The current role of precision surgery in oligometastatic prostate cancer.

Oligometastatic prostate cancer (omPCa) is a novel intermediate disease state characterized by a limited volume of metastatic cells and specific locations. Accurate staging is paramount to unmask oligometastatic disease, as provided by prostate-specific membrane antigen-positron emission tomography. Driven by the results of prospective trials employing conventional and/or modern staging modalities, the treatment landscape of omPCa has rapidly evolved over the last years. Several treatment-related questions comprising the concept of precision strikes are under development. For example, beyond systemic therapy, cohort studies have found that cytoreductive radical prostatectomy (CRP) can confer a survival benefit in select patients with omPCa. More importantly, CRP has been consistently shown to improve long-term local symptoms when the tumor progresses across disease states due to resistance to systemic therapies. Metastasis-directed treatments have also emerged as a promising treatment option due to the visibility of oligometastatic disease and new technologies as well as treatment strategies to target the novel PCa colonies. Whether metastases are present at primary cancer diagnosis or detected upon biochemical recurrence after treatment with curative intent, targeted yet decisive elimination of disseminated tumor cell hotspots is thought to improve survival outcomes. One such strategy is salvage lymph node dissection in oligorecurrent PCa which can alter the natural history of progressive PCa. In this review, we will highlight how refinements in modern staging modalities change the classification and treatment of (oligo-)metastatic PCa. Further, we will also discuss the current role and future directions of precision surgery in omPCa.

Electric Quadrupolar Contributions in the Magnetic Phases of UNi_{4}B.

We present acoustic signatures of the electric quadrupolar degrees of freedom in the honeycomb-layer compound UNi_{4}B. The transverse ultrasonic mode C_{66} shows softening below 30 K both in the paramagnetic phase and antiferromagnetic phases down to ∼0.33 K. Furthermore, we traced magnetic field-temperature phase diagrams up to 30 T and observed a highly anisotropic elastic response within the honeycomb layer. These observations strongly suggest that Γ_{6}(E_{2g}) electric quadrupolar degrees of freedom in localized 5f^{2} (J=4) states are playing an important role in the magnetic toroidal dipole order and magnetic-field-induced phases of UNi_{4}B, and evidence some of the U ions remain in the paramagnetic state even if the system undergoes magnetic toroidal ordering.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Evidence for the Single-Site Quadrupolar Kondo Effect in the Dilute Non-Kramers System Y_{1-x}Pr_{x}Ir_{2}Zn_{20}.

Acoustic signatures of the single-site quadrupolar Kondo effect in Y_{0.966}Pr_{0.034}Ir_{2}Zn_{20} are presented. The elastic constant (C_{11}-C_{12})/2, corresponding to the Γ_{3}(E)-symmetry electric-quadrupolar response, reveals a logarithmic temperature dependence of the quadrupolar susceptibility in the low-magnetic-field region below ∼0.3 K. Furthermore, the Curie-type divergence of the elastic constant down to ∼1 K indicates that the Pr ions in this diluted system have a non-Kramers ground-state doublet. These observations evidence the single-site quadrupolar Kondo effect, as previously suggested based on specific-heat and electrical-resistivity data.

Seven Japanese Herbals Prolonged Cardiac Allograft Survival.

Japanese herbal medicines have long been used as alternative therapy because of their immunomodulatory effects. In recent years, use herbal medicines is rapidly increasing worldwide. In this study, we investigated the effect of 17 components of traditional Japanese herbal medicines on alloimmune responses in a murine model of cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA mice by using microsurgical techniques. Artemisiae capillaris herba (Inchinko) was given to CBA recipients at a dosage of 1 g/kg/day from the day of transplantation until 7 days afterward. The other 16 components were given at a dosage of 2 g/kg/day for the same time period. Naïve CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST] of 7 days). CBA transplant recipients given 2 g/kg/day of Glycyrrhizae radix (Kanzou), Poria sclerotium (Bukuryo), Pinellia tuber (Hange), Cnidii rhizome (Senkyu), Paeoniae radix (Shakuyaku), and Scutellariae radix (Ogon) had prolonged C57BL/6 allograft survival significantly (MSTs were 18, 18, 17, 14, 12, and 12 days, respectively). Moreover, CBA transplant recipients given 1g/kg/day of Artemisiae capillaris herba had prolonged C57BL/6 allograft survival (MST >100 days); however, none of other 10 components prolonged allograft survival. In conclusion, administration of 7 components of traditional Japanese herbal medicines might induce prolongation of fully major histocompatibility complex-mismatched cardiac allografts.

