Dual near-infrared II laser modulates the cellular redox state of T cells and augments the efficacy of cancer immunotherapy.

Immunotherapy, including immune checkpoint inhibitors, has revolutionized cancer treatment, but only a minor fraction of patients shows durable responses. A new approach to overcome this limitation is yet to be identified. Recently, we have shown that photobiomodulation (PBM) with near-infrared (NIR) light in the NIR-II window reduces oxidative stress and supports the proliferation of CD8+ T cells, suggesting that PBM with NIR-II light could augment anti-cancer immunity. Here, we report a novel approach to support tumor-infiltrating CD8+ T cells upon PBM with NIR-II laser with high tissue penetration depth. Brief treatments of a murine model of breast cancer with dual 1064 and 1270 nm lasers reduced the expression of the programmed cell death protein 1 (PD-1) in CD8+ T cells in a syngeneic mouse model of breast cancer. The direct effect of the NIR-II laser treatment on T cells was confirmed by the enhanced tumor growth delay by the adoptive transfer of laser-treated CD8+ T cells ex vivo against a model tumor antigen. We further demonstrated that specific NIR-II laser parameters augmented the effect of the immune checkpoint inhibitor on tumor growth. PBM with NIR-II light augments the efficacy of cancer immunotherapy by supporting CD8+ T cells. Unlike the current immunotherapy with risks of undesirable drug-drug interactions and severe adverse events, the laser is safe and low-cost. It can be broadly combined with other therapy without modification to achieve clinical significance. In addition, our study established a path to develop a novel laser-based therapy to treat cancer effectively.

Treatment of Gingival Recession in Multiple Teeth Using Coronally Advanced Flap with Connective Tissue Graft: A Case Report.

This report describes a case of gingival recession in multiple teeth with severe dentin hypersensitivity (DH) in which treatment included periodontal plastic surgery. The patient was a 34-year-old woman presenting with the chief complaint of DH at gingivalrecession sites. The patient had undergone orthodontic treatment when she was 30 years old. An initial examination revealed that none of the sites showed a probing depth of ≥4 mm and 21% of sites bleeding on probing. The clinical diagnosis was plaque-induced gingivitis. Teeth #14, 16, 23, 25, 26, 34, 35, 45, and 46 showed gingival recession ranging from 1 to 4 mm. Gingival recession at #45 extended to the muco-gingival junction. No association with alveolar bone loss was observed in any of the interdental areas. Therefore, the sites presenting with gingival recession were classified as Miller Class I, except #45, which was classified as Class II. The periodontal phenotype was 'thin'. Based on the results of clinical examination and diagnosis, initial periodontal therapy (IP) consisting of oral hygiene instruction, supra-gingival scaling, application of a desensitizing agent, and composite resin restoration was performed. The Visual Analog Scale (VAS) score, which was used to assess degree of DH, showed only a minimal decrease, however, at post-IP. Subsequently, a modified coronally advanced tunnel (a modified technique for achieving a coronally advanced flap) using a connective tissue graft was performed in #14, 16, 23, 25, 26, 45, and 46. After re-evaluation, the patient was placed on maintenance care. The series of interventions resulted in a considerable improvement in the VAS and oral health-related quality of life scores. Furthermore, a change in the periodontal phenotype, from 'thin' to 'thick', was observed, which may contribute to the prevention of further gingival recession and DH. The present case suggests that periodontal plastic surgery is an effective treatment modality for the resolution of DH.

Treatment of Chronic Periodontitis with Smoking Cessation Care and Periodontal Surgery in an Elderly Patient: A Case Report Including a 4-year Follow-up.

This report describes a case of chronic periodontitis requiring treatment including smoking cessation care and periodontal surgery in an elderly patient with a long-term smoking habit. The patient, a 79-year-old man, presented with the chief complaint of halitosis. He had a 56-year history of smoking cigarettes. An initial examination revealed that 34.5% of sites had a probing depth (PD) of ≥4 mm, with 24.1% of sites showing bleeding on probing (BOP). Open bite and loss of appropriate anterior and lateral guidance were also found. Radiographic examination revealed extensive horizontal bone resorption in the maxillary and mandibular molars. Based on a clinical diagnosis of severe generalized chronic periodontitis, initial periodontal therapy consisting of plaque control, smoking cessation care, scaling and root planing, and caries treatment of #47 was performed. Prosthetic treatment with a removable partial denture was planned for #26, which was missing. The patient quit smoking at the end of initial periodontal therapy. Subsequently, surgical periodontal therapy including open flap debridement was performed on #16, #17, #18, and #27. Following reevaluation, a full metal crown (#47) and removal partial denture (#26) were placed. The patient was then placed on supportive periodontal therapy (SPT). Periodontal treatment including surgical therapy resulted in an improvement in PD and a reduction in the number of sites with BOP. The patient has not started smoking again since initial treatment. Improvement has been adequately maintained over a 4-year period. The present results suggest that even when a patient has been exposed to a risk factor for a long time, periodontal treatment and control of that risk factor can contribute to stabilization of periodontal conditions. Some problems with occlusion have persisted, however. Additional care is necessary to retain stable periodontal conditions during SPT.

