Rabbit VX2 Liver Tumor Model: A Review of Clinical, Biology, Histology, and Tumor Microenvironment Characteristics.

The rabbit VX2 is a large animal model of cancer used for decades by interventional radiologists to demonstrate the efficacy of various locoregional treatments against liver tumors. What do we know about this tumor in the new era of targeted therapy and immune-oncology? The present paper describes the current knowledge on the clinics, biology, histopathology, and tumor microenvironment of VX2 based on a literature review of 741 publications in the liver and in other organs. It reveals the resemblance with human cancer (anatomy, vascularity, angiogenic profile, drug sensitivity, immune microenvironment), the differences (etiology, growth rate, histology), and the questions still poorly explored (serum and tissue biomarkers, genomic alterations, immune checkpoint inhibitors efficacy).

Search for a Variation of the Fine Structure Constant around the Supermassive Black Hole in Our Galactic Center.

Searching for space-time variations of the constants of Nature is a promising way to search for new physics beyond general relativity and the standard model motivated by unification theories and models of dark matter and dark energy. We propose a new way to search for a variation of the fine-structure constant using measurements of late-type evolved giant stars from the S star cluster orbiting the supermassive black hole in our Galactic Center. A measurement of the difference between distinct absorption lines (with different sensitivity to the fine structure constant) from a star leads to a direct estimate of a variation of the fine structure constant between the star's location and Earth. Using spectroscopic measurements of five stars, we obtain a constraint on the relative variation of the fine structure constant below 10^{-5}. This is the first time a varying constant of nature is searched for around a black hole and in a high gravitational potential. This analysis shows new ways the monitoring of stars in the Galactic Center can be used to probe fundamental physics.

One-year follow-up of transgene expression by integrase-defective lentiviral vectors and their therapeutic potential in spinocerebellar ataxia model mice.

We examined integrase-defective lentiviral vectors (IDLVs) with a mutant (D64V) integrase in terms of their residual integration capability, the levels and duration of transgene expression and their therapeutic potential in comparison to wild-type lentiviral vectors (WTLVs) with a wild-type integrase gene. Compared with WTLVs, the IDLV-mediated proviral integration into host-cell chromosomes was approximately 1/3850 in HeLa cells and approximately 1/111 in mouse cerebellar neurons in vivo. At 2 months, transgene expression by IDLVs in the mouse cerebellum was comparable to that by WTLVs, but then significantly decreased. The mRNA levels at 6 and 12 months after injection in IDLV-infected cerebella were approximately 26% and 5%, respectively, of the mRNA levels in WTLV-injected cerebella. To examine the therapeutic potential, IDLVs or WTLVs expressing a molecule that enhances the ubiquitin-proteasome pathway were injected into the cerebella of spinocerebellar ataxia type 3 model mice (SCA3 mice). IDLV-injected SCA3 mice showed a significantly improved rotarod performance even at 1 year after-injection. Immunohistochemistry at 1 year after injection showed a drastic reduction of mutant aggregates in Purkinje cellsfrom IDLV-injected, as well as WTLV-injected, SCA3 mice. Our results suggest that because of the substantially reduced risk of insertional mutagenesis, IDLVs are safer and potentially effective as gene therapy vectors.

Intra-articular fate of degradable poly(ethyleneglycol)-hydrogel microspheres as carriers for sustained drug delivery.

A novel degradable microsphere (MS) for intra-articular drug delivery, composed of a polyethylene glycol (PEG) core containing degradable regions made of short poly-(lactic-co-glycolic acid) (PLGA) sequences - named PEG-hydrogel MS - was injected into the cavity of sheep shoulder joint, and compared to non-degradable MS devoid of hydrolysable crosslinker in terms of location, degradation and inflammation. One week after intra-articular injection both groups of MS were localized beneath the synovial lining of the synovial fringes located at bottom of the shoulder joint, while a fraction of particles remained in synovial fluid. Histological analyses made one and 4 weeks after intra-articular injection showed cell proliferation around the non-degradable MS entrapped within the synovium. By contrast, degradable PEG-hydrogel MS were surrounded by few cells. The degradation of degradable PEG-hydrogel MS within the synovium was slow and was not fully complete after four weeks. Our findings indicate that the tissue entrapment of MS below the synovial lining was independent of the material degradability, while degradable PEG-hydrogel MS are less inflammatory than the non-degradable one. Degradable PEG-hydrogel MS offer several advantages over the non-degradable MS as carriers for a sustained drug delivery in synovial tissue according to the low intensity of inflammatory reaction triggered in synovium.

