Platelet PD-L1 suppresses anti-cancer immune cell activity in PD-L1 negative tumors.

Strategies that interfere with the binding of the receptor programmed cell death protein-1 (PD-1) to programmed death ligand-1 (PD-L1) have shown marked efficacy against many advanced cancers, including those that are negative for PD-L1. Precisely why patients with PD-L1 negative tumors respond to PD-1/PD-L1 checkpoint inhibition remains unclear. Here, we show that platelet-derived PD-L1 regulates the growth of PD-L1 negative tumors and that interference with platelet binding to PD-L1 negative cancer cells promotes T cell-induced cancer cytotoxicity. These results suggest that the successful outcomes of PD-L1 based therapies in patients with PD-L1 negative tumors may be explained, in part, by the presence of intra-tumoral platelets. Altogether, our findings demonstrate the impact of non-cancer/non-immune cell sources of PD-L1 in the tumor microenvironment in the promotion of cancer cell immune evasion. Our study also provides a compelling rationale for future testing of PD-L1 checkpoint inhibitor therapies in combination with antiplatelet agents, in patients with PD-L1 negative tumors.

Psychoacoustics and neurophysiological auditory processing in patients with Charcot-Marie-Tooth disease types 1A and 2A.

BACKGROUND AND PURPOSE: Hidden hearing loss has been reported in patients with Charcot-Marie-Tooth (CMT) disease; however, the auditory-processing deficits have not been widely explored. We investigated the psychoacoustic and neurophysiological aspects of auditory processing in patients with CMT disease type 1A (CMT1A) and type 2A (CMT2A). METHODS: A total of 43 patients with CMT1A and 15 patients with CMT2A were prospectively enrolled. All patients with CMT disease had normal sound-detection ability by using pure-tone audiometry. Spectral-ripple discrimination, temporal modulation detection and auditory frequency-following response were compared between CMT1A, CMT2A and control groups. RESULTS: Although all participants had normal audiograms, patients with CMT disease had difficulty understanding speech in noise. The psychoacoustic auditory processing was somewhat different depending on the underlying pathophysiology of CMT disease. Patients with CMT1A had degraded auditory temporal and spectral processing. Patients with CMT2A had no reduced spectral resolution, but they showed further reduced temporal resolution than the patients with CMT1A. The amplitudes of the frequency-following response were reduced in patients with CMT1A and CMT2A, but the neural timing remained relatively intact. CONCLUSIONS: When we first assessed the neural representation to speech at the brainstem level, the grand average brainstem responses were reduced in both patients with CMT1A and CMT2A compared with healthy controls. As the psychoacoustic aspects of auditory dysfunctions in CMT1A and CMT2A were somewhat different, it is necessary to consider future auditory rehabilitation methods based on their pathophysiology.

Once-daily dosing of amikacin for treatment of Mycobacterium abscessus lung disease.

SETTING: Tertiary referral centre, Samsung Medical Center, South Korea. OBJECTIVE: To evaluate the pharmacokinetic parameters and toxicities of once-daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus. DESIGN: A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015. RESULTS: With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 µg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047). CONCLUSION: Our results suggest that once-daily AMK for 4 weeks with a target Cmax of 55-65 µg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity.

Automatic facial pore analysis system using multi-scale pore detection.

BACKGROUND/PURPOSE: As facial pore widening and its treatments have become common concerns in the beauty care field, the necessity for an objective pore-analyzing system has been increased. Conventional apparatuses lack in usability requiring strong light sources and a cumbersome photographing process, and they often yield unsatisfactory analysis results. This study was conducted to develop an image processing technique for automatic facial pore analysis. METHODS: The proposed method detects facial pores using multi-scale detection and optimal scale selection scheme and then extracts pore-related features such as total area, average size, depth, and the number of pores. Facial photographs of 50 subjects were graded by two expert dermatologists, and correlation analyses between the features and clinical grading were conducted. We also compared our analysis result with those of conventional pore-analyzing devices. RESULTS: The number of large pores and the average pore size were highly correlated with the severity of pore enlargement. In comparison with the conventional devices, the proposed analysis system achieved better performance showing stronger correlation with the clinical grading. CONCLUSION: The proposed system is highly accurate and reliable for measuring the severity of skin pore enlargement. It can be suitably used for objective assessment of the pore tightening treatments.

