Dynamic alterations of circulating T lymphocytes and the clinical response in patients with head and neck squamous cell carcinoma treated with nivolumab.

Cancer immunotherapy using immune checkpoint inhibitors (ICIs) has been recognized as a novel therapeutic option for head and neck squamous cell carcinoma (HNSCC). However, only approximately 20-30% of patients with recurrent/metastatic (R/M) HNSCC benefit. Moreover, the mechanisms underlying the response to ICIs remain unclear. We investigated the proportion, activation status, and expression level of immune checkpoint molecules in circulating T cell subsets in R/M HNSCC patients treated with nivolumab using flow cytometry and mass cytometry, and then determined whether treatment response was associated with these values. We also assessed the changes in the frequency of tumor-associated antigens, MAGE-A4 and p53, -specific T cells prior to and after nivolumab treatment using the IFN-γ ELISPOT assay. The proportion of activated CD4+ and CD8+ TEMRA cells significantly increased in the disease-controlled patients but not in disease-progressed patients. As expected, the expression of PD-1 in T cells markedly decreased regardless of the therapeutic response. Meanwhile, T cell immunoglobulin mucin-3 expression on CD8+ T cells was significantly higher in patients with disease progression than in disease-controlled patients after treatment. The frequency of the tumor-associated antigens, MAGE-A4- and p53-specific T cells, was not correlated with clinical responses; however, in the disease-controlled patients, the frequency of MAGE-A4-specific T cells was significantly augmented. We concluded that in R/M HNSCC patients treated with nivolumab, circulating T cells show dynamic alterations depending on treatment efficacy. An analysis of the immunokinetics of circulating T cells could thus provide new insights into rational therapeutic strategies in cancer immunotherapy for HNSCC.

Molecular phenotypes of circulating tumor cells and efficacy of nivolumab treatment in patients with head and neck squamous cell carcinoma.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Biomarkers of the therapeutic efficacy of ICIs have been extensively investigated. In this study, we aimed to analyze whether molecular phenotypes of circulating tumor cells (CTCs) are associated with treatment responses and clinical outcomes in patients with R/M HNSCC treated with nivolumab. Peripheral blood samples were collected before treatment initiation and after four infusions of nivolumab. CTCs isolated by depletion of CD45-positive cells were analyzed to determine the expression of EPCAM, MET, KRT19, and EGFR using real-time quantitative polymerase chain reaction. CTC-positive samples were analyzed to determine the expression of PIK3CA, CCND1, SNAI1, VIM, ZEB2, CD44, NANOG, ALDH1A1, CD47, CD274, and PDCD1LG2. Of 30 patients treated with nivolumab, 28 (93.3%) were positive for CTCs. In 20 CTC-positive patients, molecular alterations in CTCs before and after nivolumab treatment were investigated. Patients with MET-positive CTCs had significantly shorter overall survival than those with MET-negative CTCs (p = 0.027). The expression level of CCND1 in CTCs of disease-controlled patients was significantly higher than that of disease-progressed patients (p = 0.034). In disease-controlled patients, the expression level of CCND1 in CTCs significantly decreased after nivolumab treatment (p = 0.043). The NANOG expression in CTCs was significantly increased in disease-controlled patients after nivolumab treatment (p = 0.036). Our findings suggest that the molecular profiling of CTCs is a promising tool to predict the treatment efficacy of nivolumab.

Corrigendum: Total synthesis and absolute configuration of avenolide, extracellular factor in Streptomyces avermitilis.

This corrects the article DOI: 10.1038/ja.2011.90.

Brainstem infarction associated with HHV-6 infection in an infant.

INTRODUCTION: The relevant literature includes several case reports on cerebral infarction in children with HHV-6 infection; however, there is no report of brain stem infarction. CASE: An 11-month-old girl was hospitalized because of fever. She was unable to stand up and meet her mother's gaze. Magnetic resonance imaging (MRI) indicated a right pons and mid-brain lesion; a diagnosis of brainstem infarction was made. After her fever subsided, a rash developed on her trunk and limbs; blood examination results indicated a primary HHV-6 infection. She was treated with aspirin, edaravone, and mannitol to prevent further complications. At the age of 18months, the auditory brainstem response (ABR) was unremarkable and she is developing well. DISCUSSION AND CONCLUSION: A limited number of studies have reported HHV-6 infection-associated infarction, and no cases of brainstem infarction have been reported. One possible cause of cerebral infarction is antiphospholipid antibody syndrome (APS) triggered by the infection. HHV-6 may also directly infect vascular endothelial cells and cause angiopathy. However, the real mechanism of infarction remains unclear. Our patient had a favorable prognosis despite brainstem infarction.

