Efficacy of avelumab plus axitinib versus sunitinib by numbers of IMDC risk factors and target tumor sites at baseline in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline. METHODS: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed. RESULTS: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage. CONCLUSIONS: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites.

Relationship between the combination of polyunsaturated fatty acids intake and psychological distress during pregnancy: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

No studies have examined the association of the combination of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs intake with psychological distress during pregnancy. To examine these associations, we divided Japanese pregnant women into 25 groups based on combining quintiles of n-3 PUFAs intake and quintiles of n-6 PUFAs intake. We conducted multivariable logistic regression analyses to assess the risk of psychological distress during pregnancy (Kessler Psychological Distress Scale ≥ 5 or 13). Compared to the third quintile of both n-3 PUFAs and n-6 PUFAs intake, the groups with unbalanced intake, high intake of both, and low intake of both were associated with a higher risk of both Kessler Psychological Distress Scale ≥ 5 and 13 in early and mid-pregnancy. Further research is needed to identify the precise combination of n-3 PUFAs and n-6 PUFAs intake associated with the lowest psychological distress during pregnancy.

Gastrectomy with or without omentectomy for cT3-4 gastric cancer: a multicentre cohort study.

BACKGROUND: Omentectomy is performed widely for locally advanced gastric cancer to prevent disease recurrence. However, its clinical benefit is unknown. METHODS: This retrospective cohort study compared the outcome of gastrectomy with preservation of the omentum (GPO) and gastrectomy with resection of the omentum (GRO) among patients with cT3-T4 gastric cancer who underwent gastrectomy between 2006 and 2012 in one of five participating institutions. A consensus conference identified 28 variables potentially associated with outcome after gastrectomy for the estimation of propensity scores, and propensity score matching (PSM) was undertaken to control for possible confounders. Postoperative surgical outcomes, overall survival and disease recurrence were compared between GPO and GRO. RESULTS: A total of 1758 patients were identified, of whom 526 remained after PSM, 263 in each group. Median follow-up was 4·9 (i.q.r. 3·1-5·9) years in the GRO group and 5·0 (2·5-6·8) years in the GPO group. The incidence of postoperative complications of Clavien-Dindo grade III or more was significantly higher in the GRO group (17·5 versus 10·3 per cent; P = 0·016). Five-year overall survival rates were 77·1 per cent in the GRO group and 79·4 per cent in the GPO group (P = 0·749). There were no significant differences in recurrence rate or pattern of recurrence between the groups. CONCLUSION: Overall survival and disease recurrence were comparable in patients with cT3-4 gastric cancer who underwent GPO or GRO.

ANTECEDENTES: La omentectomía se realiza ampliamente en el cáncer gástrico localmente avanzado para prevenir la recidiva de la enfermedad. Sin embargo, se desconoce su beneficio clínico. MÉTODOS: Este estudio retrospectivo comparó el resultado de la gastrectomía con preservación del omento (gastrectomy with preservation of the omentum, GPO) con la gastrectomía con resección del omento (gastrectomy with resection of the omentum, GRO) para el cáncer gástrico con estadio clínico T3/T4. Se incluyeron pacientes sometidos a gastrectomía por cáncer gástrico clínico T3/T4 (2006-2012) y se recogieron datos relevantes de 5 hospitales participantes. A través de una conferencia de consenso se identificaron 28 variables potencialmente asociadas con el resultado tras la gastrectomía, mediante las cuales se estimaron las puntuaciones de propensión, utilizándose el emparejamiento por puntuación de propensión (propensity score matching, PSM) para el control de posibles factores de confusión. Los resultados quirúrgicos postoperatorios, la supervivencia global y la recidiva de la enfermedad se compararon entre las gastrectomías con GPO y GRO. RESULTADOS: En total, se identificaron 1.758 pacientes, seleccionándose 526 (263 GRO y 263 GPO) tras el PSM. La mediana (rango intercuartílico) de seguimiento fue de 4,9 años (3,1-5,9) en el grupo GRO y de 5,0 años (2,5-6,8) en el grupo GPO. La incidencia de complicaciones postoperatorias de Clavien-Dindo grado III o más alto fue significativamente más elevada en el grupo GRO que en el grupo GPO (17,1% versus 9,1%; P = 0,010). La supervivencia global a los 5 años fue del 77,1% para el grupo GRO y del 79,4% para el grupo GPO (P = 0,749). No hubo diferencias estadísticamente significativas en la tasa de recidiva o patrón de recidiva entre ambos grupos. CONCLUSIÓN: La supervivencia global y la recidiva de la enfermedad son comparables en pacientes con cáncer gástrico estadio clínico T3-4 sometidos a GPO o GRO.