Intraoral pH and temperature during sleep with and without mouth breathing.

To measure and compare the intraoral pH and temperature of individuals during sleep with and without mouth breathing. Ten healthy participants [mean age = 25·8 (± 4·3)] wore a custom-made appliance fitted with a pH probe and thermocouple for two sets of 48 h. Continuous pH and temperature measurements were taken from the palatal aspect of the upper central incisors. To simulate mouth breathing during sleep, participants wore a nose clip for two nights of the four, with the first group (n = 5) wearing the nose clip during the first night and the rest (n = 5) wearing the nose clip during the second night of sleep to balance any potential bias from the wearing sequence. Both qualitative and quantitative analyses were conducted. The mean intraoral pH during daytime was 7·3 (± 0·4) and during sleep was 7·0 (± 0·5). The mean intraoral pH during sleep with mouth breathing was 6·6 (± 0·5), which was statistically significant compared with the normal sleep condition (P < 0·01). The intraoral pH decreased slowly over the hours of sleep in all participants. When sleeping with forced mouth breathing, intraoral pH showed a greater fall over a longer period of time. The mean intraoral temperature was 33·1 °C (± 5·2) during daytime and 33·3 °C (± 6·1) during sleep, with no statistical significance between sleep with and without mouth breathing (P > 0·05). The results suggest that mouth breathing during sleep is related to a decrease in intraoral pH compared with normal breathing during sleep, and this has been proposed as a causal factor for dental erosion and caries.

Continuous measurement of intra-oral pH and temperature: development, validation of an appliance and a pilot study.

To describe a novel approach for continuous measurement of intra-oral pH and temperature in individuals carrying out normal daily activities over 24 h. We designed, validated and constructed a custom-made appliance fitted with a pH probe and a thermocouple. Six subjects wore the appliance over a 24-h period for two non-consecutive days, while the intra-oral pH and temperature were measured continuously and recorded. Intra-oral pH and temperature were very similar across different recording days, the difference being not statistically significant (P ≥ 0.14). There was a noticeable difference in the pattern of variation of pH between day and night. During the day, the mean pH was 7.3 (±0.4) and dropped markedly only after consumption of acidic food and drinks. The intra-oral pH decreased slowly during sleep with an average pH of 6.6 (±0.4) being recorded. The difference between day and night was statistically significant (P = 0.002). The mean intra-oral temperature was 33.9 °C (±0.9) during daytime and 35·9 °C (±0·5) during sleep (P = 0.013) with minor fluctuations occurring over 24 h. The continuous and simultaneous intra-oral pH and temperature measurement system described in this report is reliable, easy to construct, able to measure variables over a sustained period and may serve as a future diagnostic tool in a number of applications.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Analytic parallel-polarized light imaging technique using various light-emitting diodes: a comparison with skin conductance values.

BACKGROUND: The quantitative difference of the light reflected from a skin surface can be analyzed using parallel-polarized light (PPL) photography when combined with an analytic technique similar to colorimetric photography. OBJECTIVE: To improve the PPL photography technique as an assessment tool for the evaluation of skin condition using light-emitting diodes (LED) of different colors. METHOD: Parallel-polarized light images were taken using white and green LED illuminators. The acquired images were transformed to CIELAB coordinates. An in-house skin conductance meter was constructed to assess skin hydration level. A dermatologist evaluated the clinical grading of dryness and glossiness. These clinical severities were also compared statistically with the CIELAB values. RESULTS: As with the green illuminator, the correlation analysis of whole sites showed that the L* value positively correlated with age (r = 0.18677, P < 0.05), and that the a* value has negative and positive relationships with age (r = -0.20528, P < 0.05) and glossiness (r = 0.20885, P < 0.05) respectively. CONCLUSION: The correlations between CIELAB values and multiple characteristics of skin were more significant when green LED was applied than when white light was applied. In addition, coherent relationships between the grade of dryness and skin conductance values showed that visual assessment could be appropriate for the study as with objective measurement.

