remnant liver volume. It is characterized by rapid and large growth of future remnant liver and potential of widening the indication of curative resection with extended major hepatectomy for liver malignancies. It showed, however, much higher morbidity and mortality than extended hepatectomy after portal vein embolization. Here, we review the literatures and examine the role of ALPPS in Japan, where zero mortality after hepatectomy is highly expected.

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This article was retracted.

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Transarterial chemoembolization (TACE) is one of the standard locoregional treatments for intermediate stage hepatocellular carcinoma (HCC). Transarterial radioembolization (TARE) using β-emitting yttrium-90 (90Y) integral to the glass matrix of the microspheres has been developed as an alternative to TACE in recent years. Thus, we conducted a meta analysis to evaluate the safety and efficacy of TARE versus TACE for unresectable HCC. We searched PubMed, EMBASE, Web of science and the Cochrane Library for clinical trials comparing TARE with TACE for unresectable HCC. Response rate, overall survival (OS), time to progression (TTP), hospitalization time days and clinical complications were analyzed and compared. Eight studies published from 2009 to 2014, with a total of 1,499 patients, were included in this meta-analysis. The pooled results showed that TARE (90Y) is significantly better in OS (HR = 0.74; 95% CI: 0.61-0.90), 3-year OS rates (RR = 1.75; 95% CI = 1.01-3.03, p = 0.05), TTP (HR = 0.61; 95% CI: 0.41-0.89), hospitalization time days (mean difference = −2.66; 95% CI: −4.08 - −1.24) and some complications (abdominal pain [RR = 0.30, 95% CI: 0.11-0.83, p = 0.02]) for patients with HCC, but did not affect tumor response (CR [RR = 1.06; 95% CI = 0.51-2.22], PR [RR = 1.24; 95% CI = 0.79-1.94], SD [RR = 1.13; 95% CI = 0.92-1.39], PD[RR = 0.75; 95% CI = 0.37-1.51], over-all tumor control [RR = 1.16; 95 % CI = 0.94-1.44]). The current meta-analysis suggests that TARE (Y90) is significantly better in OS, 3-year OS rates, TTP, hospitalization time days and some complications for patients with HCC.

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P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. In the present study, we constructed a recombinant adenovirus vector of p311 (called Ad-P311) and transferred it into rat renal proximal tubular epithelial cells (NRK-52E) to explore the effect of P311 on epithelial-mesenchymal transition (EMT) of NRK-52E cells induced by TGF-β1 and to elucidate its underlying mechanism against EMT. After successfully construction of Ad-P311 and transfer into NRK-52E cells, the proliferation and growth of P311-expressing cells was detected by MTT assay. TGF-β1 was used to induce NRK-52E cells and Western blot analysis was used to examine the EMT markers (E-cadherin and α-smooth muscle actin (α-SMA)), signal transducers (p-Smad2/3 and Smad7). Integrin Linked Kinase (ILK) as a key intracellular mediator that controls TGF-β1-induced-EMT was also assayed by Western blot analysis. The results showed that P311 transfection could significantly inhibit the proliferation and growth of TGF-β1 induced NRK-52E cells. The results also showed that TGF-β1 could induce EMT in NRK-52E cells through Smad-ILK signaling pathway with an increase in α-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression. However, P311 efficiently blocked Smad-ILK pathway activation and attenuated all these EMT changes induced by TGF-β1. These findings suggest that P311 might be involved in the pathogenesis of renal fibrosis by inhibiting the EMT process via TGF-β1-Smad-ILK pathway. P311 might be a novel target for the control of renal fibrosis and the progression of CKD.

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Several studies have reported that dehydroepiandrosterone (DHEA) promotes osteoblast proliferation and inhibits osteoblast apoptosis and that DHEA inhibits osteoclast maturation. However, whether DHEA regulates osteoblast differentiation remains unclear. The present study first examined the effect of DHEA on bone morphology in vivo. DHEA was found to increase bone volume (BV), bone mineral density (BMD), and the number of trabeculae in bone (Th.N) and it was found to decrease trabecular spacing in bone (Th.sp) in ovariectomized (OVX) mice. Next, the effect of DHEA on osteoblast differentiation was examined in vitro and osteoblastogenesis-related marker genes, such as Runx2, Osterix, Collagen1, and Osteocalcin, were also detected. DHEA increased osteoblast production in mesenchymal stem cells (MSCs) cultured in osteoblastogenic medium, and DHEA increased the expression of Runx2 and osterix, thereby increasing the expression of osteocalcin and collagen1. Immune cells and bone interact, so changes in immune cells were detected in vivo. DHEA increased the number of Foxp3⁺ regulatory T cells (Tregs) in the spleen but it did not affect CTLA-4 or IL-10. When MSCs were treated with DHEA in the presence of Tregs, alkaline phosphatase (ALP) activity increased. Osteoblasts and adipocytes are both generated by MSCs. If osteoblast differentiation increases, adipocyte differentiation will decrease, and the reverse also holds true. DHEA was found to increase the number of adipocytes in osteoblastogenic medium but it had no effect on the number of adipocytes and expression of PPARγ mRNA in adipogenic medium. This finding suggests that osteoblasts may be involved in adipocyte production. In conclusion, the current results suggest that DHEA can improve postmenopausal osteoporosis (PMO) by up-regulating osteoblast differentiation via the up-regulation of the expression of osteoblastogenesis-related genes and via an increase in Foxp3⁺ Tregs.