Thermo-, photo-, and mechano-responsive liquid crystal networks enable tunable photonic crystals.

Tunable photonic crystals exhibiting optical properties that respond reversibly to external stimuli have been developed using liquid crystal networks (LCNs) and liquid crystal elastomers (LCEs). These tunable photonic crystals possess an inverse opal structure and are photo-responsive, but circumvent the usual requirement to contain dye molecules in the structure that often limit their applicability and cause optical degradation. Herein, we report tunable photonic crystal films that reversibly tune the reflection peak wavelength under thermo-, photo- and mechano-stimuli, through bilayering a stimuli-responsive LCN including azobenzene units with a colourless inverse opal film composed of non-responsive, flexible durable polymers. By mechanically deforming the azobenzene containing LCN via various stimuli, the reflection peak wavelength from the bilayered film assembly could be shifted on demand. We confirm that the reflection peak shift occurs due to the deformation of the stimuli-responsive layer propagating towards and into the inverse opal layer to change its shape in response, and this shift behaviour is repeatable without optical degradation.

Antibacterial polyetheretherketone implants immobilized with silver ions based on chelate-bonding ability of inositol phosphate: processing, material characterization, cytotoxicity, and antibacterial properties.

We developed a novel antibacterial implant by forming a hydroxyapatite (HAp) film on polyetheretherketone (PEEK) substrate, and then immobilizing silver ions (Ag(+) ) on the HAp film based on the chelate-bonding ability of inositol phosphate (IP6). First, the PEEK surface was modified by immersion into concentrated sulfuric acid for 10 min. HAp film was formed on the acid-treated PEEK via the soft-solution process using simulated body fluid (SBF), urea, and urease. After HAp coating, specimens were immersed into IP6 solution, and followed by immersion into silver nitrite solution at concentrations of 0, 0.5, 1, 5 or 10 mM. Ag(+) ions were immobilized on the resulting HAp film due to the chelate-bonding ability of IP6. On cell-culture tests under indirect conditions by Transwell, MC3T3-E1 cells on the specimens derived from the 0.5 and 1 mM Ag(+) solutions showed high relative growth when compared with controls. Furthermore, on evaluation of antibacterial activity in halo test, elution of Ag(+) ions from Ag(+) -immobilized HAp film inhibited bacterial growth. Therefore, the above-mentioned results demonstrated that specimens had both biocompatibility and strong antibacterial activity. The present coating therefore provides bone bonding ability to the implant surface and prevents the formation of biofilms in the early postoperative period.

Zinc-substituted hydroxyapatite: a biomaterial with enhanced bioactivity and antibacterial properties.

Hydroxyapatite (HA) is a synthetic biomaterial and has been found to promote new bone formation when implanted in a bone defect site. However, its use is often limited due to its slow osteointegration rate and low antibacterial activity, particularly where HA has to be used for long term biomedical applications. This work will describe the synthesis and detailed characterization of zinc-substituted HA (ZnHA) as an alternative biomaterial to HA. ZnHA containing 1.6 wt% Zn was synthesized via a co-precipitation reaction between calcium hydroxide, orthophosphoric acid and zinc nitrate hexahydrate. Single-phase ZnHA particles with a rod-like morphology measuring ~50 nm in length and ~15 nm in width, were obtained and characterized using transmission electron microscopy and X-ray diffraction. The substitution of Zn into HA resulted in a decrease in both the a- and c-axes of the unit cell parameters, thereby causing the HA crystal structure to alter. In vitro cell culture work showed that ZnHA possessed enhanced bioactivity since an increase in the growth of human adipose-derived mesenchymal stem cells along with the bone cell differentiation markers, were observed. In addition, antibacterial work demonstrated that ZnHA exhibited antimicrobial capability since there was a significant decrease in the number of viable Staphylococcus aureus bacteria after in contact with ZnHA.

Phylogeography of a northeast Asian spruce, Picea jezoensis, inferred from genetic variation observed in organelle DNA markers.