Genetic variants of AICDA/CASP14 associated with childhood brain tumor.

We conducted a hospital-based case-control study in Korea to investigate whether apoptosis- and cell cycle control-related genes are associated with childhood brain tumor. Incident brain tumor cases (N = 70) and non-cancer controls (N = 140), frequency-matched by age and gender, were selected from 3 teaching hospitals in Seoul between 2003 and 2006. Tag single nucleotide polymorphisms (SNPs) (N = 297) in 30 genes related to apoptosis and cell cycle control were selected using a pairwise linkage-disequilibrium-based algorithm. Five tag SNPs in 2 genes (AICDA and CASP14) remained significant after adjusted multiple tests. The most significant association with childhood brain tumor risk was for IVS1-401G>C in the AICDA gene [odds ratio (OR) = 2.8; 95% confidence interval (95%CI) = 1.25-6.46]; the polymorphism *9276A>C of CASP14 was associated with decreased brain tumor risk (OR = 0.4; 95%CI = 0.19-0.95). We concluded that genetic polymorphisms in AICDA and CASP14 are associated with risk for brain tumor in Korean children.

Activation of eukaryotic initiation factor-2 α-kinases in okadaic acid-treated neurons.

Phosphorylation of eukaryotic initiation factor-2 alpha (eIF2 alpha) is increased in Alzheimer's disease (AD) and this protein can be phosphorylated by several kinases, including double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), amino acids-regulated eIF2 alpha kinase (GCN2) and heme-regulated eIF2 alpha kinase (HRI). PKR and PERK especially are activated in the AD brain, and GCN2 is reported to increase presenilin-1 (PS1) activity. Okadaic acid (OA), a protein phosphatase-2A (PP2A) inhibitor, is known to increase tau phosphorylation, beta-amyloid (A beta) deposition and neuronal death, which are the pathological characteristics of AD. Here, we show that the phosphorylation of eIF2 alpha is increased and its kinases, PKR, PERK and GCN2 are activated in rat neurons by OA. Activating transcription factor (ATF4) which induces apoptosis in response to eIF2 alpha phosphorylation was increased and translocated to nuclei in OA-treated neurons. These results suggest that the successive events of activation of eIF2 alpha kinases and eIF2 alpha phosphorylation leading to ATF4 nuclear translocation may contribute to neuronal death. However, PKR inhibitors did not reduce eIF2 alpha phosphorylation or neuronal toxicity despite inhibiting PKR activity. These results suggest that PKR might not be the most responsible kinase for eIF2 alpha phosphorylation or cell death in PP2A-inhibited conditions such as AD.

Intratendinous ganglion cyst of the semimembranosus tendon.

Intratendinous ganglion cyst is a very rare lesion with an unknown aetiology that originates within the tendon. We encountered a case of 43-year-old woman who complained of a palpable, non-tender mass in the thigh with increasing swelling. An intratendinous ganglion cyst in the semimembranosus tendon of the lower extremity was diagnosed and located by ultrasound and MRI. Nine months after a surgical excision, there were recurrent ganglion cysts along the semimembranosus tendon. We describe this case with a review of the relevant literature.

G protein beta3 subunit, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms in Koreans with irritable bowel syndrome.

BACKGROUND: The association between irritable bowel syndrome (IBS) based on Rome III criteria and G protein beta3 subunit (GNB3), interleukin (IL)-10, and tumor necrosis factor (TNF)-alpha gene polymorphisms is uncertain. METHODS: Case and control subjects were recruited from Korean visitors to the Health Promotion Center and Digestive Disease Center for gastrointestinal endoscopy. G protein beta3 subunit, IL-10, and TNF-alpha gene polymorphisms were genotyped using a polymerase chain reaction-based method. Multifactor dimensionality reduction (MDR) analysis was used to assess gene-gene interactions. KEY RESULTS: Genotype and allele frequencies of GNB3 showed marginal significance between the healthy controls and IBS patients (chi(2) = 5.92, P = 0.052; chi(2) = 3.76, P = 0.053). G protein beta3 subunit T allele was more strongly correlated with IBS with constipation (12 of constipation-dominant type and 31 of mixed type) than with 51 diarrhea-dominant type and 88 normal subjects (chi(2) = 13.91, P = 0.008). Multifactor dimensionality reduction analysis revealed that there were no significant interactions of GNB3, IL-10, and TNF-alpha gene variants with susceptibility to IBS (P > 0.05). CONCLUSIONS & INFERENCES: The results suggest that GNB3 825T allele might be associated with IBS with constipation in Koreans.