Is Thrombus With Subcutaneous Edema Detected by Ultrasonography Related to Short Peripheral Catheter Failure? A Prospective Observational Study.

Short peripheral catheter (SPC) failure is an important clinical problem. The purpose of this study was to clarify the relationship between SPC failure and etiologies such as thrombus, subcutaneous edema, and catheter dislodgment using ultrasonography and to explore the risk factors associated with the etiologies. Two hundred catheters that were in use for infusion, excluding chemotherapy, were observed. Risk factors were examined by logistic regression analysis. Sixty catheters were removed as the result of SPC failure. Frequency of thrombus with subcutaneous edema in SPC failure cases was significantly greater than in those cases where therapy was completed without complications (P < .01). Multivariate analysis demonstrated that 2 or more insertion attempts were significantly associated with thrombus with subcutaneous edema. Results suggest that subsurface skin assessment for catheterization could prevent SPC failure.

Removal of Peripheral Intravenous Catheters Due to Catheter Failures Among Adult Patients.

This prospective observational study was designed to clarify the rate of peripheral intravenous catheter, especially short peripheral catheter, failures among adult patients in medical and surgical wards. The study was conducted during a 2-month period at a university hospital in Tokyo, Japan. A total of 5316 catheters from 2442 patients were studied. The rate of catheter removal as a result of catheter failure was 18.8%. The reasons for removal in catheter failures were infiltration (41.3%) and pain (19.3%). Pain was a major reason for catheter failure and removal. For this reason, observing changes under the skin before signs and symptoms appear might help prevent catheter failures.

Using Ultrasonography for Vessel Diameter Assessment to Prevent Infiltration.

Small veins are a risk factor for infiltration. However, there are no data regarding the ideal vein diameter for preventing infiltration. Using ultrasound, vessel diameter and calculated ratios of the vessel diameter to the catheter gauge were measured. The relationship between the ratio and infiltration was assessed to establish a cutoff point. The mean ratio of the infiltration group was significantly smaller than that of the no-infiltration group (P < .01), and the ratio was an independent risk factor according to the multivariable analysis. The ratio of 3.3 was determined to be the cutoff point that enables health care professionals to identify veins appropriately.

The relationship between the tip position of an indwelling venous catheter and the subcutaneous edema.

The present observational study aimed to clarify the relationship between the tip position of an indwelling venous catheter and the subcutaneous edema using ultrasonography images. Data were obtained before catheter removal in a medical ward of a university hospital in Tokyo, Japan. Two hundred peripheral intravenous catheters (PIVCs) from 154 patients were observed just before removal. We analyzed data for 194 PIVCs from 150 patients. Subcutaneous edema was observed in 43.8% of ultrasonography images. According to the univariate analysis, insertion site, PIVC tip contact with the vessel wall, and irritant drug's presence were selected as independent variables for logistic regression analysis. Both irritant drug and PIVC tip contact were associated with the presence of subcutaneous edema [adjusted odds ratio (OR) = 2.68, 95% confidence interval (CI) = 1.14-6.33; and OR = 2.01, 95% CI = 1.04-3.88, respectively]. To the best of our knowledge, this is the first study to use ultrasonography to simultaneously observe PIVC tip position and subcutaneous edema. Using ultrasonography to observe PIVC may be a useful method to understand these mechanisms. Medical staff should select an appropriate vein and indwelling catheter to avoid contact of PIVC tip with the vessel wall. Further studies exploring the causality of the relationship between subcutaneous edema, catheter placement, and thrombus formation is required. In addition, further development of nursing skills and medical devices to reduce mechanical stress is required.