Effect of Periodontal Treatment on Reducing Chronic Inflammation in Systemically Healthy Patients With Periodontal Disease.

BACKGROUND: We determined the effects and an accurate marker of periodontal treatment on serum interleukin (IL)-6 and high-sensitivity C-reactive protein (HsCRP) levels in systemically healthy individuals with periodontal disease. METHODS: This multicenter study included systemically healthy individuals with periodontal disease who received initial periodontal treatment and had no periodontal treatment history. Periodontal parameters, including periodontal inflamed surface area, masticatory efficiency, and periodontal disease classification; serum IL-6 and HsCRP levels; and serum immunoglobulin (Ig)G titers against periodontal pathogens were evaluated at baseline and after treatment. Subjects were classified as low or high responders (group) based on periodontal inflamed surface area changes. RESULTS: There were 153 participants. Only periodontal inflamed surface area changes were markedly different between low and high responders. Periodontal treatment (time point) decreased both serum IL-6 and HsCRP levels. The interaction between group and time point was remarkable only for serum IL-6 levels. Changes in serum immunoglobulin (Ig)G titers against periodontal pathogens were not associated with IL-6 changes in high responders. We analyzed the indirect effect of serum anti-Porphyromonas gingivalis type 2 IgG titer changes using mediation analysis and found no significance. However, the direct effect of group (low or high responder) on IL-6 changes was considerable. CONCLUSIONS: Periodontal treatment effectively decreased serum IL-6 levels, independent of periodontal pathogen infection, in systemically healthy individuals with periodontal disease.

Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods.

To address the issue of excess polyethylene glycol (PEG)-lipid degradation observed when PEG-modified liposomes are prepared using the pH-gradient method, a concept using a novel PEG-modification method, called the post-modification method, was proposed and evaluated. To assess the proof concept, a preservation-stability study and a pharmacokinetic study were performed that compared the conventional PEG-modification method, called the pre-modification method, with the post-modification method. The results show that PEG-lipid degradation could be markedly inhibited in the post-modification method. Furthermore, the post-modification method could be used without any manufacturing process difficulties, especially with high PEG-lipid content. In addition, a higher blood circulation capability was observed in the post-modification method. Through comparative studies, it was found that the post-modification method was advantageous compared to the pre-modification method. In conclusion, the post-modification method has the potential to be a novel PEG-modification method that can achieve a higher preservation stability of PEG-lipid, a greater ease of manufacturing, and a higher blood circulation capability, especially in the manufacturing of pH-gradient liposomal products.

Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods.

Recently, a polyethylene glycol (PEG)-modification method for liposomes prepared using pH-gradient method has been proposed. The differences in the pharmacokinetics and the impact on the antitumor effect were examined; however the impact of PEG-lipid molar weight has not been investigated yet. The main purpose of this study is to evaluate the impact of PEG-lipid molar weight against the differences in the pharmacokinetics, the drug-release profile, and the antitumor effect between the proposed PEG-modification method, called the post-modification method, and the conventional PEG-modification method, called the pre-modification method. Various comparative studies were performed using irinotecan as a general model drug. The results showed that PEG-lipid degradation could be markedly inhibited in the post-modification method. Furthermore, prolonged circulation time was observed in the post-modification method. The sustained drug-release was observed in the post-modification method by the results of the drug-releasing test in plasma. Moreover, a higher antitumor effect was observed in the post-modification method. It was also confirmed that the same behaviors were observed in all comparative studies even though the PEG molecular weight was lower. In conclusion, the post-modification method has the potential to be a valuable PEG-modification method that can achieve higher preservation stability of PEG-lipid, prolonged circulation time, and higher antitumor effect with only half the amount of PEG-lipid as compared to the pre-modification method. Furthermore, it was demonstrated that PEG(5000)-lipid would be more desirable than PEG(2000)-lipid since it requires much smaller amount of PEG-lipid to demonstrate the same performances.

