Factors Contributing to the Prognosis after Second-line Therapy with Ramucirumab in Advanced Hepatocellular Carcinoma.

Objective Multiple therapeutic agents exist for advanced hepatocellular carcinoma (HCC), but prognostic factors in second-line and subsequent therapies are unclear. Ramucirumab is a molecular-targeted agent effective against hepatocytes with alpha-fetoprotein (AFP) >400 ng/mL after sorafenib failure. We examined the prognostic factors and efficacy of ramucirumab with prior therapy other than sorafenib. Methods In our retrospective multicenter study, 33 patients were treated with ramucirumab for HCC with prior therapy other than sorafenib, including 1 patient who received 2 lines of ramucirumab. We analyzed background factors, liver reserve, the prognosis, and treatment duration and efficacy. Results The median albumin-bilirubin (ALBI) value showed little change during ramucirumab treatment. The ALBI value improved in 32% of patients, and their prognoses were better than in those who did not improve. Response and efficacy rates were not as high as those in the REACH-2 study but were similar when limited to patients with 2,500 ng/mL AFP. Thirteen patients received further treatment after ramucirumab failure and they had a significantly better prognosis from ramucirumab administration and also had a significantly better prognosis from the start of the first tyrosine kinase inhibitor than who did not received further treatment. In univariate and multivariate analyses of prognostic factors, the continuation of treatment with another drug after ramucirumab failure and a good ALBI value at initiation were significant. The presence of a ramucirumab response and treatment duration were not associated with the prognosis. A good ALBI value at initiation and ALBI value improvement during treatment were also identified as independent factors associated with eligibility for further treatment after ramucirumab failure. The treatment line did not correlate with the availability of treatment with another drug after treatment failure. Conclusions ALBI value improvement with ramucirumab treatment allows for subsequent treatment after failure and an improved overall prognosis.

Condensation Behavior of Hierarchical Nano/Microstructured Surfaces Inspired by Euphorbia myrsinites.

In nature, many extant species exhibit functionalized surface structures during evolution. In particular, wettability affects the functionalization of the surface, and nano/microstructures have been found to enable functions, such as droplet jumping, thereby making self-cleaning, antifog, antibacterial, and antireflection surfaces. Important efforts are underway to understand the surface structure of plant leaves and establish rational design tools for the development of new engineering materials. In this study, we focused on the hierarchical nano/microstructure of the leaves of Euphorbia myrsinites (hereinafter, E. myrsinites), which has a hierarchical shape with microsized papillae, covered with nanosized protruding wax, and observed the condensation behavior on the leaf surface. Si is vertically etched via reactive ion etching (RIE) to artificially mimic the hierarchical nano/microstructures on the leaves of E. myrsinites. We made four types of artificial hierarchical structures, with micropillars having pillar diameters of 5.6 and 16 µm (pillar spacing of 20 and 40 µm, respectively) and heights of 6.5 and 19.5 µm, and nanopillars formed on the surface. The optical observation with a microscope revealed a very high density of condensed droplets on the artificial surface and a stable jumping behavior of droplets of 10 µm or more. Furthermore, in the samples with a micropillar diameter of 5.6 µm and a micropillar height of 19.5 µm, the droplets that had jumped and fallen thereupon bounced off, thereby preventing reattachment. As a result, no droplets of 35 µm or more could exist even after 10 min. In addition, it was clear that a small underlying droplet of less than 10 µm was generated at the bottom of the relatively large secondary droplet existing on the large micropillar of 16 µm, and a frequent coalescence of the droplets occurred. This study revealed the phenomenon of condensation on the surface of plants as well as made it possible to improve the heat exchange process by significantly promoting the heat transfer of condensation using artificial surfaces.

Dropwise Condensation on a Hierarchical Nanopillar Structured Surface.

Nanopillar structure processing has been performed on condensation surfaces to control wettability and achieve a high heat transfer coefficient via dropwise condensation and jumping droplets. Modified dry etching was performed using gold (Au) nanoparticles generated by annealing Au as a mask. High-aspect-ratio nanopillar processing was also performed to produce uniform pillar surfaces and novel hierarchical pillar surfaces. A uniform nanopillar surface with pillars having diameters of 20-850 nm and a hierarchical pillar surface with thick pillars having diameters ranging from 100 to 860 nm and thin pillars with diameters ranging from 20 to 40 nm were mixed and fabricated. Condensation experiments were performed using the noncoated nanopillar surfaces, and the condensation behaviors on the silicon (Si) surfaces were observed from above using a microscope and from the side using a high-speed camera. On the uniform surface US-3 and the hierarchical surfaces HS-1 and HS-2, droplet jumps were observed frequently in the droplet size range of 20-50 µm. In contrast, as the droplet size increased to 50 µm or more, the number of jumps observed decreased as the droplet size increased. The frequency of droplet jumps on the hierarchical surfaces from the start of condensation to approximately 2 min was higher than that on the uniform surfaces, although the density of droplet formation on the hierarchical surfaces was not relatively large. On the basis of the observation of droplet behavior from the side surface, we identified that the primary jump was due to the coalescence of droplets adhering to the surface and that the subsequent jump was caused by the droplet coalescence when the jump droplets were reattached. The primary jump occurrence rate was high on all pillar surfaces.

