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Shimazakiite occurs as greyish white aggregates up to 3 mm in diameter. Two polytypes, shimazakiite- 4M and shimazakiite-4O, have been identified, the former in nanometre-sized twin lamellae and the latter in micrometre-sized lamellae. Shimazakiite was discovered in an irregular vein in crystalline limestone near gehlenite-spurrite skarns at Fuka mine, Okayama Prefecture, Japan. Associated minerals include takedaite, sibirskite, olshanskyite, parasibirskite, nifontovite, calcite and an uncharacterized hydrous calcium borate. The mineral is biaxial (-), with the following refractive indices (at 589 nm): α = 1.586(2), β = 1.650(2), γ = 1.667(2) and 2Vcalc = 53º [shimazakiite-4M]; and α = 1.584(2), β = 1.648(2), γ = 1.670(2) and 2Vcalc = 54.88º [shimazakiite-4O]. Quantitative electronmicroprobe analyses (means of 28 and 25 determinations) gave the empirical formulae Ca2B1.92O4.76(OH)0.24 and Ca2B1.92O4.76(OH)0.24 for shimazakiite-4M and shimazakiite-4O, respectively. The crystal structure refinements: P21/c, a = 3.5485(12), b = 6.352(2), c = 19.254(6) Å , β = 92.393(13)º, V = 433.6(3) Å3 [for shimazakiite-4M]; and P212121, a = 3.55645(8), b = 6.35194(15), c = 19.2534(5) Å , V = 434.941(18) Å3[for shimazakiite-4O], converged into R1 indices of 0.1273 and 0.0142, respectively. The crystal structure of shimazakiite consists of a layer containing B2O5 units (two near-coplanar triangular corner-sharing BO3 groups) and 6- and 7-coordinate Ca atoms. Different sequences in the c direction of four layers are observed in the polytypes. The five strongest lines in the powder-diffraction pattern [listed as d in Å (I)(hkl)] are: 3.02(84)(022); 2.92(100)(104̅) 2.81(56)(104); 2.76(32)(113); 1.880(32)(118̅,126̅,126,118) [for shimazakiite-4M]; and 3.84(33)(014); 3.02(42)(022); 2.86(100)(104); 2.79(29)(113); 1.903(44)(126,118) [for shimazakiite-4O]. [ABSTRACT FROM AUTHOR]

Messenger ribonucleic acid (mRNA) vaccination against coronavirus disease 2019 (COVID-19) is an effective prevention strategy, despite a limited understanding of the molecular mechanisms underlying the host immune system and individual heterogeneity of the variable effects of mRNA vaccination. We assessed the time-series changes in the comprehensive gene expression profiles of 200 vaccinated healthcare workers by performing bulk transcriptome and bioinformatics analyses, including dimensionality reduction utilizing the uniform manifold approximation and projection (UMAP) technique. For these analyses, blood samples, including peripheral blood mononuclear cells (PBMCs), were collected from 214 vaccine recipients before vaccination (T1) and on Days 22 (T2, after second dose), 90, 180 (T3, before a booster dose), and 360 (T4, after a booster dose) after receiving the first dose of BNT162b2 vaccine (UMIN000043851). UMAP successfully visualized the main cluster of gene expression at each time point in PBMC samples (T1-T4). Through differentially expressed gene (DEG) analysis, we identified genes that showed fluctuating expression levels and gradual increases in expression levels from T1 to T4, as well as genes with increased expression levels at T4 alone. We also succeeded in dividing these cases into five types based on the changes in gene expression levels. High-throughput and temporal bulk RNA-based transcriptome analysis is a useful approach for inclusive, diverse, and cost-effective large-scale clinical studies., (© 2023 Wiley Periodicals LLC.)

Although the scope of pharmacists' work has expanded in Japan, people's perception of this is unclear. To contribute to medical care together with non- and health care professionals, clarifying the perceptions of these groups is important to best utilize pharmacist professionals. We conducted a cross-sectional questionnaire survey among non-health care professionals (n = 487) and nurses (n = 151), medical doctors (n = 133), and pharmacists (n = 204) regarding the work of pharmacists. The questionnaire comprised 56 items in four categories associated with the roles of pharmacists. For each questionnaire item, we performed logistic regression analysis to compare pharmacists' opinions with those of other professionals and non-health care professionals. Opinions were similar between pharmacists and nurses or medical doctors regarding "collecting patient information" and "providing drug information to patients." However, there were differences in perceptions regarding "medical collaboration" (nurses; 8/23 items, physicians; 11/23 items) and "community medicine" (nurses; 9/15 items, physicians; 11/15 items), and pharmacists themselves perceived greater roles related to health care collaboration and community health care. Perceptions of non-health care professionals were poorer than those of pharmacists in all categories (47/56 items). These results suggest that pharmacists must actively communicate to help others understand their specialty and build trusting relationships to improve patient care., (© 2023. The Author(s).)

A 19-year-old woman underwent prenatal ultrasonography, which confirmed the presence of an isolated cystic mass in the upper abdominal cavity of a fetus. A female infant weighing 3085 g was delivered at 36 weeks' gestation. Ultrasonography and computed tomography examination revealed a clear unilocular cyst and occupying the right side of the abdomen. The infant's respiratory status was unstable, and she fed poorly, owing to compression by the hepatic cyst. We performed ultrasound-guided aspiration of a hepatic cyst at 15 days old, but it rapidly re-grew. Therefore, we performed laparoscopic findings and fenestration of the hepatic cyst via an umbilical arc incision and the cyst wall was excised at 43 days old. The histopathological diagnosis was mesothelial cell-derived hepatic cyst. Three years after the operation, no recurrence has been observed. Hepatic cyst fenestration by umbilical incision can be performed safely in infants and it is a cosmetically superior method., (© Crown copyright 2022.)