Proximal Renal Tubular Acidosis Complicated by Severe Hypocalcemia Caused by Malnutrition and Inappropriate Long-term Use of Zoledronate: A Case Report and Review of the Literature.

An 80-year-old man presented with electrolyte abnormalities, particularly hypocalcemia (3.6 mg/dL). He was diagnosed with bone and lymph node metastases from prostate cancer seven years earlier and continuously received goserelin, bicalutamide, and zoledronate. He later developed gradually worsening hypocalcemia, hypokalemia, hypophosphatemia, hypouricemia, renal dysfunction, and weight loss. Urinary potassium and phosphate loss, renal glucosuria, metabolic acidosis, and a low urine pH (5.0) were observed. Given the acquired onset and clinical course, we diagnosed the patient with zoledronate-induced proximal renal tubular acidosis. In the present case, severe hypocalcemia may have been caused by malnutrition and inappropriate long-term use of zoledronate.

Periodontal Regenerative Therapy Using rhFGF-2 and Deproteinized Bovine Bone Mineral versus rhFGF-2 Alone: 4-Year Extended Follow-Up of a Randomized Controlled Trial.

The aim of this study was to evaluate longitudinal outcomes of recombinant human fibroblast growth factor (rhFGF)-2 plus deproteinized bovine bone mineral (DBBM) therapy in comparison with rhFGF-2 alone for treating periodontal intrabony defects. This study describes 4-year follow-up outcomes of the original randomized controlled trial. Intrabony defects in periodontitis patients were treated with rhFGF-2 (control) or rhFGF-2 plus DBBM (test). Clinical, radiographic, and patient-reported outcome (PRO) measures were used to evaluate the outcomes. Thirty-two sites were able to be followed up. At 4 years postoperatively, clinical attachment level (CAL) gains in the test and control groups were 3.5 ± 1.4 mm and 2.7 ± 1.4 mm, respectively, showing significant improvement from preoperative values but no difference between groups. Both groups showed an increase in radiographic bone fill (RBF) over time. At 4 years, the mean value for RBF in the test group (62%) was significantly greater than that in the control group (42%). In 1-2-wall defects, the test treatment yielded significantly greater RBF than the control treatment. No significant difference in PRO scores was noted between the groups. Although no significant difference in CAL gain was found between the groups at the 4-year follow-up, the combination treatment significantly enhanced RBF. Favorable clinical, radiographic outcomes, and PRO in both groups can be maintained for at least 4 years.

[Validity of hypotheses about the father/mother interpretation of Rorschach cards: tested by using a card selecting method].

This study tests the validity of hypotheses about the interpretations of Rorschach father/mother cards by having subjects select the cards. The results showed that regardless of the subject's gender, Card IV is far more often selected as the father card. However Card VII is not more often chosen as the mother card, if anything, the Color Cards are usually selected. The result of a correspondence analysis suggest that a certain combination of father and mother cards is more often selected. When the frequency of card selection is applied to the cluster of cards obtained in the study of Fukui et al (2008), the mother card is predominantly selected from the feminine/maternity-cards cluster. However, the father card was selected equally often from three clusters, indicating variation of the father figure. The results indicate the predominance of Card IV as the father card, and also confirm the lack of individuality with Card VII. Therefore, Card IV fulfills prerequisites for the father card hypothesis, while Card VII does not meet the criteria. The results do not support the validity of the hypothesis about the mother card interpretation.

Smart hospital infrastructure: geomagnetic in-hospital medical worker tracking.