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Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a naturally-occurring triterpenoid with various promising pharmacological properties. The present study was conducted to determine the protective effects of OA against oxidized low-density lipoprotein (ox-LDL) induced endothelial cell apoptosis and the possible underlying mechanisms. Our results showed that ox-LDL significantly decreased cell viability and induced apoptosis in human umbilical vein endothelial cells (HUVECs). OA in the co-treatment showed a protective effect against ox-LDL induced loss in cell viability and an increase in apoptosis, which was associated with the modulating effect of OA on ox-LDL induced hypoxia-inducible factor 1α(HIF-1α) expression. Moreover, our results showed that the modulating effect of OA against ox-LDL induced HIF-1α expression was obtained via inhibition of lipoprotein receptor 1 (LOX-1)/reactive oxygen species (ROS) signaling. Collectively, we suggested that the protective effect of OA against ox-LDL induced HUVEC apoptosis might, at least in part, be obtained via inhibition of the LOX-1/ROS/HIF-1α signaling pathway.

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Increasing evidence supports that cancer stem cells (CSCs) are responsible for driving tumor initiation and maintenance. Zinc-finger E-box binding homeobox 1 (ZEB1) is a transcription factor for regulating tumor progression, and contributes to maintenance of CSC-like properties. The goal of the present study is to investigate the effect of decreasing ZEB1 expression on the B16F10 CSC-like properties. The recombinant shRNA targeting ZEB1 were transfected into melanoma B16F10 cells, and shZEB1-CD133⁺CD44⁺ CSCs were isolated from the stable transfected cells using the magnetic-associated cell sorting method. The shZEB1-CD133⁺CD44⁺ CSC-like properties were systematically analyzed. The results show the B16F10 shZEB1-CD133⁺CD44⁺ CSCs significantly decreased the ability of clonogenicity, cellular proliferation, migration, and invasion. Importantly, tumorigenicity and tumor lung metastasis was significantly inhibited in B16F10 shZEB1-CD133⁺CD44⁺ CSCs compared with B16F10 scramble-CD133⁺CD44⁺ CSCs. The decrease of ZEB1 expression markedly resulted in down-regulation of vimentin and N-cadherin expression as well as up-regulation of E-cadherin expression in tumor tissues from the mice injected with B16F10 shZEB1-CD44⁺CD133⁺ CSCs. These findings contribute to understanding the maintenance of B16F10 CD133⁺CD44⁺ CSC-like properties that was closely associated with ZEB1 expression. ZEB1 may serve as a new therapeutic target for treatment of malignant melanoma.

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Although the initiation of antiretroviral therapy (ART) has promoted the reconstitution of CD4+ T-cell count in the HIV infected population, not all patients can achieve the normalization of their immunologic functions. We analysed the variables associated with immunologic recovery, which is commonly regarded as the increase of CD4 to 350 cell/μL after a year of ART. We collected data from 3,485 patients attending a university-based HIV clinic from June 2005 to July 2014 in Shanghai, China. Logistic regression test was performed to analyse the risk factors for suboptimal CD4+ recovery following yearlong ART. The CD4+ T-cell of 723 participants (41.5% of the 1744 subjects) showed more than 350 cell/μL after one year of ART. Compared with baseline CD4 > 350 cell/μL, patients with baseline CD4 ≤ 200 cell/μL or 200 < CD4 ≤ 350 cell/μL were 42.6, 4.5 times more likely to be incomplete CD4 recovery, respectively. The risk of suboptimal immunologic recovery among patients with regimen including AZT or d4T were 2.1, 2.4 times higher compared with TDF, respectively. In our study, between optimal CD4 recovery group and suboptimal recovery group, there were no significant differences in age, gender, marital status, transmission routes, WHO stage, and CD4 recovery rates. As for the dynamic CD4 change, we found the CD4 recovery rates were 49.9% and 61.8% in the second and third year of ART, respectively. Patients who had a low level of CD4+ T-cell count (< 200 cell/μL) during the initiation of ART exhibited more difficulties recovering to a normal level. Furthermore, the regimen, including AZT or d4T, was not beneficial to CD4 recovery. So, more efforts should be made to guarantee the early diagnosis and timely treatment for HIV/AIDS patients, and simultaneously optimize antiretroviral therapy.

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Fms-like tyrosine kinase 3 (Flt-3) is a cytokine receptor expressed on the surface of bone-marrow progenitor of hematopoietic cells. Flt-3 ligands are produced by peripheral blood mononuclear cells, and found in various human body fluids. Flt-3 signal is involved in the regulation of vessel formation as well as B cell differentiation, suggesting that Flt-3 signal contributes to the pathogenesis of vascular abnormalities and immune dysregulation in rheumatic diseases. The aim of the present study is to examine serum Flt-3 ligand levels in patients with various rheumatic diseases, and to evaluate the possibility that serum Flt-3 ligand levels can be a useful disease marker. Sera were obtained from 20 dermatomyositis (DM) patients, 36 systemic sclerosis (SSc) patients, 10 systemic lupus erythematosus (SLE) patients, 10 scleroderma spectrum disorder (SSD) patients, 4 mixed connective tissue disease (MCTD) patients, and 12 normal subjects. Flt-3 ligand levels were determined with ELISA. Serum Flt-3 ligand levels were significantly elevated in patients with DM, SSc, SSD and MCTD compared to those in normal subjects. DM patients with elevated Flt-3 ligand levels were accompanied with significantly increased CRP levels and increased frequency of heliotrope rash than those with normal levels. In addition, SSc patients with elevated Flt-3 ligand levels showed significantly reduced frequency of nailfold bleeding. Serum Flt-3 ligand levels can be a marker of cutaneous manifestation in DM and a marker of microangiopathy in SSc. Clarifying the role of Flt-3 ligand in rheumatic diseases may lead to further understanding of these diseases and new therapeutic approaches.

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