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A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of ∼100 nm have been widely used to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles (with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-β inhibitor to increase the permeability of the tumours. Drug-loaded polymeric micelles with a diameter of 30 nm can penetrate poorly permeable tumours to achieve an antitumour effect.

Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-β (TGF-β) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-β repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-β, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-β negatively contributes to maintain the CICs within the cancer.

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (−6.2% and −5.4%, respectively) and women (−5.7% and −4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

Background: Several human cancers have been found to contain cancer stem-like cells (CSCs) having cancer-initiating ability. However, only a few reports have shown the existence of CSCs in bone and soft tissue sarcomas. In this study, we identified and characterised side population (SP) cells that showed drug-resistant features in human bone sarcoma cell lines. Methods: In seven osteosarcoma cell lines (OS2000, KIKU, NY, Huo9, HOS, U2OS and Saos2) and in one bone malignant fibrous histiocytoma (MFH) cell line (MFH2003), the frequency of SP cells was analysed. Tumourigenicity of SP cells was assessed in vitro and in vivo . Gene profiles of SP cells and other populations (main population; MP) of cells were characterised using cDNA microarrays. Results: SP cells were found in NY (0.31%) and MFH2003 (5.28%). SP cells of MFH2003 formed spherical colonies and re-populated into SP and MP cells. In an NOD/SCID mice xenograft model, 1 × 10 3 sorted SP cell-induced tumourigenesis. cDNA microarray analysis showed that 23 genes were upregulated in SP cells. Conclusions: We showed that SP cells existed in bone sarcoma cell lines. SP cells of MFH2003 had cancer-initiating ability in vitro and in vivo . The gene profiles of SP cells could serve as candidate markers for CSCs in bone sarcomas.

The objective is to evaluate the efficacy of anthocyanin-rich purple-fleshed sweet potato (PSP) beverage on the serum levels of gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in healthy Caucasians with borderline hepatitis. Forty healthy Caucasians (41–69 years) consumed three bottles of the PSP beverage (177 mg anthocyanins per 125-ml bottle) or placebo (1.3 mg) per day for 8 weeks. Thirty-nine subjects completed the study and two subjects were excluded from statistical analysis. GGT levels in the PSP group on days 15 and 43 were lower ( P =0.077 and 0.038, respectively), AST levels in the PSP group on days 29 and 43 were lower ( P =0.010 and 0.045, respectively) and ALT level in the PSP group on day 43 was lower ( P =0.037) than in the placebo group. The PSP beverage did not induce clinically relevant changes in other blood and clinical chemistry parameters.

This paper first uses a low-speed stereoscopic particle image velocimetry (SPIV) system to measure the convergent statistical quantities of the flow field and then simultaneously measure the time-resolved flow field and the wall mass transfer rate by a high-speed SPIV system and an electrochemical system, respectively. We measure the flow field and wall mass transfer rate under upstream pipe Reynolds numbers between 25 000 and 55 000 at three specific locations behind the orifice plate. Moreover, we apply proper orthogonal decomposition (POD), stochastic estimation and spectral analysis to study the properties of the flow field and the wall mass transfer rate. More importantly, we investigate the large-scale coherent structures’ effects on the wall mass transfer rate. The collapse of the wall mass transfer rates’ spectra by the corresponding time scales at the three specific positions of orifice flow suggest that the physics of low-frequency wall mass transfer rates are probably the same, although the flow fields away from the wall are quite different. Furthermore, the spectra of the velocity reconstructed by the most energetic eigenmodes agree well with the wall mass transfer rate in the low-frequency region, suggesting that the first several energetic eigenmodes capture the flow dynamics relevant to the low-frequency variation of the wall mass transfer. Stochastic estimation results of the velocity field associated with large wall mass transfer rate at all three specific locations further reveal that the most energetic coherent structures are correlated with the wall mass transfer rate.

The ability of the cerebellar cortex to learn from experience ensures the accuracy of movements and reflex adaptation, processes which require long-term plasticity at granule cell (GC) to Purkinje neuron (PN) excitatory synapses. PNs also receive GABAergic inhibitory inputs via GCs activation of interneurons; despite the involvement of inhibition in motor learning, its role in long-term plasticity is poorly characterized. Here we reveal a functional coupling between ionotropic GABA A receptors and low threshold Ca V 3 calcium channels in PNs that sustains calcium influx and promotes long-term potentiation (LTP) at GC to PN synapses. High frequency stimulation induces LTP at GC to PN synapses and Ca V 3-mediated calcium influx provided that inhibition is intact; LTP is mGluR1, intracellular calcium store and Ca V 3 dependent. LTP is impaired in Ca V 3.1 knockout mice but it is nevertheless recovered by strengthening inhibitory transmission onto PNs; promoting a stronger hyperpolarization via GABA A receptor activation leads to an enhanced availability of an alternative Purkinje-expressed Ca V 3 isoform compensating for the lack of Ca V 3.1 and restoring LTP. Accordingly, a stronger hyperpolarization also restores Ca V 3-mediated calcium influx in PNs from Ca V 3.1 knockout mice. We conclude that by favoring Ca V 3 channels availability inhibition promotes LTP at cerebellar excitatory synapses.

Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2. Bleomycin (BLM) is an anticancer agent that introduces DNA breaks. The authors reported that Ad-FIR involved in the BLM-induced DNA damage repair response and thus applicable for other DNA damaging agents. To examine the effect of Ad-FIR on DNA damage repair, BLM, X-ray and carbon-ion irradiation were used as DNA damaging agents. The biological effects of high linear energy transfer (LET) radiotherapy used with carbon-ion irradiation are more expansive than low-LET conventional radiotherapy, such as X-rays or γ rays. High LET radiotherapy is suitable for the local control of tumors because of its high relative biological effectiveness. Ad-FIR enhanced BLM-induced DNA damage indicated by γH2AX in vitro . BLM treatment increased endogenous nuclear FIR expression in TE-2 cells, and P27Kip1 expression was suppressed by TP53 siRNA and BLM treatment. Further, Ad-FIRΔexon2, a dominant-negative form of FIR that lacks exon2 transcriptional repression domain, decreased Ku86 expression. The combination of Ad-FIR and BLM in TP53 siRNA increased DNA damage. Additionally, Ad-FIR showed synergistic cell toxicity with X-ray in vitro and significantly increased the antitumor efficacy of carbon-ion irradiation in the xenograft mouse model of TE-2 cells ( P =0.03, Mann–Whitney’s U- test) and was synergistic with the sensitization enhancement ratio (SER) value of 1.15. Therefore, Ad-FIR increased the cell-killing activity of the carbon-ion beam that avoids late-phase severe adverse effects independently of the TP53 status in vitro . Our findings indicated the feasibility of the combination of Ad-FIR with DNA damaging agents for future esophageal cancer treatment.

This paper presents a unique tribological system that is able to produce no measurable wear of material combination and that reduces friction markedly in the ultralow regime under boundary lubrication. Ultralow friction (0.03) was obtained by sliding hydrogen-free Diamond-Like-Carbon ta-C against ta-C lubricated with Poly-alpha Olefin base oil containing Glycerol Mono-Oleate (GMO) additive. The origin of ultralow friction in these conditions has been investigated by surface analysis techniques. Results are in agreement with the formation of a OH-terminated carbon surface. This new surface chemistry might be formed by the tribochemical reaction of alcohol function groups with the friction-activated ta-C atoms. The origin of low friction could be due to the very low-energy interaction between OH-terminated surfaces.

Determining the gene that plays a key role in brain–gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[15-O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg  to 40 mm Hg  than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg  compared with 0 mm Hg  was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.