Introduction: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic even after vaccination. We aimed to identify immunological heterogeneity over time in vaccinated healthcare workers using neutralization antibodies and neutralizing activity tests., Methods: Serum samples were collected from 214 healthcare workers before vaccination (pre) and on days 22, 90, and 180 after receiving the first dose of BNT162b2 vaccine (day 0). Neutralization antibody (NAb, SARS-CoV-2 S-RBD IgM/IgG) titers and two kinds of surrogate virus neutralization tests (sVNTs) were analyzed (UMIN000043851)., Results: The NAb (SARS-CoV-2 S-RBD IgG) titer peaked on day 90 after vaccination (30,808.0 μg/ml ± 35,211; p < 0.0001) and declined on day 180 (11,678.0 μg/ml ± 33,770.0; p < 0.0001). The neutralizing activity also peaked on day 90 and declined with larger individual differences than those of IgG titer on day 180 (88.9% ± 15.0%, 64.8% ± 23.7%, p < 0.0001). We also found that the results of POCT-sVNT (immunochromatography) were highly correlated with those of conventional sVNT (ELISA)., Conclusions: Neutralizing activity is the gold standard for vaccine efficacy evaluation. Our results using conventional sVNT showed large individual differences in neutralizing activity reduction on day 180 (64.8% ± 23.7%), suggesting an association with the difference in vaccine efficacy. POCT-sVNT is rapid and user-friendly; it might be used for triage in homes, isolation facilities, and event venues without restrictions on the medical testing environment., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background/aim: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment., Patients and Methods: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history., Results: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients., Conclusion: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The aim of our study was to evaluate the efficacy and safety of docetaxel plus ramucirumab with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC)., Results: Sixty-one pretreated NSCLC patients underwent docetaxel plus ramucirumab. Primary prophylactic PEG-G-CSF was performed in 52 (85%) patients (prophylactic group). No febrile neutropenia (FN) (0%) was confirmed in 52 prophylactic group patients, whereas FN was observed in 3 (33%) of 9 non-prophylactic group patients. Among prophylactic group, median lines of prior therapy was 2 (range, 1-9). Median cycles of docetaxel plus ramucirumab was 3 (range, 1-25) (9 and 3 cases moved to ramucirumab and docetaxel monotherapies, respectively). Response rate and disease control rate were 30.8% and 73.1%, respectively. Median progression-free survival was 4.5 (95% confidence interval [CI], 3.0-6.6) months. Median overall survival was 11.4 (95% CI, 8.0-13.9) months. Six (11.5%) patients had grade 3/4 neutropenia. Observed grade 3 (incidence ≥10%) adverse event (AE) was oral mucositis (13.5%). There were no grade 4/5 non-hematological AEs., Conclusions: Our study demonstrated the efficacy and safety of docetaxel plus ramucirumab with PEG-G-CSF in clinical practice. Primary prophylactic PEG-G-CSF could markedly reduce incidence of FN., Methods: We retrospectively reviewed medical records of pretreated NSCLC cases who had received docetaxel plus ramucirumab in our departments., Competing Interests: CONFLICTS OF INTEREST Akito Hata received lecture fee from Chugai, Astra Zeneca, Boeringer Ingelheim, and Eli Lilly. Daijiro Harada has received lecture fees from Ono, Bristol-Myers Squibb, Yakult Honsha, Kyowa Hakko Kirin, AstraZeneca, Nippon Boehringer Ingelheim and Eli Lilly Japan. Toshiyuki Kozuki has received honoraria from Chugai, AstraZeneca, Eli Lilly Japan, Boehringer–Ingelheim, Ono, Bristol-Myers Squibb, Taiho, MSD, Pfizer and Kyowa Hakko Kirin, and research funding from Chugai, AstraZeneca, MSD, and Eli Lilly Japan. Naoyuki Nogami has received honoraria from Astellas, AstraZeneca, Ono, Taiho, Chugai, Eli Lilly, Boehringer Ingelheim and Pfizer. Nobuyuki Katakami received grants from Astra Zeneca, Eisai, Ono, Kyowa Kirin, Shionogi, Daiichi-Sankyo, Taiho, Chugai, Eli Lilly, Boeringer Ingelheim, and Merck Serono, and payment for lectures from Dainippon Sumitomo, Chugai, Boeringer Ingelheim, Astra Zeneca, Eli Lilly, Taiho, Janssen, Novartis, Pfizer, Ono, and Daiichi-Sankyo. The other authors declare no conflicts of interest.

It is thought that apolipoprotein A-I (apoA-I) spontaneously exchanges between high-density lipoprotein (HDL)-bound and lipid-free states, which is relevant to the occurrence of preβ-HDL particles in plasma. To improve our understanding of the mechanistic basis for this phenomenon, we performed kinetic and thermodynamic analyses for apoA-I exchange between discoidal HDL-bound and lipid-free forms using fluorescence-labeled apoA-I variants. Gel filtration experiments demonstrated that addition of excess lipid-free apoA-I to discoidal HDL particles promotes exchange of apoA-I between HDL-associated and lipid-free pools without alteration of the steady-state HDL particle size. Kinetic analysis of time-dependent changes in NBD fluorescence upon the transition of NBD-labeled apoA-I from HDL-bound to lipid-free state indicates that the exchange kinetics are independent of the collision frequency between HDL-bound and lipid-free apoA-I, in which the lipid binding ability of apoA-I affects the rate of association of lipid-free apoA-I with the HDL particles and not the rate of dissociation of HDL-bound apoA-I. Thus, C-terminal truncations or mutations that reduce the lipid binding affinity of apoA-I strongly impair the transition of lipid-free apoA-I to the HDL-bound state. Thermodynamic analysis of the exchange kinetics demonstrated that the apoA-I exchange process is enthalpically unfavorable but entropically favorable. These results explain the thermodynamic basis of the spontaneous exchange reaction of apoA-I associated with HDL particles. The altered exchangeability of dysfunctional apoA-I would affect HDL particle rearrangement, leading to perturbed HDL metabolism.

The effect of cholesterol on the uptake of a fluorinated general anesthetic, sevoflurane (SF, fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl]ethyl ether) was studied by multinuclear, high-resolution nuclear magnetic resonance (NMR) spectroscopy in combination with a pulsed-field gradient technique. Using large unilamellar vesicles of egg phosphatidylcholine/egg phosphatidylglycerol/cholesterol as model fluid cell membranes, the (19)F and (1)H NMR chemical shifts, longitudinal relaxation times (T1), and diffusion coefficients (D(eff)) were systematically analyzed to quantify the modulation of SF uptake to the lipid membrane by cholesterol. All NMR parameters (chemical shift, T1, and D(eff)) showed that SF uptake is limited by the presence of cholesterol in the membrane. It was found that SF uptake at 40 mol% cholesterol is limited to 50%-60% of the partitioning fraction in the absence of cholesterol in the membrane. This finding is attributed to the loss of motional freedom in the rigid membrane environment, as demonstrated by the gradual slowdown of lipid mobility D(eff) with increase in cholesterol concentration from 0 mol% to 40 mol%.