Upregulation of Fas and downregulation of CD94/NKG2A inhibitory receptors on circulating natural killer cells in patients with new-onset psoriasis.

BACKGROUND: Psoriasis has been considered as a T-helper 1 cell-mediated autoimmune disease driven by collaboration with multiple components of innate and acquired immune cells. Natural killer (NK) cells have been shown to bridge innate and acquired immunity, and thus could potentially contribute to the pathophysiology of psoriasis. OBJECTIVES: To investigate the phenotypic changes of circulating NK cells in patients with new-onset psoriasis. METHODS: Fifteen patients with plaque psoriasis (eight women and seven men) who visited our clinic after their first episode of psoriasis and did not have a history of previous systemic therapy or phototherapy participated in this study. Peripheral blood mononuclear cells were isolated and stained with a panel of antibodies against cell surface receptors expressed on T and/or NK cells and analysed by flow cytometry. RESULTS: As compared with normal healthy volunteers, patients with new-onset psoriasis showed no significant changes in numbers of peripheral NK, NK-T or T cells. NK activating receptors 2B4, CD48, NKG2D, CD16 and CD56 were found to be unchanged in new-onset psoriasis. However, the expression of Fas (activation-induced death receptor) was upregulated, whereas the expression of the NK inhibitory receptors CD94 and NKG2A was dramatically reduced on NK cells of new-onset psoriasis. These changes occurred at the level of mean fluorescent intensity, but minimally affected percentages of cells expressing Fas, CD94 and NKG2A. CONCLUSIONS: Our findings demonstrate that changes in the expression of Fas and CD94/NKG2A receptors on NK cells may occur during new-onset psoriasis, and are likely to contribute to the pathogenesis of psoriasis.

Effects of neolignans from the stem bark of Magnolia obovata on plant pathogenic fungi.

AIMS: To characterize antifungal principles from the methanol extract of Magnolia obovata and to evaluate their antifungal activities against various plant pathogenic fungi. METHODS AND RESULTS: Four neolignans were isolated from stem bark of M. obovata as antifungal principles and identified as magnolol, honokiol, 4-methoxyhonokiol and obovatol. In mycelial growth inhibition assay, both magnolol and honokiol displayed more potent antifungal activity than 4-methoxyhonokiol and obovatol. Both magnolol and honokiol showed similar in vivo antifungal spectrum against seven plant diseases tested; both compounds effectively suppressed the development of rice blast, tomato late blight, wheat leaf rust and red pepper anthracnose. 4-Methoxyhonokiol and obovatol were highly active to only rice blast and wheat leaf rust respectively. CONCLUSIONS: The extract of M. obovata and four neolignans had potent in vivo antifungal activities against plant pathogenic fungi. SIGNIFICANCE AND IMPACT OF THE STUDY: Neolignans from Magnolia spp. can be used and suggested as a novel antifungal lead compound for the development of new fungicide and directly as a natural fungicide for the control of plant diseases such as rice blast and wheat leaf rust.

Changes in soft tissue composition are the primary predictors of 4-year bone mineral density changes in postmenopausal women.