Possibility of Flat-Band Ferromagnetism in Hole-Doped Pyrochlore Oxides Sn_{2}Nb_{2}O_{7} and Sn_{2}Ta_{2}O_{7}.

Quantum mechanics tells us that the hopping integral between local orbitals makes the energy band dispersive. In a lattice with geometric frustration, however, dispersionless flat bands may appear due to quantum interference. Several models possessing flat bands have been proposed theoretically, and many attracting magnetic and electronic properties are predicted. However, despite many attempts to realize these models experimentally, compounds that are appropriately described by this model have not been found so far. Here we show that pyrochlore oxides Sn_{2}Nb_{2}O_{7} and Sn_{2}Ta_{2}O_{7} are such examples, by performing first-principles band calculation and several tight-binding analyses. Moreover, spin-polarized band calculation shows that the hole-doped systems Sn_{2}Nb_{2}O_{6}N and Sn_{2}Ta_{2}O_{6}N have complete spin polarization, and their magnetic moments are mostly carried by Sn-s and N-p orbitals, which are usually nonmagnetic. These compounds are not only candidates for ferromagnets without a magnetic element, but also will provide an experimental platform for a flat-band model which shows a wide range of physical properties.

Computational Design of Flat-Band Material.

Quantum mechanics states that hopping integral between local orbitals makes the energy band dispersive. However, in some special cases, there are bands with no dispersion due to quantum interference. These bands are called as flat band. Many models having flat band have been proposed, and many interesting physical properties are predicted. However, no real compound having flat band has been found yet despite the 25 years of vigorous researches. We have found that some pyrochlore oxides have quasi-flat band just below the Fermi level by first principles calculation. Moreover, their valence bands are well described by a tight-binding model of pyrochlore lattice with isotropic nearest neighbor hopping integral. This model belongs to a class of Mielke model, whose ground state is known to be ferromagnetic with appropriate carrier doping and on-site repulsive Coulomb interaction. We have also performed a spin-polarized band calculation for the hole-doped system from first principles and found that the ground state is ferromagnetic for some doping region. Interestingly, these compounds do not include magnetic element, such as transition metal and rare-earth elements.

Yogurt Feeding Induced the Prolongation of Fully Major Histocompatibility Complex-Mismatched Murine Cardiac Graft Survival by Induction of CD4+Foxp3+ Cells.

Yogurt is a nutrient-rich food and the beneficial effects of yogurt on both health and immunomodulatory effects are well documented. In this pilot study, we investigated the effects of commercially produced yogurt R-1 on alloimmune responses in a murine cardiac transplantation model. The R-1 is produced by Meiji Co., Ltd., and contains live and active lactic acid bacteria (lactobacillus bulgaricus OLL1073R-1) mainly. CBA (H2k) mice underwent transplantation of a C57BL/6 (H2b; B6) heart and received oral administration of 1 mL, 0.1 mL, and 0.01 mL of R-1 from the day of transplantation until 7 days afterward. Additionally, we prepared one group of CBA recipients given 1 mL of R-1 sterilized by microwave for 7 days. Histological and immunohistochemical studies were performed. Naïve CBA mice rejected B6 cardiac graft acutely (median survival time [MST]: 7 days). CBA recipients given of 1 mL of R-1 had significantly prolonged B6 allograft survival (MST, 27 days). However, other doses of 0.1 mL and 0.01 mL of R-1 did not prolonged allograft survival (MSTs, 9 days and 8.5 days, respectively). Also, CBA recipients administered microwaved R-1 had no prolongation of B6 allograft (MST, 9 days). Histological and immunohistochemical studies showed the cardiac allograft from R-1-exposed CBA recipients had preserved graft and vessel structure and the number of infiltrated CD4+, CD8+, and Foxp3+ cells in R-1-exposed CBA recipients increased, respectively. In conclusion, our findings imply that yogurt containing active lactic acid bacteria could change alloimmune responses partially and induce the prolongation of cardiac allograft survival via CD4+Foxp3+ regulatory cells.