Influence of degradation on inflammatory profile of polyphosphazene coated PMMA and trisacryl gelatin microspheres in a sheep uterine artery embolization model.

Embolization with microspheres is widely applied to treat uterine fibroids. However, the foreign body reaction that could result from the degradation of the microspheres remains to be evaluated to adequately appreciate the tissular tolerance to such biomaterials. We compared herein the in situ degradation of PMMA microspheres coated with polyphosphazene (PMMA-PPms) and trisacryl gelatin microspheres (TGms) and we thoroughly investigated the induced local inflammatory responses, at 1 and 4 weeks after uterine artery embolization in sheep, by using immunohistochemistry and microarray analyses. PMMA-PPms underwent an acute and partial degradation that was associated with the early recruitment of phagocytic cells (CD172a+ and MHCII+), and with the up-regulated expression of genes involved in the movement of phagocytes (ALOX5AP, CXCL2, CXCL5, IL8, PTGS2, YARS). By contrast, TGms were not degraded and triggered a different inflammation profile including the recruitment of FBR Giant Cells and T-lymphocytes (CD4+) and the increased expression of genes involved in lymphocyte activation (CXCL10, IL2RG, IRAK4, MALT1). Our results indicate that, in contrast to a non-degradable microsphere such as TGms which is associated to a poorly inflammatory foreign body reaction that rapidly resolves, PMMA-PPms, which is partially degradable, rapidly recruits and activates inflammatory phagocytes, thus delaying the resolution of the foreign body reaction.

Gram stain index of a natural bacterial community at a nutrient gradient in the freshwater environment.

Species succession of a natural bacterial community was indicated by the Gram stain index (GSI) using an experimental nutrient gradient in an oligotrophic pond created with an in situ gradostat. Various trophic conditions, ranging from eutrophic to mesotrophic, were formed experimentally with continuous inflow of sterile peptone solution in the gradostat, while the water mass outside the gradostat was oligotrophic. The GSI spectra of the natural bacterial populations show different profiles in accordance with the trophic level of the ambient water and the time progression of adaptation to different levels of eutrophication. Therefore, GSI can be used as a potential indicator of organic pollution in aquatic environments.

Photometric application of the Gram stain method to characterize natural bacterial populations in aquatic environments.

The Gram stain method was applied to the photometric characterization of aquatic bacterial populations with a charge-coupled device camera and an image analyzer. Escherichia coli and Bacillus subtilis were used as standards of typical gram-negative and gram-positive bacteria, respectively. A mounting agent to obtain clear images of Gram-stained bacteria on Nuclepore membrane filters was developed. The bacterial stainability by the Gram stain was indicated by the Gram stain index (GSI), which was applicable not only to the dichotomous classification of bacteria but also to the characterization of cell wall structure. The GSI spectra of natural bacterial populations in water with various levels of eutrophication showed a distinct profile, suggesting possible staining specificity that indicates the presence of a particular bacterial population in the aquatic environment.

In situ gradostat for the study of a natural phytoplankton community with an experimental nutrient gradient.

A new in situ gradostat was devised to study the dynamics of natural communities having nutrient gradients within aquatic habitats. This semi-enclosed mesocosm consisted of three components: i.e. three transparent, concentric cylindrical culture chambers, with diameters of 70, 60 and 40 cm, and 20 cm deep, supported by four flotation buoys, a medium reservoir, and a pump to supply the medium to the mesocosm. Water exchange between compartments was achieved via holes in the cylindrical walls, the number and size of the holes being chosen to regulate the rate of exchange. Sterile culture medium was pumped into the central (first) chamber and diffused outwards into the second and third chambers through the perforated walls. Suitable perforations could achieve a concentration gradient of up to 9.5 times between the first and third chambers within 12 h. The system was designed with the following characteristics: (1) an experimental semi-enclosed system in the natural environment; (2) to maintain equivalence with the external water except for the experimental factors; and (3) to form a manipulable gradient of experimental factors across the mesocosm. Using the in situ gradostat, the response of a natural phytoplankton community to a nitrate gradient was determined. A gradient from oligotrophic to eutrophic was maintained for 10 days in an oligotrophic pond. The mean growth rate of phytoplankton was lower in the eutrophic zone than that in the mesotrophic zone, where the highest mean growth rate was observed. The growth rate of each dominant phytoplankter showed its own pattern, but all rates were highest in the mesotrophic environment of the second chamber.