Evaluation of a recombinant measles virus expressing hepatitis C virus envelope proteins by infection of human PBL-NOD/Scid/Jak3null mouse.

In this study, we infected NOD/Scid/Jak3null mice engrafted human peripheral blood leukocytes (hu-PBL-NOJ) with measles virus Edmonston B strain (MV-Edm) expressing hepatitis C virus (HCV) envelope proteins (rMV-E1E2) to evaluate the immunogenicity as a vaccine candidate. Although human leukocytes could be isolated from the spleen of mock-infected mice during the 2-weeks experiment, the proportion of engrafted human leukocytes in mice infected with MV (10(3)-10(5)pfu) or rMV-E1E2 (10(4)pfu) was decreased. Viral infection of the splenocytes was confirmed by the development of cytopathic effects (CPEs) in co-cultures of splenocytes and B95a cells and verified using RT-PCR. Finally, human antibodies against MV were more frequently observed than E2-specific antibodies in serum from mice infected with a low dose of virus (MV, 10(0)-10(1)pfu, and rMV-E1E2, 10(1)-10(2)pfu). These results showed the possibility of hu-PBL-NOJ mice for the evaluation of the immunogenicity of viral proteins.

A study of the association between sleep habits and problematic behaviors in preschool children.

This preliminary study examined the association between sleep habits and problematic behaviors in healthy preschool children using an internationally standardized method. Two groups of 4-6-yr-old healthy Japanese children were recruited. Children in Group A (n=68) met one or more of the following three conditions: they went out from their home with adults after 21:00 h two or more times a week, they went to bed after 23:00 h four or more times a week, and they returned home after 21:00 h three or more times a week, while those in Group B (n=67) met none of these conditions. Sleep-wake logs and the Child Behavior Checklist (CBCL)/4-18 were completed daily for two weeks. The CBCL consists of questions with 113 items categorized into eight subscale items: (I) Withdrawn, (II) Somatic complaints, (III) Anxious/depressed, (IV) Social problems, (V) Thought problems, (VI) Attention problems, (VII) Delinquent behavior, and (VIII) Aggressive behavior. Internalizing (I+II+III), externalizing (VII+VIII), and total scale scores were also derived. Generally, the higher the score, the greater the likelihood of problematic behaviors in that scale. We compared both the CBCL scores and distribution of the CBCL score-determined clinical classification of behavior (normal, borderline, and abnormal) between the groups. Correlation coefficients between CBCL scores and each of the seven indices of the studied sleep habits (wake-up times, bedtimes, nocturnal sleep duration, nap duration, total sleep duration, and range of variation in wake-up and bedtime) were also assessed. Group A children showed significantly shorter average nocturnal sleep, nap, and total sleep duration, significantly later average bedtimes and wake-up times, and a significantly greater range of variation in bedtimes and wake-up times than Group B children. The CBCL score of the total scale was significantly higher in Group A than Group B children. The distribution of the clinical classifications of behavior between the two groups showed no significant differences. Although nocturnal sleep, nap, and total sleep duration did not correlate with total CBCL score, it showed a high positive correlation with wake-up times, bedtimes, and ranges of variation in both wake-up and bed times. The distribution of the clinical classification for the total scale showed significant differences between early and late risers, and also between regular and irregular sleepers. The number of children classified as normal for the total scale score was higher in early risers and regular sleepers than in late risers and irregular sleepers. Preschool children of Group A, late risers, late sleepers, irregular risers, and irregular sleepers were likely to show problematic behaviors.

Synthesis of 1,3-thiazine derivatives and their evaluation as potential antimycobacterial agents.

A series of eight 5,6-dihydro-4H-1,3-thiazine derivatives was synthesized by the BF3 x Et2O-catalyzed reaction of selected alpha,beta-unsaturated ketones with thiobenzamide at room temperature. The antimycobacterial activities of these compounds were determined against Mycobacterium tuberculosis H37Rv (ATCC 27294) using the Alamar blue susceptibility assay. Three compounds, 5-hydroxy-3-phenyl-4-aza-2-thiabicyclo[3.3.1]none-3-ene 3a, 4-hydroxy-4-methyl-6-pentyl-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3b, and 4-ethyl-4-hydroxy-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3c exhibited inhibitory activities of 97, 77 and 76%, respectively, at a concentration of 6.25 microg/ml. The actual MIC99 for the most active of these compounds, 3a, was also determined to be >6.25 microg/ml. These results, and especially those for 3a, suggest that 1,3-thiazines are potential lead compounds in the search for new antitubercular agents.