One Way to Design a Valence-Skip Compound.

Valence-skip compound is a good candidate with high T c and low anisotropy because it has a large attractive interaction at the site of valence-skip atom. However, it is not easy to synthesize such compound because of (i) the instability of the skipping valence state, (ii) the competing charge order, and (iii) that formal valence may not be true in some compounds. In the present study, we show several examples of the valence-skip compounds and discuss how we can design them by first principles calculations. Furthermore, we calculated the electronic structure of a promising candidate of valence skipping compound RbTlCl3 from first principles. We confirmed that the charge-density wave (CDW) is formed in this compound, and the Tl atoms in two crystallographic different sites take the valence Tl1+ and Tl3+. Structure optimization study reveals that this CDW is stable at the ambient pressure, while this CDW gap can be collapsed when we apply pressure with several gigapascals. In this metallic phase, we can expect a large charge fluctuation and a large electron-phonon interaction.

Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report.

An autosomal dominant hereditary disease, Epstein syndrome (ES) is characterized by sensorineural hearing impairment, macrothrombocytopenia, and hereditary nephritis, and can progress to end-stage kidney disease after puberty. Generally, kidney transplantation is difficult to perform in Epstein syndrome owing to the high risk of perioperative bleeding. Additionally, due to previous platelet transfusions, ES patients sometimes have antihuman leukocyte antigen (HLA) antibodies, including antiplatelet antibodies and donor-specific anti-HLA antibodies (DSA), which may result in refractoriness to platelet transfusion and antibody-mediated rejection (AMR). We report a case of successful kidney transplantation in a patient with ES who had DSA and antiplatelet antibodies. To prevent AMR, we used a desensitization protocol (a combination of plasmapheresis, rituximab, and basiliximab induction). Surveillance biopsy performed at 4 months and 1 year after transplantation showed no pathological findings suggesting AMR. To prevent perioperative bleeding complications, we infused the patient with HLA-matched platelets, thereby maintaining the platelet count at >10.0 × 10(4)/µL, and no postoperative episodes of bleeding occurred.

Expression profiles of NOS isoforms in gingiva of nNOS knockout mice.

Nitric oxide is a gaseous molecule associated with many distinct physiological functions, and is derived from L-arginine catalyzed by nitric oxide synthase (NOS). Nitric oxide synthase has 3 isoforms: nNOS, iNOS and eNOS. Although these NOS isoforms are believed to play an important role in gingival tissue, little information is available on their morphological dynamics. The aim of this study was to investigate the profiles of NOS isoforms in deficiency of nNOS in gingiva of mice. Twelve male (6 normal (C57BL/6) and 6 nNOS knockout) mice were used. All mice were 5-week-old, weighing approximately 20-25 g each. After sacrifice, the jaws of the mice were removed by mechanical means and specimens analyzed by histology, in situ hybridization and immunohistochemistry. Immunohistochemical observation revealed positive staining for iNOS and eNOS, especially in lamina propria. Similar results in the mRNA expression levels were shown by in situ hybridization analysis. It may suggest that iNOS and eNOS compensated nNOS deficiency in the gingiva of nNOS knockout mice.