Range-wide genetic variation of the widespread cold-temperate spruce Picea jezoensis was studied throughout northeast Asia using maternally inherited mitochondrial DNA and paternally inherited chloroplast DNA markers. This study assessed 33 natural populations including three varieties of the species in Japan, Russia, China, and South Korea. We depicted sharp suture zones in straits around Japan in the geographical distribution pattern of mitochondrial haplotypes (GST=0.901; NST=0.934). In contrast, we detected possible extensive pollen flow without seed flow across the straits around Japan during the past population history in the distribution pattern of chloroplast haplotypes (GST=0.233; NST=0.333). The analysis of isolation by distance of the species implied that by acting as a barrier for the movement of seeds and pollen, the sharp suture zones contributed considerably to the level of genetic differentiation between populations. Constructed networks of mitochondrial haplotypes allowed inference of the phylogeographical history of the species. We deduced that the disjunction with Kamchatka populations reflects range expansion and contraction to the north of the current distribution. Within Japan, we detected phylogeographically different types of P. jezoensis between Hokkaido and Honshu islands; P. jezoensis in Honshu Island may have colonized this region from the Asian continent via the Korean peninsula and the species in Hokkaido Island is likely to have spread from the Asian continent via Sakhalin through land bridges. Japanese endemism of mitochondrial haplotypes in Hokkaido and Honshu islands might have been promoted by separation of these islands from each other and from the Asian continent by the straits during the late Quaternary.

Th1 polarization in murine IgA nephropathy directed by bone marrow-derived cells.

IgA nephropathy is the most common form of progressive glomerulonephritis although the pathophysiology of this nephropathy is unclear. The ddY mouse is a spontaneous animal model with variable incidence and extent of glomerular injury mimicking human IgA nephropathy. Here, we transplanted bone marrow cells from 20-week-old ddY mice with beginning or quiescent IgA nephropathy into irradiated similar ddY mice, C57Bl/6 (Th1 prone) mice, or BALB/c (Th2 prone) mice. Serum IgA/IgG complex and Th1/Th2 polarization of spleen cells was determined by enzyme-linked immunosorbent assay and confirmed by fluorescent cytometric analysis. The ddY mice with commencing IgA nephropathy demonstrated strong polarization toward Th1, while those with quiescent disease were Th2 polarized. Serum levels of IgA/IgG2a immune complex significantly correlated with the severity of the glomerular lesions. Bone marrow taken from mice with commencing IgA nephropathy conferred IgA nephropathy with Th1 polarization in recipient-quiescent mice, while transplantation from the quiescent mice ablated glomerular injury and mesangial IgA/IgG deposition in those commencing IgA disease. However, adoptive transfer of CD4(+) T cells from those whose disease began failed to induce any IgA deposition or renal injury. Our study suggests that bone marrow cells, presuming IgA producing cells, may initiate this disease. Th1 cells may be involved in the pathophysiology of the disease after glomerular IgA deposition.

Analysis of feeding behavior with direct linear transformation.

AIM: The sucking pattern of term infants is composed of a rhythmic alteration of expression and suction movements. The aim is to evaluate if direct linear transformation (DLT) method could be used for the assessment of infant feeding. SUBJECT AND METHODS: A total of 10 gnormalh infants and two infants with neurological disorders were studied using DLT procedures and expression/suction pressure recordings. Feeding pattern of seven gnormalh infants were evaluated simultaneously recording DLT and pressures. The other infants were tested non-simultaneously. We placed markers on the lateral angle of the eye, tip of the jaw, and throat. The faces of infants while sucking were recorded in profile. The jaw and throat movements were calculated using the DLT procedure. Regression analysis was implemented to investigate the relationship between suction and expression pressures and eye-jaw and eye-throat movement. All regression analyses investigated univariate relationships and adjusted for other covariates. RESULTS: Ten gnormalh infants demonstrated higher suction pressure than expression pressure, and their throat movements were larger than jaw movements. Two infants with neurological problems did not generate suction pressure and demonstrated larger movements in their jaw than throat. The simultaneous measurement (n=7) showed a significant correlation, not only between eye-jaw distance and the expression pressure, but also between eye-throat distance and suction pressure. The change in the eye-jaw distance was smaller than the changes in the eye-throat distance in gnormalh infants (p<0.001). CONCLUSIONS: The DLT method can be used to evaluate feeding performance without any special device.

Development of porous ceramics with well-controlled porosities and pore sizes from apatite fibers and their evaluations.

Porous hydroxyapatite (HAp) ceramics possessing well-controlled porosities and pore sizes were developed by firing apatite-fiber compacts mixed with carbon beads and agar. The total porosities could be controlled in the range from 40 to 85% by varying compaction pressure (20-40 MPa), firing temperature (1000-1300 degrees C) and carbon/HAp ratio (0/10-10/10 (w/w)). Most of the pores were regarded as open pores. The pore sizes were mainly affected by the carbon-bead diameter (5, 20 or 150 microm) and partly by the compaction pressure and the firing temperature. The pore sizes of the porous HAp ceramics derived from the carbon beads of 150 microm in diameter were distributed in the two separate ranges of several micrometers and more than 100 microm.

Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity.