By combination of differential scanning calorimetry (DSC) and fluorescence spectroscopy of 6-propionyl-2-(dimethylamino)naphthalene (Prodan), we elucidated the thermotropic phase behavior of hydrogenated soybean phosphatidylcholine (HSPC)-cholesterol binary liposome membrane which has similar lipid composition to Doxil®, the widely used liposome product in treatment of various tumors. We found that the characteristic points at cholesterol mole fraction (Xch)=0.023 and 0.077 correspond to the hexagonal lattice, in which cholesterol molecules are considered to be regularly distributed in all regions of HSPC lipid bilayer with 1 : 42 and 1 : 12 units, respectively, as static averaged structures. Apparent endothermic peak disappeared at Xch=0.40 in the DSC thermograms, indicating the existence of single liquid ordered phase at Xch>0.40. In addition, fluorescence measurements of Prodan and its lauroyl derivative in poly(ethylene glycol) (PEG)-modified liposomes indicated that PEG modification has a negligible effect on the phase behavior of HSPC-cholesterol binary liposome membrane. These results may provide useful information in developing novel liposome products whose stability and encapsulated drug release are controlled.

Apolipoprotein A-I (apoA-I) accepts cholesterol and phospholipids from ATP-binding cassette transporter A1 (ABCA1)-expressing cells to form high-density lipoprotein (HDL). Human apoA-I has two tertiary structural domains and the C-terminal domain (approximately amino acids 190-243) plays a key role in lipid binding. Although the high lipid affinity region of the C-terminal domain of apoA-I (residues 223-243) is essential for the HDL formation, the function of low lipid affinity region (residues 191-220) remains unclear. To evaluate the role of residues 191-220, we analyzed the structure, lipid binding properties, and HDL formation activity of Δ191-220 apoA-I, in comparison to wild-type and Δ223-243 apoA-I. Although deletion of residues 191-220 has a slight effect on the tertiary structure of apoA-I, the Δ191-220 variant showed intermediate behavior between wild-type and Δ223-243 regarding the formation of hydrophobic sites and lipid interaction through the C-terminal domain. Physicochemical analysis demonstrated that defective lipid binding of Δ191-220 apoA-I is due to the decreased ability to form α-helix structure which provides the energetic source for lipid binding. In addition, the ability to form HDL particles in vitro and induce cholesterol efflux from ABCA1-expressing cells of Δ191-220 apoA-I was also intermediate between wild-type and Δ223-243 apoA-I. These results suggest that despite possessing low lipid affinity, residues 191-220 play a role in enhancing the ability of apoA-I to bind to and solubilize lipids by forming α-helix upon lipid interaction. Our results demonstrate that the combination of low lipid affinity region and high lipid affinity region of apoA-I is required for efficient ABCA1-dependent HDL formation., (© 2013.)

Purpose: We retrospectively investigated the radiographic findings in patients with atlanto-axial subluxation (AAS) due to rheumatoid arthritis, and clarified the effect of reduction of the atlanto-axial angle (AAA) on the cranio-cervical and subaxial angles., Methods: Forty-one patients, consisting of 29 females and 12 males, with AAS treated by surgery were reviewed. The average patient age at surgery was 61.0 years, and the average follow-up period was 4.0 years. We investigated the AAA at the neutral position in lateral cervical radiographs before surgery and at the last follow-up. In addition, we also investigated the clivo-axial angle (CAA) and the subaxial angle (SAA) at the neutral position before and after surgery., Results: Due to pre-operative AAA, the patients were classified into three groups as follows: (1) the kyphotic group (K group), (2) the neutral group (N group), and (3) the lordotic group (L group). The average AAA values at the neutral position in the K group before and after surgery were 6.0° and 18.1°, respectively (P < 0.001). In the N group 19.7° and 21.7°, respectively (P < 0.05), and in the L group 31.6° and 27.0°, respectively (P < 0.01). However, no significant differences in the average CAA values were found before and after surgery in all groups. Furthermore, no significant differences in the SAA values were seen before and after surgery in all groups., Conclusions: A proper reduction of the AAA did not affect the cranial angles or induce kyphotic malalignment of the subaxial region after atlanto-axial arthrodesis. However, if we can obtain a significant and large reduction of AAA in patients showing kyphosis before surgery, then this reduction will be offset in the atlanto-occipital joint and we should therefore pay special attention to its morphology after surgery.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of polyglutamine repeats in the Ataxin-1 protein. An accumulating body of cerebellar, histological and behavioral analyses has proven that SCA1-knock-in mice (in which the endogenous Atxn1 gene is replaced with mutant Atxn1 that has abnormally expanded 154 CAG repeats) work as a good tool, which resembles the central nervous system pathology of SCA1 patients. However, the peripheral nervous system pathology of the model mice has not been studied despite the fact that the clinical manifestation is also characterized by peripheral involvement. We show here that spinal motor neurons are degenerated in SCA1-knock-in mice. Histologically, some spinal motor neurons of the SCA1-knock-in mice have polyglutamine aggregates in their nuclei and also thinner and demyelinated axons. Electrophysiological examinations of the mice showed slower nerve conduction velocities in spinal motor neurons and lower amplitudes of muscle action potential, compared to wild-type mice. Consistently, the mice displayed decrease in rearing number and total rearing time. These results suggest that the knock-in mice serve as a definite model that reproduces peripheral involvement and are therefore useful for research on the peripheral nervous system pathology in SCA1 patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Atlanto-axial subluxation (AAS) is caused by multiple conditions; however, idiopathic AAS patients without RA, upper-cervical spine anomalies or any other disorder are rarely encountered. This study retrospectively investigated the radiographic findings in idiopathic AAS patients, and clarified the differences between those AAS patients and those due to RA., Methods: Fifty-three patients with AAS treated by transarticular screw fixation were reviewed. The subjects included 8 idiopathic patients (ID group) and 45 RA patients (RA group). The study investigated the atlanto-dental interval (ADI) value and space available for spinal cord (SAC) at the neutral and maximal flexion position., Results: The average ADI value at the neutral position in the ID and RA groups before surgery was 7.8 and 7.2 mm, respectively (p > 0.74). The average ADI value at the flexion position in the two groups was 10.3 and 11.7 mm, respectively (p > 0.06). The average SAC value at the neutral position in the two groups was 12.0 and 17.1 mm, respectively (p < 0.01). Finally, the average SAC value at the flexion position in the two groups was 10.7 and 13.5 mm, respectively (p < 0.01)., Conclusions: The SAC value at both the neutral and flexion positions in idiopathic AAS patients was significantly smaller than those values in RA-AAS patients. This may be because the narrowing of the SAC in the idiopathic group easily induces cervical myelopathy. Furthermore, surgery was often recommended to RA patients, because of the neck pain induced by RA-related inflammation of the atlanto-axial joint, regardless of any underlying myelopathy.