Successful ganciclovir therapy in a patient with human herpesvirus-6 encephalitis after unrelated cord blood transplantation: usefulness of longitudinal measurements of viral load in cerebrospinal fluid.

BACKGROUND: There have been no reports of human herpesvirus-6 (HHV-6) encephalitis treatment based on both HHV-6 DNA load and the antiviral agent's concentration in the cerebrospinal fluid (CSF). PATIENT: A 20-year-old male with a hematological malignancy developed HHV-6 encephalitis 15 days after unrelated cord blood transplantation (UCBT). He had fever, chest pain, memory impairment, and insomnia. His CSF showed no increased cell counts, but the amount of HHV-6 DNA was elevated to 2.0 × 10(6) copies/ìgDNA. Magnetic resonance imaging (MRI) of the head revealed abnormal high-intensity signals in the left limbic system on T2-weighted and diffusion-weighted images. Intravenous administration of ganciclovir (GCV) was initiated at 5 mg/kg every 12 h on day 18, and was continued until day 137. The amount of HHV-6 DNA in the plasma became undetectable on day 25. The HHV-6 load in the CSF decreased to 1.5 × 10(3) copies/ìgDNA on day 32, and reached undetectable levels on day 53. The mean concentration of GCV 1 h after an infusion of 5 mg/kg was 4.12 mg/mL in plasma and 0.7 mg/mL in CSF. The chest pain and insomnia disappeared on days 35 and 47, respectively. Memory defects recovered up to day 85. CONCLUSION: Serial quantification of HHV-6 DNA in CSF may be useful for successful treatment with GCV in post-transplant HHV-6 encephalitis.

Expression of Mn-SOD, iNOS and eNOS mRNAs in osteoblasts from the maxilla of osteopetrotic mice.

Active oxygens and free radicals are involved in the metabolism and clinical conditions of tissues; however, little is known about the localisation and expression levels of associated enzymes. The expressions of active oxygens, free radicals and associated enzymes are reported to be site-specific; therefore, the expression states of free radical enzymes differ between sites, even within the same cell. In particular, there has been no report concerning the catabolic enzymes of active oxygens in osteoblasts of the maxilla, other than normal osteoblasts that were weakly positive by immunohistochemical staining. We conducted this study to elucidate the relationship between osteodystrophy and radical-associated enzymes by investigating mRNAs of enzymes associated with active oxygens and free radicals using osteoblasts from the maxilla of normal and osteopetrotic model (op/op) mice. In op/op mouse maxilla osteoblasts, mRNAs of Mn-SOD, i-NOS and e-NOS were strongly positive. Mn-SOD and iNOS enzymes were considered to be highly expressed in osteoblasts of the narrowed medullary cavity of this bone.

Ultrastructural immunolocalization of dentin matrix protein 1 on Sharpey's fibers in monkey tooth cementum.

Despite the importance of dentin matrix protein 1 (DMP1) in the formation of mineralized tissue, including dentinogenesis and osteogenesis, its precise role in cementogenesis remains to be clarified fully. The purpose of our study was to demonstrate the ultrastructural immunolocalization of DMP1 in monkey molar tooth cementum. Japanese Macaca fuscata monkeys were fixed by perfusion. The upper molar teeth and accompanying periodontium then were dissected and demineralized with EDTA. Cryosections were obtained, incubated in anti-DMP1 polyclonal antibody, and processed by immunoperoxidase and immunogold labeling. Intense immunoperoxidase staining for DMP1 was observed in acellular extrinsic fiber cementum, particularly in Sharpey's fibers. Cementocyte lacunae with canaliculi showed DMP1 staining in the apical region of the tooth root. Electron immunomicroscopy revealed the close proximity of DMP1 to collagen fibrils in Sharpey's fibers at the mineralization front. Intense immunogold labeling was localized on the walls of the cementocyte lacunae in cellular cementum. These results should contribute to better understanding of the role of DMP1, not only in Sharpey's fiber biomineralization, but also in the maintenance of the cementocyte lacunar space in cementum.