Tumor-infiltrating lymphocytes, particularly CD8(+) T cells, could be a manifestation of antitumor immunity. We clinicopathologically analyzed the biological significance of tumor-infiltrating lymphocytes in 221 patients with renal cell carcinoma without preoperative treatments. More abundant infiltration of tumor tissue not only by CD8(+) but also CD4(+) T cells was associated with shorter survival of the patients, because of the positive correlation between the number of lymphocytes and representative tumor grade factors. This suggests that immune cell reactions are more pronounced as the tumor grade/biological malignancy progresses, probably because of increased antigenicity of tumor cells. We next analyzed the proliferative activity of CD8(+) T cells that infiltrated in tumor cell nests, which could also reflect antitumor immunity. Higher labeling index of Ki-67, a proliferation-associated antigen, among CD8(+) T cells in contact to tumor cells was associated with a longer survival by both uni- and multivariate analyses. Our data in human renal cell carcinoma suggest that infiltration of tumor tissue by T cells itself does not denote the efficacy of antitumor immunity because of its dependence on the biological malignancy of tumor cells, but infiltration of tumor tissue by CD8(+) T cells bearing more pronounced proliferative activity could reflect effective antitumor immunity. This concept would be important for future immunotherapy of human cancer.

Optical chamber system designed for microscopic observation of living cells under extremely high hydrostatic pressure.

A novel pressure chamber system has been developed for the study of living cells under conditions of extremely high hydrostatic pressure up to 100 MPa (1 atm = 0.101325 MPa). The temperature in the chamber is thermostatically controlled in the range from 2 degrees to 80 degrees C. Two high-pressure pumps are employed for continuous perfusion of the chamber with culture medium and a chemical solution under high hydrostatic pressure conditions. The chamber has a 2-mm-thick glass window 2 mm in diameter, with a minimum working distance of 3.8 mm. The chamber system is designed to be adaptable to a variety of microscopic and imaging techniques. Using this chamber system, we successfully carried out real-time observations of elongated Escherichia coli and rounded HeLa cells under pressure.

[Bulbocavernosus reflex induced by bladder filling in a neurogenic bladder patient due to spinal arteriovenous malformation. A case report].

A 59-year-old man with spinal arteriovenous malformation at L-1 level was referred to our clinic for urinary retardation and urinary protraction. Bulbocavernosus reflex (BCR) was performed at empty bladder and at the storage phase during cystometry. BCR was evoked by compressing the glans penis. The evoked reflexes were examined by palpatating the contractile responses of the bulbocavernosus muscle and bipolar surface electrodes on each side of para-perineal raphe. Evoked response of BCR couldn't be detected at empty bladder, but obvious responses of BCR were detected at about 300 ml bladder filled. For further evaluation, a concentric needle electrode was inserted into the periurethral striated muscle to examine the evoked potential of BCR. The responses were unstable at empty bladder, but stable evoked potentials were obtained at storage phase. BCR performed only at empty bladder may cause false negative result.

Genetically synthesized antibody-binding protein self-assembled on hydrophobic matrix.

A unique antibody-binding protein, (E12B2)n, was genetically synthesized, which was characterized by a hydrophobic peptide, E12, at one terminus and an antibody-binding peptide, B2, at the other. It was clarified by atomic force microscopy (AFM) imaging that this protein was efficiently self-assembled on a hydrophobic solid surface. (E12B2)n self-assembled on a microplate exhibited an excellent performance of antibody-binding affinity. The proposed design of antibody-binding protein seems promising in immobilizing antibody molecules on hydrophobic solid surfaces.

New approach to transport improvement in a helical magnetic axis system by introduction of effective toroidal curvature

A new approach to transport improvement in a helical magnetic axis stellarator is proposed. First of all, the proposal is presented for the L = 1 system. The effective toroidal curvature term epsilon(T), defined as the sum of the usual toroidal curvature and one of the nearest satellite harmonics of the helical field, determines confinement conditions of localized trapped particles. There exists a certain correlation between the smallness of epsilon(T) and the omnigeneity. This approach would give rise to the possibility of a stellarator design study in a wider parameter domain than quasisymmetry approaches.

Measurement of blood clearance time by Limulus G test of Candida-water soluble polysaccharide fraction, CAWS, in mice.