By using the perpendicular-exchange-biased Pt/Co/α-Cr(2)O(3) system, we provide experimental evidence that the unreversed uncompensated Cr spins exist at the Co/α-Cr(2)O(3) interface. The unreversed uncompensated Cr spin manifests itself in both the vertical shift of an element-specific magnetization curve and the relative peak intensity of soft-x-ray magnetic circular dichroism spectrum. We also demonstrate an in situ switching of the interfacial Cr spins and correspondingly a reversal of the exchange bias without interfacial atomic diffusion. Such switching shows the direct relationship between the interfacial antiferromagnetic spins and origin of the exchange bias. The demonstrated switching of exchange bias would likely offer a new design of advanced spintronics devices, using the perpendicular-exchange-biased system, with low power consumption and ultrafast operation.

Cell-penetrating peptides are arginine- and lysine-rich cationic peptides that can readily enter cells not only by themselves but also carrying other macromolecular cargos. In fact, we have reported that polycationic polymer such as poly-l-lysine (PLL) and poly-l-arginine (PLA) translocate through negatively charged phospholipid liposome membranes. In this work, we made a comparative study of the interaction of PLL or PLA with lipid membranes consisting of negatively charged phospholipids to understand the role of basic amino acid residue (i.e. arginine and lysine) in the membrane-penetrating activity of polypeptides. PLA and PLL translocated into giant unilamellar vesicle composed of soybean phospholipids. ζ-potential and turbidity measurements demonstrated the electrostatic binding of PLL and PLA to large unilamellar vesicle (LUV). Fluorescence studies using membrane probes revealed that the binding of PLA and PLL to LUV affects the hydration and packing of the membrane interface region, in which the membrane insertion of PLA appeared to be greater than PLL. Differential scanning calorimetry showed that the enthalpy of the gel to liquid-crystalline phase transition for dipalmitoyl phosphatidylglycerol vesicle was greatly reduced by binding of PLL and PLA, in which the reduction is much larger in PLA than in PLL. Circular dichroism measurements in 2,2,2-trifluoroethanol/water mixture or in the presence of LUV indicated that the propensity of PLA to form α-helical structure is greater than PLL. Consistently, attenuated total reflection-Fourier transform infrared spectroscopy revealed that there is greater α-helical structure in PLA bound to LUV compared to PLL, which has much less ordered structure. Furthermore, isothermal titration calorimetry measurements demonstrated that the contribution of enthalpy to the energetics of binding to LUV is two-fold larger in PLA than in PLL. These results suggest that the stronger interaction of arginine residue with negatively charged phospholipid membranes compared to lysine residue appears to facilitate the conformational change in cationic polypeptide and its insertion into lipid membrane interior., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

This report presents a case of non-traumatic posterior atlanto-occipital dislocation. A 36-year-old female was referred with a history of numbness of the extremities, vertigo and neck pain for 1 year. The patient had no history of trauma. The axial rotation of range of motion of the cervical spine was severely restricted. A lateral cervical radiograph in the neutral position demonstrated a posterior atlanto-occipital dislocation. A coronal view on a computed tomography (CT) reconstruction image showed a loss of angle of the bilateral atlanto-occipital joint, and a sagittal reconstruction view of CT images also demonstrated flatness of atlanto-occipital joint. Instrumented occipito-cervical fusion was performed after reduction. A lateral cervical radiograph in the neutral position 1 year after surgery showed the reduction of atlanto-occipital joint, moreover, it was maintained even in an extended position. The patient had neurologic improvement after surgery. Flatness of the bilateral atlanto-occipital joint may have induced this instability. Occipital-cervical fusion was chosen in the present case since the patient showed restricted axial rotation of the neck before surgery. The surgery improved the preoperative symptoms including the function of cervical spine evaluated by JOACMEQ.

This report presents a case of atlanto-axial subluxation after treatment of pyogenic spondylitis of the atlanto-occipital joint. A 60-year-old male had 1-month history of neck pain with fever. Magnetic resonance imaging showed inflammation around the odontoid process. Intravenous antibiotic therapy was administrated immediately. After 6 weeks, CRP had returned almost to normal. After 4 months, laboratory data was still normal, but the patient experienced increasing neck pain. Lateral cervical radiography in the neutral position showed instability between C1 and C2. Computed tomography showed a bony union of the atlanto-occipital joint and severe destruction of the atlanto-axial joint on the left side. Transarticular screw fixation for the atlanto-axial joint was performed. A lateral cervical radiograph in the neutral position after surgery showed a solid bony union. Neck pain improved following surgery. We speculate that spondylitis of the atlanto-occipital joint induced a loosening of the transverse ligament and articulation of the atlanto-axial joint. A bony fusion of the atlanto-occipital joint after antibiotic treatment resolved the pyogenic inflammation concentrated stress to the damaged atlanto-axial joint, resulting in further damage. The atlanto-axial instability was finally managed by the insertion of a transarticular screw.

Arginine-rich, cell-penetrating peptides (e.g., Tat-peptide, penetratin, and polyarginine) are used to carry therapeutic molecules such as oligonucleotides, DNA, peptides, and proteins across cell membranes. Two types of processes are being considered to cross the cell membranes: one is an endocytic pathway, and another is an energy-independent, nonendocytic pathway. However, the latter is still not known in detail. Here, we studied the effects of the chain length of polyarginine on its interaction with an anionic phospholipid large unilamellar vesicle (LUV) or a giant vesicle using poly-l-arginine composed of 69 (PLA69), 293 (PLA293), or 554 (PLA554) arginine residues, together with octaarginine (R8). ζ-potential measurements confirmed that polyarginine binds to LUV via electrostatic interactions. Circular dichroism analysis demonstrated that the transition from the random coil to the α-helix structure upon binding to LUV occurred for PLA293 and PLA554, whereas no structural change was observed for PLA69 and R8. Fluorescence studies using membrane probes revealed that the binding of polyarginine to LUV affects the hydration and packing of the membrane interface region, in which the degree of membrane insertion is greater for the longer polyarginine. Isothermal titration calorimetry measurements demonstrated that although the binding affinity (i.e., the Gibbs free energy of binding) per arginine residue is similar among all polyarginines the contribution of enthalpy to the energetics of binding of polyarginine increases with increasing polymer chain length. In addition, confocal laser scanning microscopy showed that all polyarginines penetrate across giant vesicle membranes, and the order of the amount of membrane penetration is R8 ≈ PLA69 < PLA293 ≈ PLA554. These results suggest that the formation of α-helical structure upon lipid binding drives the insertion of polyarginine into the membrane interior, which appears to enhance the membrane penetration of polyarginine.