COPICAT: a software system for predicting interactions between proteins and chemical compounds.

UNLABELLED: Since tens of millions of chemical compounds have been accumulated in public chemical databases, fast comprehensive computational methods to predict interactions between chemical compounds and proteins are needed for virtual screening of lead compounds. Previously, we proposed a novel method for predicting protein-chemical interactions using two-layer Support Vector Machine classifiers that require only readily available biochemical data, i.e. amino acid sequences of proteins and structure formulas of chemical compounds. In this article, the method has been implemented as the COPICAT web service, with an easy-to-use front-end interface. Users can simply submit a protein-chemical interaction prediction job using a pre-trained classifier, or can even train their own classification model by uploading training data. COPICAT's fast and accurate computational prediction has enhanced lead compound discovery against a database of tens of millions of chemical compounds, implying that the search space for drug discovery is extended by >1000 times compared with currently well-used high-throughput screening methodologies. AVAILABILITY: The COPICAT server is available at http://copicat.dna.bio.keio.ac.jp. All functions, including the prediction function are freely available via anonymous login without registration. Registered users, however, can use the system more intensively.

Total synthesis and absolute configuration of avenolide, extracellular factor in Streptomyces avermitilis.

The first total synthesis of extracellular factor, "Avenolide", in Streptomyces avermitilis has been achieved using a convergent approach. The stereogenic centers in two key segments were installed using Sharpless epoxidation and dihydroxylation. This synthetic study allowed the determination of the absolute configuration of avenolide as 4S,10R, and yielded important information on its structure-activity relationship.

Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis.

Gram-positive bacteria of the genus Streptomyces are industrially important microorganisms, producing >70% of commercially important antibiotics. The production of these compounds is often regulated by low-molecular-weight bacterial hormones called autoregulators. Although 60% of Streptomyces strains may use γ-butyrolactone-type molecules as autoregulators and some use furan-type molecules, little is known about the signaling molecules used to regulate antibiotic production in many other members of this genus. Here, we purified a signaling molecule (avenolide) from Streptomyces avermitilis--the producer of the important anthelmintic agent avermectin with annual world sales of $850 million--and determined its structure, including stereochemistry, by spectroscopic analysis and chemical synthesis as (4S,10R)-10-hydroxy-10-methyl-9-oxo-dodec-2-en-1,4-olide, a class of Streptomyces autoregulator. Avenolide is essential for eliciting avermectin production and is effective at nanomolar concentrations with a minimum effective concentration of 4 nM. The aco gene of S. avermitilis, which encodes an acyl-CoA oxidase, is required for avenolide biosynthesis, and homologs are also present in Streptomyces fradiae, Streptomyces ghanaensis, and Streptomyces griseoauranticus, suggesting that butenolide-type autoregulators may represent a widespread and another class of Streptomyces autoregulator involved in regulating antibiotic production.

[Evaluation of an adaptive filter for CT under low-CNR condition: comparison with linear filter].

The use of an adaptive filter for CT images is becoming a common procedure and is said to reduce image noise while preserving sharpness and helping to reduce the required X-ray dose. Although many reports support this view, the validity of such evaluations is arguable. When the linearity of a system is in question, physical performance indexes should be measured under conditions similar to those of clinical use. Evaluations of diagnosis using clinical images may be fallible because the non-filtered image used as the reference might not have been optimally reconstructed. We have chosen simple, but commonly used, adaptive filters for our evaluation. As a reference for comparing performance, we designed linear filters that best approximate the noise characteristics of the adaptive filters. MTF is measured through observation of the edge-spread function. Clinical abdominal images are used to compare the performance of adaptive filters and linear filters. We conclude that the performance of the type of adaptive filter we have chosen is virtually the same as that of the linear filter, as long as the image quality of soft tissues is our interest. Both the noise SD and MTF are virtually the same if the contrast of the object is not substantially higher than 150 HU. Images of soft tissues obtained with the use of adaptive filters are also virtually the same as those obtained by linear filters. The edge-preservation characteristic of this adaptive filter is not observable for soft tissues.

Polymerase chain reaction-denaturing gradient gel electrophoresis analysis of microbial community structure in landfill leachate.