PURPOSE: Location visualization is essential for locating people/objects, improving efficiency, and preventing accidents. In hospitals, Wi-Fi, Bluetooth low energy (BLE) Beacon, indoor messaging system, and similar methods have generally been used for tracking, with Wi-Fi and BLE being the most common. Recently, nurses are increasingly using mobile devices, such as smartphones and tablets, while shifting. The accuracy when using Wi-Fi or BLE may be affected by interference or multipath propagation. In this research, we evaluated the positioning accuracy of geomagnetic indoor positioning in hospitals. MATERIALS AND METHODS: We compared the position measurement accuracy of a geomagnetic method alone, Wi-Fi alone, BLE beacons alone, geomagnetic plus Wi-Fi, and geomagnetic plus BLE in a general inpatient ward, using a geomagnetic positioning algorithm by GiPStech. The existing Wi-Fi infrastructure was used, and 20 additional BLE beacons were installed. Our first experiment compared these methods' accuracy for 8 test routes, while the second experiment verified a combined geomagnetic/BLE beacon method using 3 routes based on actual daily activities. RESULTS: The experimental results demonstrated that the most accurate method was geomagnetic/BLE, followed by geomagnetic/Wi-Fi, and then geomagnetic alone. DISCUSSION: The geomagnetic method's positioning accuracy varied widely, but combining it with BLE beacons reduced the average position error to approximately 1.2 m, and the positioning accuracy could be improved further. We believe this could effectively target humans (patients) where errors of up to 3 m can generally be tolerated. CONCLUSION: In conjunction with BLE beacons, geomagnetic positioning could be sufficiently effective for many in-hospital localization tasks.

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy.

In the present study, we analyzed the function of a novel mutation (c.1628T>G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a+c.1628T>G or *1b+c.1628T>G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V(max) values of the variants, not due to change in their K(m) values. OATP1B1*1b+c.1628T>G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T>G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.

Use of in-Hospital Geomagnetic Fingerprinting Localization.

Recently, visualizing location of people and things in a hospital has become an issue particularly for improving work efficiency and incident prevention. Although radio frequency waves such as Wi-Fi and Bluetooth are commonly used in indoor positioning, they have several limitations owing to their physical characteristics. We proposed in-hospital hybrid positioning technique, involving a combination of radio waves and geomagnetic fingerprinting techniques. We compared accuracy of proposed technique with that of Wi-Fi- and BLE-based techniques.

Digital gene atlas of neonate common marmoset brain.

Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene-atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research.

Population Pharmacokinetic and Exposure-Response Analysis of Weekly Teriparatide in Osteoporosis Patients.

Teriparatide is a potent therapeutic agent for the treatment of osteoporosis. One of the aims of this analysis was to develop a population pharmacokinetic (PPK) model to understand the pharmacokinetic characteristics of the once-weekly formulation of teriparatide. Another aim was to develop an exposure-response model to describe the relationship between change in bone mineral density (BMD) and teriparatide exposure after weekly subcutaneous administration. The PPK analysis showed that apparent total body clearance was significantly influenced by estimated creatinine clearance and the presence of osteoporosis. A data set consisting of lumbar spine BMD values for 513 osteoporosis patients whose area under the concentration-time curve (AUC) of teriparatide acetate was estimated by the developed PPK model was then compiled. Exposure-response analysis showed that the percentage change from baseline of BMD was well described by a function of the AUC of teriparatide acetate, time, and coadministration of alfacalcidol and a calcium preparation. The analysis indicated that AUC is an important parameter for predicting BMD response to once-weekly teriparatide in osteoporosis patients.

Morphological features and important parameters of large optic discs for diagnosing glaucoma.

PURPOSE: To compare the optic disc parameters of glaucomatous eyes to those of non-glaucomatous eyes with large discs. METHODS: We studied 225 consecutive eyes with large optic discs (>2.82 mm2): 91 eyes with glaucoma and 134 eyes without glaucoma. An eye was diagnosed with glaucoma when visual field defects were detected by the Humphrey Field Analyzer. All of the Heidelberg Retina Tomograph II (HRT II) parameters were compared between the non-glaucomatous and glaucomatous eyes. A logistic regression analysis of the HRT II parameters was used to establish a new formula for diagnosing glaucoma, and the sensitivity and specificity of the Moorfields Regression Analysis (MRA) was compared to the findings made by our analyses. RESULTS: The mean disc area was 3.44±0.50 mm2 in the non-glaucomatous group and 3.40±0.52 mm2 in the glaucoma group. The cup area, cup volume, cup-to-disc area ratio, linear cup/disc ratio, mean cup depth, and the maximum cup depth were significantly larger in glaucomatous eyes than in the non-glaucomatous eyes. The rim area, rim volume, cup shape measurement, mean retinal nerve fiber layer (RNFL) thickness, and RFNL cross-sectional area were significantly smaller in glaucomatous eyes than in non-glaucomatous eyes. The cup-to-disc area ratio, the height variation contour (HVC), and the RNFL cross-sectional area were important parameters for diagnosing the early stage glaucoma, and the cup-to-disc area ratio and cup volume were useful for diagnosing advanced stage glaucoma in eyes with a large optic disc. The new formula had higher sensitivity and specificity for diagnosing glaucoma than MRA. CONCLUSIONS: The cup-to-disc area ratio, HVC, RNFL cross-sectional area, and cup volume were important parameters for diagnosing glaucoma in eyes with a large optic disc. The important disc parameters to diagnose glaucoma depend on the stage of glaucoma in patients with large discs.