As the principal component of high-density lipoprotein (HDL), apolipoprotein (apo) A-I plays essential roles in lipid transport and metabolism. Because of its intrinsic conformational plasticity and flexibility, the molecular details of the tertiary structure of lipid-free apoA-I have not been fully elucidated. Previously, we demonstrated that the stability of the N-terminal helix bundle structure is modulated by proline substitution at the most hydrophobic region (residues around Y18) in the N-terminal domain. Here we examine the effect of proline substitution at S55 located in another relatively hydrophobic region compared to most of the helix bundle domain to elucidate the influences on the helix bundle structure and lipid interaction. Fluorescence measurements revealed that the S55P mutation had a modest effect on the stability of the bundle structure, indicating that residues around S55 are not pivotally involved in the helix bundle formation, in contrast to the insertion of proline at position 18. Although truncation of the C-terminal domain (Δ190-243) diminishes the lipid binding of apoA-I molecule, the mutation S55P in addition to the C-terminal truncation (S55P/Δ190-243) restored the lipid binding, suggesting that the S55P mutation causes a partial unfolding of the helix bundle to facilitate lipid binding. Furthermore, additional proline substitution at Y18 (Y18P/S55P/Δ190-243), which leads to a drastic unfolding of the helix bundle structure, yielded a greater lipid binding ability. Thus, proline substitutions in the N-terminal domain of apoA-I that destabilized the helix bundle promoted lipid solubilization. These results suggest that not only the hydrophobic C-terminal helical domain but also the stability of the N-terminal helix bundle in apoA-I are important modulators of the spontaneous solubilization of membrane lipids by apoA-I, a process that leads to the generation of nascent HDL particles., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A retrospective study was carried out to compare the preventive effects of single and repeat treatment with dexamethasone (DEX) on delayed nausea and emesis in patients who had received carboplatin (CBDCA)-based combination chemotherapy. Sixty-four patients were evaluated. Efficacy was assessed using the nausea and emesis score, food intake score and the requirement for antiemetic medication. These forward scores were categorized as three-grade during the first 5 days after chemotherapy. Acute nausea and emesis were well controlled in both groups on day 1. Mean values of the nausea and emesis score on day 3 evening and the food intake score on day 4 morning in the repeat-treatment group was 1.31 ± 0.93 and 3.46 ± 1.03, respectively, which were significantly better when compared with the single-treatment group (2.00 ± 1.52; P = 0.028 and 2.79 ± 1.12; P = 0.018, respectively). Multivariate logistic regression analysis revealed that less frequent dispensing of antiemetic medication was significantly associated with the repeat-treatment group (adjusted odds ratio, 0.153; 95% confidence interval, 0.026-0.734; P = 0.018). These results suggest that repeat-dose DEX may be more effective than single-dose DEX for the prevention of delayed nausea and emesis after CBDCA-based combination chemotherapy., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Among 143 cases of laparoscopic adrenalectomy carried out from 1993 to the present, 13 patients in whom the surgical manipulation presented problems were examined. Problems occurred due to the condition of the adrenal tumors themselves in six patients, whereas problems occurred due to the operative history in four patients. There were three patients with no operative history but with strong intraperitoneal adhesion. In patients with a history of laparotomy in other fields such as open cholecystectomy, gastrectomy or colostomy, operations were possible in most patients by examining the trocar site preoperatively. Patients with strong adhesion even without a history of surgery could be handled by full separation of the adhesion during surgery. In patients with bleeding in the adrenal tumors, large adrenal tumors, or tumors impacted in the liver, methods such as changing the sequence of separation procedures were required. In patients with a history of renal subcapsular hematomas due to extracorporeal shock wave lithotripsy (ESWL), it was not possible to understand the conditions of adrenal or perinephritic adhesion in preoperative imaging diagnosis, but resection was possible by changing the order of separation procedures and by using optimal instruments and devices. As with any surgery, including open surgeries, it is necessary to obtain knowledge on how to deal with variations in laparoscopic adrenalectomy to assure safe outcomes and to always consider effective methods for coping with unexpected difficulties.

Simple one-pot methods for preparation of 2-oxazolines have been developed using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). Treatment of a mixture of carboxylic acids and 2-haloethylammonium salts with DMT-MM in methanol followed by refluxing in the presence of KOH gives oxazolines.

Background: The objective of this study was to evaluate the clinical outcome of combined immunotherapy with interferon-alpha (IFN-alpha) and low-dose interleukin-2 (IL-2) for Japanese patients with metastatic renal cell carcinoma (RCC) who had undergone radical nephrectomy., Methods: This study included 13 patients who were diagnosed as having metastatic RCC following radical nephrectomy. These patients received a subcutaneous injection of IFN-alpha (6 x 10(6) IU per day) three times per week and an intravenous injection of IL-2 (1.4 x 10(6) IU per day) twice per week. Tumor response was evaluated every 16 weeks, and as a rule, this weekly regimen was repeated 50 times in patients with evidence of objective response or stable disease., Results: One of the 13 patients dropped out because of severe toxicity; hence, 12 patients were evaluable, with a median follow-up period of 18 months after the start of this combined therapy. Six patients (50.0%) achieved objective responses, with 1 complete response (CR), while only 2 (16.7%) demonstrated progressive disease. The median duration of response in the 6 responders was 13.5 months. Toxicity associated with this combined immunotherapy was limited to WHO grade 1 or 2 in these 12 patients. All patients were alive at last follow-up, and 2 remain disease-free after 1 additional patient showed a CR following surgical resection of the remaining metastatic disease., Conclusion: Our preliminary experience suggests that long-term, repeated treatment with IFN-alpha and low-dose IL-2 is feasible in Japanese patients with metastatic RCC who have undergone radical nephrectomy. Although it will be necessary to accumulate data from a larger number of patients with a longer follow-up period, the combined immunotherapy tested in this study may become the preferred therapy for Japanese patients with metastatic RCC.