Different clinical and neuropathologic phenotypes of familial ALS with A315E TARDBP mutation.

OBJECTIVE: To present the relationship between TARDBP gene mutation and clinicopathologic findings of a Japanese pedigree affected by familial amyotrophic lateral sclerosis (FALS). METHODS: The clinical, genetic, and neuropathologic characteristics of 4 members of a Japanese pedigree affected by FALS were examined. RESULTS: All the patients showed motor neuron signs, and 2 of them also had parkinsonism. We identified A315E TARDBP mutation in one patient per clinical disease type and found loss of anterior horn cells, Bunina bodies, and phosphorylated TDP-43-positive neuronal and glial cytoplasmic inclusions in both the patients. However, the patient with only motor neuron signs had degeneration of the posterior column and spinocerebellar tracts as well as neuronal loss of the Clarke column, and the patient with both motor neuron signs and parkinsonism had severe nigral degeneration without Lewy pathology. CONCLUSION: The clinical and neuropathologic phenotypes of FALS may differ even with the same mutation of TARDBP, encoding TDP-43. Isolated TDP-43 pathology can produce ALS-plus syndrome.

Combination of super chilling and high carbon dioxide concentration techniques most effectively to preserve freshness of shell eggs during long-term storage.

This study was made to examine the combined effects of stored temperature and carbon dioxide atmosphere on shell egg quality. The shell eggs were packed into polyethylene terephthalate/polyethylene (PET/PE) pouches and stored at 0 degrees C (super chilling), 10 degrees C, and 20 degrees C, respectively for 90 d. The atmospheric carbon dioxide concentration was controlled to obtain the 3 concentration levels of high (about 2.0%), medium (about 0.5%), and low (below 0.01%). Changes in Haugh unit (HU) values, weakening of vitelline membranes, and generation of volatiles were analyzed to evaluate the freshness of shell eggs. Results showed that, compared with the other combinations, the technique of super chilling and high carbon dioxide concentration enabled shell eggs to be most effectively stored for 90 d, based on estimations of the statistical significances of differences in HU values, and on maintaining the initial HU values during storage. In addition, the storage of shell eggs using this combination technique was found to significantly prevent the weakening of the vitelline membrane based on the estimations of numbers of eggs without vitelline membrane breakage when eggs broke, and significantly lowered the incidence of hexanal in the yolk from exposure to the gas chromatographic-mass spectrometric analyses of volatiles. Thus, these results confirmed that the combination of super chilling and high carbon dioxide concentration was the most effective technique for preserving shell eggs during a long term of 90 d compared with other combination techniques.

Relationship of smoking and smoking cessation with oral health status in Japanese men.

BACKGROUND AND OBJECTIVE: Smoking has been associated with the number of natural teeth a person has and with the likelihood of periodontitis. The purpose of this study was to determine the relationships between the number of teeth present and periodontal diseases with smoking habits in a cohort of Japanese men. MATERIAL AND METHODS: The study group comprised 1088 men, 40-75 years of age. Oral examinations were conducted in dental clinics. Information on smoking status and on oral health behavior was collected from self-administered questionnaires. The relationship between oral health status and smoking status was estimated using adjusted odds ratios. RESULTS: Compared with those whom had never smoked, the odds ratios of having more than eight missing teeth and having periodontitis, among current smokers, were 1.67 and 1.74, respectively. In those who had stopped smoking for 11 years or longer, there was no increase in the odds ratio of having more than eight missing teeth and periodontitis, compared with those whom had never smoked. CONCLUSION: Smoking has a positive association with missing teeth and periodontitis. However, smoking cessation is beneficial for oral health. The odds of having more than eight missing teeth, or of having periodontitis, in those who had never smoked was similar to that of individuals who reported that they had stopped smoking for 11 years or more.

Immunohistochemical localization of elastin, fibrillins and microfibril-associated glycoprotein-1 in the developing periodontal ligament of the rat molar.