UNLABELLED: Changes in body weight influence bone mineral density, but the role of body composition is not clear in postmenopausal women. Body weight and soft tissue composition predicted bone changes independent of calcium supplementation and exercise frequency, indicating that soft tissue composition should be measured in clinical trials. INTRODUCTION: The purpose of this study was to examine the relationship between changes in body weight and composition and changes in 4-year bone mineral density (BMD) after accounting for age, 4-year exercise frequency (EX), and 4-year calcium supplement intake (CA) in postmenopausal women with and without hormone therapy (HT). METHODS: Postmenopausal women (aged 40-65 years) either using HT (for 1-3.9 years) or not using HT (for > or =1 year) were recruited to the study. EX and CA was monitored throughout the study and 167 women completed 4 years. BMD and soft tissue composition measurements were made using dual-energy X-ray absorptiometry. Regression was used to predict 4-year BMD changes from EX, CA, age, baseline and 4-year changes in body weight and composition. HT users (n = 115, 55.3 +/- 4.3 years) and non-users (n = 52, 57.5 +/- 4.7 years) were analyzed separately. RESULTS: The models predicting regional BMD changes that included soft tissue composition changes explained the most variation compared with those with body weight or EX and CA alone. Larger amounts of variation in BMD changes were explained in the no HT group. CONCLUSION: Body composition changes are important positive predictors of BMD changes independent of EX and CA supplementation, but their contribution varies according to bone site and with HT use.

Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and olanzapine-induced weight gain among Korean schizophrenic patients.

BACKGROUND: Weight gain can be an adverse effect of antipsychotics that significantly affects long-term health and treatment compliance. Many reports have suggested that the 5-HT2C receptor gene (HTR2C) is related to appetite and eating behaviours associated with body weight change. We hypothesized that there was a relationship between the HTR2C -759C/T polymorphism and olanzapine-induced weight gain. METHOD: Seventy-nine Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment for at least 3 months. We controlled the use of drugs other than olanzapine except benzodiazepines and anticholinergics. Genotyping for the HTR2C -759C/T polymorphism was performed on all participants. RESULT: We found that long-term treatment with olanzapine resulted in mean gains in weight and BMI of 5.2 kg and 1.93 kg/m(2), respectively. However, body weight changes from baseline to the study endpoint were not significantly associated with genotypes. The frequency of the T allele did not differ significantly between subjects with weight gains below and above a clinically significant cutoff, defined as 7% relative to baseline (chi(2) = 0.213, P = 0.445), indicating that the T allele had no protective effect against olanzapine-induced weight gain. DISCUSSION AND CONCLUSION: The findings from this study do not support the presence of a relationship between the -759C/T polymorphism of the HTR2C gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.

Construction of a BAC library of Korean ginseng and initial analysis of BAC-end sequences.

We estimated the genome size of Korean ginseng (Panax ginseng C.A. Meyer), a medicinal herb, constructed a HindIII BAC library, and analyzed BAC-end sequences to provide an initial characterization of the library. The 1C nuclear DNA content of Korean ginseng was estimated to be 3.33 pg (3.12 x 10(3) Mb). The BAC library consists of 106,368 clones with an average size of 98.61 kb, amounting to 3.34 genome equivalents. Sequencing of 2167 BAC clones generated 2492 BAC-end sequences with an average length of 400 bp. Analysis using BLAST and motif searches revealed that 10.2%, 20.9% and 3.8% of the BAC-end sequences contained protein-coding regions, transposable elements and microsatellites, respectively. A comparison of the functional categories represented by the protein-coding regions found in BAC-end sequences with those of Arabidopsis revealed that proteins pertaining to energy metabolism, subcellular localization, cofactor requirement and transport facilitation were more highly represented in the P. ginseng sample. In addition, a sequence encoding a glucosyltransferase-like protein implicated in the ginsenoside biosynthesis pathway was also found. The majority of the transposable element sequences found belonged to the gypsy type (67.6%), followed by copia (11.7%) and LINE (8.0%) retrotransposons, whereas DNA transposons accounted for only 2.1% of the total in our sequence sample. Higher levels of transposable elements than protein-coding regions suggest that mobile elements have played an important role in the evolution of the genome of Korean ginseng, and contributed significantly to its complexity. We also identified 103 microsatellites with 3-38 repeats in their motifs. The BAC library and BAC-end sequences will serve as a useful resource for physical mapping, positional cloning and genome sequencing of P. ginseng.

Spontaneous gastrosplenic fistula: a rare complication of splenic diffuse large cell lymphoma.

A gastrosplenic fistula is a very rare complication with a gastric or splenic lesion. Splenic, diffuse, large cell lymphoma may be one cause of this distinctive complication. We present a patient with spontaneous gastrosplenic fistula secondary to pathologically proven diffuse splenic large cell lymphoma, with radiography and computed tomography.