Designing a novel in vitro drug-release-testing method for liposomes prepared by pH-gradient method.

In order to evaluate the drug-release behavior from pH-gradient liposomal formulation, a simple release-testing method without using biological components was newly designed on the basis of inversed ammonia gradient principle. Various factors influencing drug-release (releasing factor) were examined. As a result, releasing factor's concentration, pH, osmolarity in test fluid, and releasing factor's structure were found to be the critical factors to be optimized. Various vincristine-loaded liposomes with different lipid compositions or with different lipid/cholesterol ratio were tested for drug-release behavior and successfully obtained drug-release profiles reflecting differences in the physicochemical properties of individual liposomes. Furthermore, since the comparative release study of vincristine-loaded liposomes and doxorubicin-loaded liposomes could reproduce the phenomena as other researchers recently reported, a possibility was suggested for the proposed method to estimate the physicochemical status of drug inside of liposomes. Proof of concept study concluded, as a whole, that the novel release-testing method would be useful for a formulation study and also useful as a tool for the quality assurance or quality control in the manufacturing of pH-gradient liposomal products.

Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells.

OBJECTIVES: SLCO1B1*5 and SLCO1B1*15 have been reported to reduce the clearance of pravastatin in healthy volunteers. However, there remains controversy in the effects of SLCO1B1*5 on the activity of OATP1B1 in vitro. In addition, the effect of SLCO1B1*15 on the function of OATP1B1 has not been studied using cDNA-expression systems. Object of the present study was to study the influence of SLCO1B1*5, *15 and *15+C1007G, a novel haplotype found in a patient with pravastatin-induced myopathy, on the functional properties of OATP1B1 by transient expression systems of HEK293 and HeLa cells using endogenous conjugates and statins as substrates. METHODS: Transporting assays for endogenous substrates were performed using tritium labeled estradiol-17beta-D-glucuronide and estrone-3-sulfate. Quantitation of pravastatin, atorvastatin, cerivastatin and simvastatin were carried out using HPLC tandem mass spectrometry. RESULTS: The transporting activities of cells expressing SLCO1B1*5, *15 and *15+C1007G decreased significantly but those of SLCO1B1*1b, *1a+C1007G and *1b+C1007G were not altered for all of the substrates tested except for simvastatin. Kinetic analysis of pravastatin and atorvastatin showed that Km values were not altered but Vmax values decreased significantly in cells expressing SLCO1B1*5, *15 and *15+C1007G. Immunocytochemical study showed that SLCO1B1*5, *15 and *15+C1007G proteins are localized not only at the plasma membrane but also in the intracellular space. CONCLUSIONS: These findings suggest that 521T>C, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this SNP.

Cell-adhesive and blood-coagulant properties of ultrathin poly(methyl methacrylate) stereocomplex films.

Isotactic (it) and syndiotactic (st) poly(methyl methacrylate)s (PMMAs) were assembled on a poly(ethylene terephthalate) cell disk (as a solid substrate), which is normally used for cell culture, to produce ultrathin stereocomplex films. Static contact angles of the films using air bubbles in aqueous phase revealed the stepwise assembly of both polymers. More L929 fibroblast cells adhered and were flattened on the ultrathin stereocomplex films, compared to homogeneous PMMA films and to spin-coated films comprised of a mixed solution of it- and st-PMMAs with a molar ratio of 1 : 2, which is the stoichiometry of a stereocomplex. The difference in the number of adherent cells was greatest after the first 3 h of incubation. Pre-adsorption of proteins, which are related to cell adhesion, onto the stereocomplex film potentially modulated the cell-adhesive properties. Fresh whole human blood did not coagulate on the complex film for 20 min, although blood coagulated after 15 min on the homogeneous films and on the 1 : 2 mixed film. Platelets did not adhere onto the complex films after 15 min of incubation, which was consistent with the results of blood coagulation. These observations indicate that the stereocomplex formation of PMMAs on the surface of films strongly affects the bioactivity of these films.