Acoustic changes in voice after tonsillectomy.

UNLABELLED: The vocal tract from the glottis to the lips is considered to he a resonator and the voice is changeable depending upon the shape of the vocal tract. In this report, we examined the change in pharyngeal size and acoustic feature of voice after tonsillectomy. METHODS: Subjects were 20 patients. The distance between both anterior pillars (glossopalatine arches), and between both posterior pillars (pharyngopalatine arches) was measured weekly. For acoustic measurements, the five Japanese vowels and Japanese conversational sentences were recorded and analyzed. RESULTS: The distance between both anterior pillars became wider 2 weeks postoperatively, and tended to become narrower thereafter. The distance between both posterior pillars became wider even after 4 weeks postoperatively. No consistent changes in F0, F1 and F2 were found after surgery. Although there was a tendency for a decrease in F3, tonsillectomy did not appear to change the acoustical features of the Japanese vowels remarkably. It was assumed that the subject may adjust the shape of the vocal tract to produce consistent speech sounds after the surgery using auditory feedback.

Acarboxy prothrombin (PIVKA II) as a tumour marker for hepatocellular carcinoma and other liver diseases.

The clinical usefulness of plasma abnormal prothrombin, defined as protein induced by vitamin K absence or antagonist II: (PIVKA II) as a tumour marker for hepatocellular carcinoma (HCC) and other liver diseases has been evaluated. PIVKA II concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) with monoclonal antibody that reacts with PIVKA II but does not cross-react with normal prothrombin. Seventy four patients (74%) out of 100 with HCC had abnormal PIVKA II levels above 0.5 AU/ml (median = 3.4 AU/ml). The level was above 1.0 AU/ml in 66 (66%) of the patients. In contrast the level of PIVKA II was low in patients with bilharzial periportal fibrosis (median = 0.09 AU/ml), patients with liver cirrhosis (median = 0.13 AU/ml), patients with hepatitis (median = 0.025 AU/ml), and essentially undetectable in all the 34 controls. The diagnostic ability of serum alphafoetoprotein (AFP) was also evaluated in these patients. AFP alone can diagnose 51% of the HCC cases. Of the remaining patients with low or negative AFP levels (65%) can be diagnosed using PIVKA II. Abnormal prothrombin is a potential marker for the laboratory diagnosis of hepatocellular carcinoma.

[A study of voice mutation and physical growth--a longitudinal observation].

Past studies on the relationship between mutational voice change and body growth were generally made on grouped subjects and no exact longitudinal observation was performed. In the present report, a longitudinal study was made on 100 young male students in their puberty, in which voice recordings and measurements of physical parameters including body height and weight were performed twice for each subject with yearly interval. Information on subjective evaluation of voice abnormality was also obtained from each subject. The recorded voice samples were subjected to subsequent analysis for obtaining fundamental frequency (F0) and formant values. The following results were obtained. 1. A negative correlation in the rate of change was observed between F0 and physical parameters such as body height and weight, and sitting height. 2. It was suggested that the mutational period consisted of the rapid and slow phases. The rate of growth in body height and sitting height was more significant in the rapid phase. 3. Subjective voice abnormality and physical growths such as the development of the laryngeal prominence were often noted even before the rapid phase. After the rapid phase was over, all the cases showed secondary sexual characteristics including the laryngeal prominence. 4. Before and during the rapid phase, there was a tendency for the values of F1 and F2 to increase, while that of F3 to decrease. After the rapid phases was over, there was a trend that F1 and F2 increased, while F3 remained unchanged.