The structures of microbial communities in water samples obtained from a landfill site that had been a source of environmental pollution by emitting hydrogen sulfide were elucidated using polymerase chain reaction-denaturing gradient gel electrophoresis. The microbial communities, which consisted of a limited number of major microorganisms, were stable for several months. Microorganisms capable of degrading such chemical compounds as 2-hydroxybenzothiazole and bisphenol A were observed in landfill leachate. Microorganisms responsible for the production of hydrogen sulfide were not the primary microbes detected, even in water samples obtained from the site of gas emission.

Removal of tetrafluoroborate ion from aqueous solution using magnesium-aluminum oxide produced by the thermal decomposition of a hydrotalcite-like compound.

Magnesium-aluminum oxide (Mg-Al oxide) prepared by the thermal decomposition of a hydrotalcite-like compound was found to have potential for treating NaBF(4) wastewater. The Mg-Al oxide removed the BF(4)(-) and F(-) and H(3)BO(3) from the NaBF(4) solution. With increasing Mg-Al oxide quantity and time, the BF(4)(-) concentration decreased and the degree of BF(4)(-), F(-), and boron removal increased. The decrease in the BF(4)(-) concentration resulted from uptake by the Mg-Al oxide and not hydrolysis. The Mg-Al oxide took up F(-) from the solution preferentially. The Mg-Al oxide also converted the H(3)BO(3) in the aqueous solution into H(2)BO(3)(-), which it took up.

Synthesis and sulfate ion-exchange properties of a hydrotalcite-like compound intercalated by chloride ions.

To reduce the generation of hydrogen sulfide gas from sulfate ions, we synthesized a layered double hydroxide hydrotalcite-like compound intercalated with chloride ions in the interlayer (HT-Cl) using a coprecipitation reaction. The resultant HT-Cl material had a Mg/Al molar ratio of approximately 2, and the molar fraction of the chloride ions on the intercalated anion layer of the HT was 0.90. A higher molar fraction of chloride ions can be inserted into the interlayers of the HT by increasing the initial concentration ratio of chloride ions to aluminum ions [Cl(-)](0)/[Al(3+)](0) in the solution. Approximately 98% of the sulfate ions in the solution were removed within 10 min after adding 1.12 times the stoichiometric quantity of synthesized HT-Cl, which contained a Mg/Al molar ratio of 2 equal to a solution containing a 12 mM calcium sulfate solution.

[The efficacy of safety winged steel needles on needlestick injuries].

Safety winged steel needles were introduced at the University of Tokyo Hospital in January 2001. We studied their effect in needlestick injuries. A total of 952 'needlestick and sharp-object injuries were reported. From January 1999 to December 2004, Cases of injury with winged steel needles decreased dramatically soon after safety devices were introduced, from 19.8% in Apr.-Dec.2000 to 6.7% in 2001 and 5.5% in 2002 (p < .01). They began to increase, however, in July 2002, decreased again after medical staff members mere given lectures and notices by e-mail. Due to the introduction of safety devices, cases classified as a "while recapping a used needle" and "when puncturing rubber stoppers" decreased. Among 17 injuries with safety winged steel needles, the most common cases were "safety mechanism not activated". We estimated that 76.5% of cases with safety winged steel needles could be prevented if they were used properly. In conclusion, the introduction of safety winged steel needles effectively reduced cases of injury with such needles. It is thus important to regularly remind hospital staff of safety device techniques and information reduce the such injuries.

Preliminary investigation of the supply of chemical species to an aqueous solution using a hydrogen-oxygen flame.

A new method of supplying radical species to aqueous solutions using a hydrogen-oxygen flame is investigated. When a hydrogen-oxygen flame is directed on the surface of an aqueous solution, hydroxyl radicals (*OH) produced in the flame are extracted into the aqueous phase. The presence of *OH in the aqueous solution was confirmed by electron paramagnetic resonance with spin trapping using 5,5-dimethyl-1-pyrroline-N-oxide. The extraction of *OH into the aqueous solution was monitored using a quantitative analysis of hydrogen peroxide (H2O2). The effects of the hydrogen and oxygen gas flow rates, hydrogen/oxygen ratio, and atmosphere on H2O2 formation were studied. When the hydrogen-oxygen flame blew on a phosphate buffer solution (pH 6.7) under an Ar atmosphere, the concentration of H2O2 increased with the blowing time of the flame and the flow rate of hydrogen gas. Under air, nitrate and nitrite ions were formed in the aqueous phase in addition to H2O2, and the H2O2 concentration was lower than that under argon. The application of this new method to an aqueous solution of Cu(II)-ethylenediaminetetraacetic acid (EDTA) caused a remarkable decrease in the concentration of Cu(II)-EDTA and total organic carbon.

Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan.

OBJECTIVES: To evaluate the immune status of healthcare workers (HCWs) against measles, rubella, mumps, and varicella in Japan, and to promote an adequate vaccination program among HCWs. SETTING: University of Tokyo Hospital. PARTICIPANTS: Eight hundred seventy-seven HCWs. DESIGN: Serologic screening for measles, rubella, mumps, and varicella was performed on HCWs. Antibodies against measles, rubella, and mumps were detected using hemagglutination inhibition (HI) assay ($4.20 per test). If serum was negative by HI assay, enzyme-linked immunosorbent assay (EIA) was performed ($12.60 per test). Anti-varicella antibodies were detected by EIA only. RESULTS: Among tested HCWs, 98.5%, 90.4%, 85.8%, and 97.2% had immunity to measles, rubella, mumps, and varicella, respectively. All those born before 1970 were seropositive for measles. However, individuals susceptible to rubella, mumps, and varicella were present in all age groups. The sensitivities and negative predictive values of HI assay compared with EIA were 86.6% and 11.3% for measles, 99.1% and 92.2% for rubella, and 47.8% and 24.1% for mumps, respectively. For measles and mumps, prevaccination screening by HI assay in combination with EIA led to significant savings compared with EIA only. In contrast, it was estimated that prevaccination screening using only HI assay would be more economical for rubella. CONCLUSIONS: Aggressive screening and vaccination of susceptible HCWs was essential regardless of age. Prevaccination serologic screening using a combination of HI assay and EIA was more economical for measles and mumps.

Decomposition of 2-bromophenol in NaOH solution at high temperature.

2-Bromophenol was reacted in aqueous sodium hydroxide at 200-250 degrees C. The decomposition rate was remarkably faster at 250 degrees C than at 225 or 200 degrees C, and the percentage debromination reached almost 100% in 1M NaOH at 250 degrees C for 4h. The percentage increased with NaOH concentration over the range 0.1-1M. Aliphatic compounds, such as 2,2-dimethoxypropane and 4-hydroxy-4-methyl-2-pentanone, and aromatic compounds, such as phenol and cresol, were formed as decomposition products. The formation of carboxylic acids, such as formic, acetic, and propionic acids, in the presence of oxygen was also confirmed. Under a nitrogen atmosphere, the oxidation caused by oxygen in solution was suppressed and hydrolysis became the dominant reaction in the decomposition of 2-bromophenol.

The simultaneous removal of calcium and chloride ions from calcium chloride solution using magnesium-aluminum oxide.

We investigated the removal of Ca(2+) and Cl(-) from CaCl(2) solution at 20-60 degrees C, using magnesium-aluminum oxide, Mg(0.80)Al(0.20)O(1.10), prepared by the thermal decomposition of a hydrotalcite-like compound, Mg(0.80)Al(0.20)(OH)(2)(CO(3))(0.10).0.78 H(2)O. The degree of Ca(2+) and Cl(-) removal from the solution increased with increasing initial CaCl(2) concentration, temperature, and quantity of Mg(0.80)Al(0.20)O(1.10) added. When Mg(0.80)Al(0.20)O(1.10) was added to 0.25 M CaCl(2) solution in a Mg(0.80)Al(0.20)O(1.10)/CaCl(2) molar ratio of 20, the degree of Ca(2+) and Cl(-) removal from the solution at 60 degrees C after 0.5 h was 93.0% and 98.2%, respectively. These results reveal that Mg(0.80)Al(0.20)O(1.10) has the capacity to remove Ca(2+) and Cl(-) simultaneously from aqueous solution.