Introduction: The objective of this study was to determine whether the tumor volume in radical prostatectomy specimens of patients with prostate cancer who underwent neoadjuvant hormonal therapy (NHT) could be used as a prognostic predictor., Patients and Methods: In this study, we included 96 patients who underwent NHT followed by radical prostatectomy between January 1995 and July 2003 in our institutions. Several clinicopathological factors of these patients were analyzed, focusing on the association between tumor volume in radical prostatectomy specimens and disease recurrence., Results: The tumor volume in radical prostatectomy specimens after NHT was significantly associated with capsular penetration, seminal vesicle invasion, and lymph node metastases, among the factors examined in this study. The biochemical recurrence-free survival rates in patients with tumor volumes <1.0 cm(3) were significantly higher than in those having tumor volumes > or =1.0 cm(3). However, multivariate analysis showed that the tumor volume could not be used as an independent predictor for biochemical recurrence., Conclusions: In patients who received NHT prior to radical prostatectomy, the tumor volume was shown to correlate with other prognostic indicators. Furthermore, a higher probability of biochemical recurrence was noted, when there was a residual tumor volume > or =1.0 cm(3) after NHT. Thus, careful follow-up and, if necessary, additional treatment should be considered in cases demonstrating tumor volumes > or =1.0 cm(3) after NHT.

We report herein a rare case of esophageal carcinoma producing alpha-fetoprotein (AFP). A 69-year-old man presenting elevated AFP was admitted in order to investigate its origin, which several liver examinations done before admission had not revealed. At admission, his serum AFP was 76.9 ng/ml whereas other tumor markers were within normal range. As the patient complained of mild swallowing disturbance, gastrointestinal examinations were performed, and an esophageal carcinoma was found at the esophagogastric junction. The patient underwent subtotal esophagectomy and the esophagus was reconstructed by gastric tube. The postoperative course was uneventful and the serum AFP level normalized immediately after the operation. Histopathological examination demonstrated the tumor to be poorly-differentiated adenosquamous carcinoma, which contained scattered adenocarcinoma composed of clear cells positive to AFP by an immunohistochemical stain. The patient has been well for six months after the surgery without any sign of recurrence.

Background: The objective of this study was to retrospectively investigate the effectiveness of transurethral resection of bladder tumor (TURBT) and intravesical instillation therapy for stage T1, grade 3 (T1G3) transitional cell carcinoma (TCC) of the urinary bladder., Methods: Between January 1995 and December 1997, 97 patients with T1G3 TCC of the urinary bladder were treated by TURBT and adjuvant intravesical instillation with bacillus Calmette-Guérin (BCG) or other anticancer agents. The recurrence-free survival rates were evaluated according to several clinicopathological factors. The cases that progressed to muscle invasive disease were also analysed., Results: In this series, the median follow-up period was 25 months (range, 5- 41) after the initial TURBT. Intravesical recurrence was noted in 44 patients (45%), and the 1, 2, and 3 year recurrence-free survival rates were 72%, 58%, and 42%, respectively. Multivariate analyses revealed that the risk of intravesical recurrence was significantly higher for patients who did not receive BCG therapy, irrespective of age, gender, tumor size, multiplicity, pathological stage, concomitant carcinoma in situ, and lymphovascular involvement. Moreover, after a median of 10 months, disease progression occurred in seven patients (7%), of which only one patient was treated by BCG therapy after initial TURBT., Conclusion: These findings suggest that intravesical instillation with BCG combined with TURBT is an effective conservative treatment for T1G3 TCC of the bladder. Patients with negative prognostic factors should be treated by BCG rather than other anticancer agents after TURBT.

We examined the usefulness of prostate specific antigen alph-1-antichymotrypsin complex (PSA-ACT) and its indices for the detection of prostate cancer in patients with a prostate specific antigen (PSA) level between 2.1 and 10.0 ng/ml. Between July 1999 and October 2001, 151 patients with a PSA level between 2.1 and 10.0 ng/ml underwent a systematic biopsy under transrectal ultrasound (TRUS) guidance. The clinical values of total PSA, PSA-ACT, PSA density (PSAD), PSA-ACT density (PSA-ACTD), PSA transition zone density (PSATZD) and PSA-ACT transition zone density (PSA-ACTTZD) for the detection of prostate cancer were compared by using receiver operating characteristic (ROC) curve analysis. Of the 151 patients, 36 (23.8%) were histologically confirmed as having prostate cancer. The differences between patients with prostate cancer and benign prostatic disease were significant with respect to the PSA and PSA-ACT related parameters examined in this study. According to ROC curve analysis, the area under the curve (AUC) of PSA-ACTTZD was the greatest of all the parameters. The differences was significant between the AUC of PSA-ACTTZD and total PSA (p < 0.05). The cutoff value of PSA-ACTTZD with 0.20 ng/ml2 showed the highest sum of sensivitity (90%) and specificity (55%). Also, in 86 patients with a PSA level between 2.1 and 6.0 ng/ml, the AUC of PSA-ACTTZD was the greatest of all the parameters. Measuring the level of PSA-ACT and its indices may provide a better differentiation of prostate cancer and benign prostatic disease than total PSA alone in patients with intermediate PSA levels. PSA-ACTTZD is the most useful indicator among PSA-ACT and its volume indices.

Objectives: To compare the serum and urinary carcinoembryonic antigen (CEA) levels for assessment of possible risk of malignant transformation in patients with orthotopic neobladder., Methods: The serum and urinary levels of CEA, nutritional status, and acid-base and electrolyte balances were studied in 87 patients after radical cystectomy (22 with ileal neobladder, 28 with colon neobladder, and 37 with ileal conduit). The results of these groups were compared., Results: The serum CEA level in patients with colon neobladder, ileal neobladder, and ileal conduit was 5.4 +/- 3.0, 3.7 +/- 1.6, and 3.1 +/- 1.5 ng/mL, respectively. The serum CEA level in the colon neobladder group was significantly higher than the levels in the remaining two groups (P <0.05); 16 patients (57%) with colon neobladder had elevated serum CEA values (ie, greater than 5 mg/mL). Elevated serum CEA was observed in only 5 (23%) and 3 (8%) patients with ileal neobladder or ileal conduit, respectively. The serum CEA value in these patients was associated with the urinary CEA value (P <0.001), but not the other factors examined., Conclusions: These findings suggest that colon bladder replacement caused significantly increased serum CEA values compared with ileal neobladder or ileal conduit; however, the elevated serum CEA level correlated with the urinary CEA level, irrespective of other clinical factors. Therefore, the elevated serum CEA in the colon neobladder group may have been due to reabsorption of CEA in urine rather than to an association with malignant changes in the bowel segments used for neobladder creation.

We report a case of nephrostomy tract tumor seeding following percutaneous pyeloscopic manipulation of a renal pelvic carcinoma. To our knowledge, this is the second reported case of such a lesion surrounding the nephrostomy tract. Percutaneous pyeloscopic treatment carries a potential risk of local tumor spillage and implantation in the nephrostomy tract.