The Limulus G test, responsive to beta-1,3-D-glucan, is a well-established method for the detection of invasive fungal infection. We have recently found that Candida albicans released a water-soluble polysaccharide fraction (CAWS) into synthetic medium (Uchiyama et al., FEMS Immunol. Med. Microbiol. 24 (1999) 411-420). CAWS was composed of a mannoprotein-beta-glucan complex and activated Limulus factor G, and thus would be similar to the Limulus active substance in patient's blood. In a preliminary investigation, we have found that CAWS is lethal when administered intravenously in a murine system. In this study, we examined the toxicity and then the fate of CAWS in mice. The lethal toxicity was strain-dependent and strain DBA/2 was the most resistant. The toxicity was, at least in part, reduced by salbutamol sulfate and prednisolone treatment in the sensitive strains. On intravenous administration, the half clearance time (t1/2) was approximately 40 min in mice (DBA/2). On intraperitoneal administration, CAWS appeared in the blood with a peak concentration at 1 h. In order to establish a treatment plan, it is important to demonstrate the onset and the termination of deep-seated mycosis. The Limulus G test is suitable for the above purpose; however, it is necessary to fully understand the fate of beta-1,3-D-glucan in patients' blood.

Osteogenesis coordinated in C3H10T1/2 cells by adipogenesis-dependent BMP-2 expression system.

A novel tissue engineering for bone formation has been proposed, to make osteoblast differentiation balanced by transfecting the mesenchymal stem cells with a gene encoding human bone morphogenetic protein-2 (hBMP-2) under the control of adipocyte specific lipoprotein lipase (LPL) promoter. Due to the promoter specificity, the initiation of BMP transcription is dependent on adipogenesis. For 14-day culture in the presence of ascorbic acid (asc) and beta-glycerophosphate (gly), nontransfected mouse embryonic fibroblast C3H10T1/2 (10T1/2) cells showed extensive accumulation of lipid droplets and adipocyte specific enzyme glycerol-3-phosphate dehydrogenase (G3PDH) mRNA expression, but exhibited neither BMP-2 expression, high alkaline phosphatase (ALP) activity which reflects osteoblast phenotype. On the other hand, transfected 10T1/2 cells showed hBMP-2 expression, high ALP activity and low level of G3PDH. mRNA expression accompanied with minimal lipid droplets. These results indicate that 10T1/2 cells are proved to be differentiated with maintaining coordinated balance of adipogenesis and osteogenesis, when they are transfected by the gene encoding hBMP-2 under the control of LPL promoter.

Extracorporeal shock wave lithotripsy for a ureteral stone in crossed fused renal ectopia.

BACKGROUND: A 63-year-old woman presented with right flank pain and macroscopic hematuria. RESULTS/METHODS: A plain film showed a calcific shadow on the right iliac bone. On excretory urography, the right kidney was seen in the normal position, but the left kidney was not. Bilateral retrograde pyelogram revealed the S-shaped kidney and mild obstruction from a 12 x 5 mm calculus in the proximal ureter of the crossed kidney. The patient was successfully treated with in situ extracorporeal shock wave lithotripsy (ESWL) treatment and is stone free at 1 month follow up. CONCLUSION: We believe this is the first case of successful ESWL in a crossed kidney.

Genetically fused protein A-luciferase for immunological blotting analyses.

The gene expression plasmid pMALU5 for the fusion protein of protein A (SpA) with a complete sequence of firefly luciferase (Luc) was constructed. The fused gene was expressed in Escherichia coli, and the resulting SpA-Luc fusion protein was purified by one-step affinity chromatography on IgG-Sepharose. The protein retained both activities: IgG binding capability of protein A and enzymatic activity of luciferase. Blotting analyses were performed with the fusion protein to determine a tumor marker of alpha-fetoprotein (AFP). AFP was detected at the lowest detection limit of 5 pg by dot blotting and Western blotting. The SpA-Luc fusion protein provides a highly selective, sensitive, and versatile marker for blotting analyses.

Electrically stimulated induction of hsp70 gene expression in mouse astroglia and fibroblast cells.

Mouse astroglial cells, which were cultured on an electrode, were found responsive to an electric stimulation of sine wave potential in enhancing hsp70 mRNA resulting from an activation of hsp70 gene expression. On the basis of this finding, electrically responsive cells were established by transfecting mouse 3T3-L1 cells with a constructed plasmid encoding hsp70 promoter and the firefly luciferase gene. A stable cell line has been established through selection of heat-stimulated luciferase expression. A 1-h electric stimulation of the cells resulted in activation of luciferase expression, which was confirmed to produce an increase in light emission. The sequential pattern of the electrically stimulated expression of luciferase was found different from that of the heat stimulation. Furthermore, the promoter was activated depending on the potential and duration of the stimulation applied. Consequently, the electric stimulation has proven effective on activating hspP70 promoter. This cell line is feasible in expressing the gene of interest by electrical stimulation, which lead us to construct environment responsive cells in general.