BACKGROUND AND OBJECTIVE: Elastic system fibers are a major component of the periodontal ligament, but little information is available about their detailed composition or the mechanism of elastogenesis in the developing periodontal ligament. The purpose of this study was to investigate immunolocalization of elastin, fibrillins and microfibril-associated glycoprotein-1 (MAGP-1) in the developing periodontal ligament of the rat molar. MATERIAL AND METHODS: Frozen sections of demineralized as well as non-demineralized periodontal ligament of Wistar rats of various ages from 19 days to 7 weeks were incubated with anti-elastin, anti-fibrillin-1 and -2 and anti-MAGP-1 antibodies followed by peroxidase-conjugated secondary antibodies. After incubation with diaminobenzidine solution, immunoreaction products were observed with a light microscope. RESULTS: In the developing periodontal ligament of 19-day-old rats, fibers immunopositive to elastin were not present, but fibers positively stained for fibrillin-2 and MAGP-1 were widely distributed throughout the ligament. The latter fibers were arranged in the apico-occlusal direction along with blood vessels. In 3-week-old rats, fibers stained for elastin were observed for the first time in the apical region of the ligament. The number and distribution pattern of these elastin-positive fibers was basically the same as those in rats aged 5 and 7 weeks. In contrast, fibrillin-2- and MAGP-1-positive fibers were more extensively distributed in the ligament, and their pattern of distribution was comparable to that of reported oxytalan fibers. Fibrillin-1 was, however, not detected either in demineralized sections or in non-demineralized sections, indicating its absence in periodontal ligament. CONCLUSION: Elastin expressed in the periodontal ligament assembled into elaunin fibers in the vicinity of blood vessels. Both fibrillin-2 and MAGP-1 are structural components not only of the elastin-associated microfibrils but also of elastin-free microfibrils, with possible roles in elastogenesis and in periodontal ligament homeostasis.

Super chilling enhances preservation of the freshness of salted egg yolk during long-term storage.

Pasteurized egg yolk with 10% (w/w) salt was stored at 5, -5, -15, -20, and -30 degrees C for 1 to 6 mo, respectively. Changes in generation of volatiles of the stored samples (5 and -5 degrees C for 6 mo) were analyzed by SPME-GC-MS. Emulsifying properties of egg yolk stored at -5, -15, -20, and -30 degrees C for 1 mo, respectively, were also evaluated by measurement of emulsion particle diameters in model emulsions prepared with the yolk samples. In addition, structural changes in low-density lipoprotein (LDL) in the egg yolks dependent on storage conditions for 6 mo were evaluated by (31)P-NMR. Volatile compounds such as hexanal, 2-methylbutanal, and 3-methylbutanal increased in egg yolk during storage at 5 degrees C; however, volatile compounds hardly increased in any samples stored at -5 degrees C (super chilling). The mean emulsion particle diameter in super chilled egg yolk was significantly smaller than that in egg yolk stored at the other lower temperatures. In addition, the results of (31)P-NMR evaluation suggested that prevention of structural changes of LDL resulted in maintenance of emulsifying properties of egg yolk. Thus, these results indicate that super chilling is an effective means of preserving salted egg yolk during long-term storage.

Relationship of smoking and smoking cessation with number of teeth present: JPHC Oral Health Study*.

BACKGROUND: Smoking is associated with the number of teeth. The purpose of this study was to determine the relationship of number of teeth with smoking and smoking cessation. METHODS: Subjects included 547 males aged between 55 and 75 years. Oral examinations were conducted in 2005. Smoking status information was collected from questionnaire surveys conducted in 1990, 1995, 2000, and 2005. The relationship between having more than eight missing teeth and smoking status was estimated with adjusted odds ratio. RESULTS: Comparing with never smokers, odds ratios of having more than eight missing teeth among current and former smokers were 1.96 and 1.86, respectively. The odds ratios in those who had stopped smoking for