Background: It is unclear whether positive interactions between radiation and androgen withdrawal for patients with locally advanced prostate cancer is synergistic or additive. The present study aimed to clarify the significance of neoadjuvant androgen ablation prior to external radiotherapy in a human prostate LNCaP tumor model and in patients with locally advanced prostate cancer., Methods: Comparisons were made between the effect of castration prior to radiation on the growth of subcutaneous LNCaP tumors implanted into male nude mice and their serum prostate-specific antigen (PSA) levels, and the results of castration or radiation alone. Twenty-nine patients with histologically proven and locally advanced adenocarcinoma of the prostate were treated with luteinizing hormone-releasing hormone analog at least 3 months before, during, and after external radiation therapy with a total dose of 70 Gy. The toxicity and response to this therapy were evaluated., Results: Treatment combining castration and radiation resulted in synergistic inhibition of LNCaP tumor growth and a significant delay in the emergence of androgen-independent recurrence as opposed to either treatment alone. The external radiotherapy was completed in 28 patients (96.6%), resulting in a reduction of serum PSA levels in all 28 patients to below 1.0 ng/mL. All patients were alive after a mean follow-up period of 34 months (range 11-53) with a 3-year PSA relapse-free survival rate of 83.7%. Among several factors examined, only the Gleason score was significantly associated with PSA relapse-free survival in univariate analysis, but not in multivariate analysis. Thirteen of 28 patients (46%) and 7 of 28 (25%) also showed at least one form of gastrointestinal or genitourinary toxicity, respectively. Of these patients, 8 with gastrointestinal toxicities, and 1 with genitourinary toxicity, experienced acute complications higher than grade 3., Conclusion: The experimental findings objectively suggested the use of neoadjuvant androgen withdrawal prior to radiation therapy. Although our clinical experience is preliminary, combined androgen ablation and radiation therapy may also be effective in controlling locally advanced prostate cancer, with tolerable side-effects.

Objective: The objective of the present study was to evaluate the usefulness of the combined systematic biopsy with serum prostate-specific antigen-alpha(1)-antichymotrypsin complex (PSA-ACT) level to predict the extent of prostate cancer., Materials and Methods: Sixty-two patients with clinically organ-confined disease who underwent radical prostatectomy were evaluated for serum PSA and PSA-ACT levels, systematic biopsy, and the pathological stage., Results: The incidence of extraprostatic disease in patients with more than half the biopsy cores positive or > or = 8 ng/ml PSA-ACT was significantly higher than those with less than half positive or <8 ng/ml PSA-ACT, respectively, whereas cancer in bilateral lobes or > or = 10 ng/ml PSA could not be used as a predictor of extraprostatic disease. Furthermore, in those with more than half the biopsy cores positive and > or = 8 ng/ml PSA-ACT or those with more than half the biopsy cores positive and > or = 10 ng/ml PSA, extraprostatic disease was significantly more common than in those with less than half positive and <8 ng/ml PSA-ACT or those with less than half positive and <10 ng/ml PSA, respectively. However, the incidence of extraprostatic disease predicted by these three variables was not significantly better than those by the two variables (percentage positive biopsy cores plus serum PSA-ACT or PSA)., Conclusions: The combined systematic biopsy with serum PSA-ACT or PSA could be used as a useful predictor for the extent of prostate cancer. Patients with more than half the biopsy cores positive and > or = 8 ng/ml PSA-ACT or > or = 10 ng/ml PSA could avoid a prostatectomy because there is a high probability that they have extraprostatic disease., (Copyright 2002 S. Karger AG, Basel)

Objective: To evaluate the clinical significance of measuring the prostate-specific antigen-alpha(1)-antichymotrypsin (PSA-ACT) for differentiating prostate cancer from benign prostate hypertrophy (BPH) and for the staging of prostate cancer., Methods: Before treatment, total PSA (tPSA) and PSA-ACT were measured in 120 patients with prostate cancer and in 150 patients with BPH using immunofluorometric techniques with different monoclonal antibodies against PSA and ACT. Furthermore, the tPSA and PSA-ACT densities of the whole prostate (PSAD and ACTD, respectively) were calculated., Results: tPSA, PSAD, PSA-ACT and ACTD levels in patients with prostate cancer paralleled the clinical stage and were significantly higher than those in patients with BPH. Furthermore, these four values were significantly higher in patients with pathologically extraprostatic disease than those with organ-confined disease. Receiver operating characteristics analysis among patients with PSA values of 4.1-10 ng/ml revealed that the areas under the curve for tPSA and ACTD were similar to those for PSA-ACT and ACTD, respectively and that no significant differences in the differentiation between prostate cancer and BPH were observed among these parameters., Conclusions: Measurement of PSA-ACT provides useful information for the clinical staging of prostate cancer and differential diagnosis between prostate cancer and BPH; however, compared with tPSA, PSA-ACT may not be significantly superior in the diagnosis and staging of prostate cancer.

Objective: To determine whether serum levels of the prostate-specific antigen-alpha1-antichymotrypsin complex (PSA-ACT) and its density (ACTD) in patients scheduled to undergo radical prostatectomy for clinically localized prostate cancer can predict organ-confined vs extraprostatic disease., Patients and Methods: Serum samples were obtained from 62 patients with clinically localized prostate cancer before they underwent radical prostatectomy. PSA and PSA-ACT were measured using immunofluorometric techniques with different monoclonal antibodies against PSA and ACT, respectively. Furthermore, the PSA and PSA-ACT densities of the whole prostate (PSAD and ACTD, respectively) were calculated. The relationships of serum PSA, PSA-ACT, PSAD, ACTD and the pathological stage of the prostatectomy specimens were analysed., Results: The disease was organ-confined or extraprostatic in 30 and 32 men, respectively. In men with organ-confined cancer, the mean PSA and PSA-ACT levels were significantly lower than in those with extraprostatic disease. Furthermore, there were significantly higher mean PSAD and ACTD levels in men with extraprostatic than with organ-confined disease. There were also significant differences in PSA, PSA-ACT, PSAD and ACTD levels at each pathological stage, whereas there was no significant association between these variables and the Gleason score. Receiver-operating characteristic curve analysis for detecting organ-confined disease showed that PSA-ACT and ACTD had a larger area under the curve than PSA and PSAD, respectively, but these differences were not significant. Furthermore, PSA-ACT and ACTD provided significantly better sensitivity for detecting organ-confined disease than PSA and PSAD, respectively., Conclusions: Measuring PSA-ACT and ACTD may improve the preoperative evaluation of patients scheduled to undergo radical prostatectomy, because these factors better differentiate extraprostatic from organ-confined disease than PSA and PSAD.

Heat shock proteins 70 (hsp70) derived from tissues and cells can elicit cytotoxic T lymphocyte (CTL) responses against peptides bound to hsp70. However, peptides can markedly differ in their affinity for hsp, and this potentially limits the repertoire of peptides available to induce CTL by the hsp immunization. Hybrid peptides consisting of a high-affinity ligand for the peptide-binding site of hsp70 joined to T cell epitopes by a glycine-serine-glycine linker were constructed. Immunization with hybrid peptides complexed to mouse hsp70 effectively primed specific CTL responses in mice and were more potent than T cell peptide epitopes alone with hsp70. In vivo immunization with hsp70 and hybrid peptides led to rejection of tumors expressing antigen with greater efficacy than immunization with peptide epitope plus hsp70. Induction of CTL responses occurred independently of CD4(+) T cells, suggesting that immunization directly primed antigen-presenting cells to elicit CD8(+) cytotoxic T cell responses without T cell help. Both peptide/hsp70 complexes and mouse hsp70 alone were able to induce cultures of mouse bone marrow-derived dendritic cells (DC) to release cytokines, including DC from endotoxin-resistant C57BL/10Sc mice. Thus, hsp70/hybrid peptide complexes can activate DC for cytokine release, providing a potential adjuvant effect that could bypass T cell help.

Peripheral blood stem cell transplantation (PBSCT) is widely performed currently instead of bone marrow transplantation (BMT) because bone marrow reconstruction is better and the procedure is less invasive. We applied 26 courses of high-dose chemotherapy (1250 mg/m2 of carboplatin, 1500 mg/m2 of etoposide and 7.5 g/m2 of ifosfamide) to 14 male patients with germ cell tumors. Eleven patients underwent high-dose chemotherapy as induction after two to three courses of conventional BEP therapy. The remaining three patients had recurrent disease after conventional chemotherapies. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34+ cells were harvested for transplantation. Although all patients had grade 4 hematotoxicity, the white blood cell count recovered to more than 1000/microl within 8-11 days after PBSCT. No treatment-related death was found. Nine of 14 patients (64.3%) remain disease free at 18 months of median follow up time (range 12-60). We conclude that high-dose chemotherapy is a safe and effective means of treating advanced or refractory germ cell tumors in male patients.

In preparation for biosynthetic studies on the 3,4-dihydroxy-2, 6-dimethyl-5-phenylvaleric acid portion of neoantimycin (1), the 1H and 13C NMR signals of 1 were assigned unambiguously by means of 2D correlation spectroscopy and NOE experiments. The previously undetermined absolute stereochemistry at C-15 and C-16 was deduced as (S) and (S). The structure of isoneoantimycin (2) was also elucidated. The methyl groups of methionine and propionate were incorporated stereospecifically into C-13 and C-12 of 1, respectively, and the configuration of the methyl group of methionine is inverted in the process. The results also suggest the intervention of phenylpyruvate as an actual precursor.

Background: The clinical outcome of patients with renal cell carcinoma with brain metastasis was analyzed., Methods: Nine patients (median age, 60 years) with primary renal cell carcinoma and distant metastasis, including brain metastasis, were treated. The median time to the development of brain metastasis was 15 months after the initial visit. Patients with poor performance status or progressive disease were treated with interferon or conservative therapy alone. Patients with good performance status and other well-controlled metastatic foci were treated either with radiotherapy, or by tumorectomy of brain metastasis, or both. The median follow-up was 26 months after the initial visit., Results: The 1-year, cause-specific survival rate was 17%. Of the 5 patients treated with alpha-interferon alone, all died of disease after the treatments, without improvement of performance status, 1 to 4 months after the diagnosis of brain metastasis. Two of 4 patients who underwent radiotherapy were treated with a combination of gamma-knife and tumorectomy of brain metastasis. They remained alive 10 and 22 months after diagnosis of brain metastasis. The 2 patients who underwent the combination treatment of gamma-knife and tumorectomy showed improvement of their performance status after these treatments for brain metastasis., Conclusion: Brain metastasis is an unfavorable prognostic factor in renal cell carcinoma. Although a larger number of patients would be necessary to demonstrate the definitive effects of gamma-knife treatment, our results suggest that the combination of gamma-knife and tumorectomy of brain metastases may be recommended for selected patients with good performance status and other well-controlled metastatic foci.

Effective tumor immunity requires recognition of tumor cells coupled with the activation of host effector responses. Fc receptor (FcR) gamma-/- mice, which lack the activating Fc gamma R types I and III, did not demonstrate protective tumor immunity in models of passive and active immunization against a relevant tumor differentiation antigen, the brown locus protein gp75. In wild-type mice, passive immunization with mAb against gp75 or active immunization against gp75 prevented the development of lung metastases. This protective response was completely abolished in FcR gamma-deficient mice. Immune responses were intact in gamma-/- mice because IgG titers against gp75 develop normally in gamma-/- mice immunized with gp75. However, uncoupling of the Fc gamma R effector pathway from antibody recognition of tumor antigens resulted in a loss of protection against tumor challenge. These data demonstrate an unexpected and critical role for FcRs in mediating tumor cytotoxicity in vivo and suggest that enhancement of Fc gamma R-mediated antibody-dependent cellular cytotoxicity by inflammatory cells is a key step in the development of effective tumor immunotherapeutics.

The melanosome is an organelle specialized for melanin synthesis that is derived from the endocytic pathway. Several melanosome membrane proteins have been identified, forming a family of proteins known as tyrosinase-related proteins. Two members of this family, tyrosinase and gp75, are well-characterized melanocyte differentiation antigens. Our previous studies have shown that gp75, the mouse brown locus protein, is sorted to melanosomes along the endocytic pathway, directed by a hexapeptide sorting signal located in the cytoplasmic tail. In this study, we report the unexpected finding that a portion of gp75 is secreted. Substantial levels of secretory gp75 were detected in melanocytic cells. Cell surface expression of gp75 was also detected, representing 2% of cellular gp75. Characterization of secretory gp75 cells showed that it is: (i) a truncated form that lacks the transmembrane region, the cytoplasmic tail where the endosomal sorting signal is located, and a small portion of the lumenal domain; (ii) more extensively glycosylated than endocytic/melanosomal gp75, containing trans-Golgi processed sugar residues; and (iii) generated post-translationally in an acid sensitive compartment after processing in the trans-Golgi, and secreted rapidly after generation. Thus, these endocytic/melanosomal membrane proteins can be processed to abundant secretory forms, probably in an endocytic compartment through a potentially novel secretory pathway.