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Presents research findings which show that many systemic memory T cells in blood carry the chemokine receptor CCR4 and therefore respond to its ligands, the chemokines TARC and MDC. How these cells include essentially all skin-homing cells; Details of the research done.

The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class III-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulins. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor Vβ usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate iii response to monoclonal anti-Vβ antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed Vβ were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (Vβ5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed Vβ. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice. [ABSTRACT FROM AUTHOR]

Background Dowling-Degos disease (DDD; MIM 179850) is an autosomal dominant genodermatosis caused by mutations in keratin 5 gene ( KRT5). KRT5 is specifically expressed in basal layer of epidermis and plays an important role in protecting epithelial cells from mechanical and non-mechanical stresses. Objective We analysed the molecular basis of DDD in a Chinese family. Methods Genomic DNA of the Chinese DDD family and a matched control cohort was isolated according to standard techniques. All exons of the KRT5 gene and adjacent exon-intron border sequences were amplified using PCR and directly sequenced. Results We identified a novel keratin 5 (K5) nonsense mutation designated c.C10T (p.Gln4X) in exon 1 of the KRT5 gene. Conclusion Our data expand the spectrum of mutations in the KRT5 gene underlying DDD. [ABSTRACT FROM AUTHOR]

Background In this study, we examined the TMB landscape of 5,660 pan-cancer cases in Chinese population, using NGS panel. We established cancer-specific and histology-specific biological pathways associated with the TMB status. In addition, as a proof on concept, an unsupervised algorithm was conducted using stepwise logistic regression to generate TMB-predicting signatures from both lung adenocarcinoma and lung squamous cell carcinoma. Methods Patients: 5,660 Chinese cancer patients across 11 cancer types Panel: Targeted sequencing was performed on tissue samples using a panel consisting of 295 or 520 cancer-related genes, spanning 1.4 and 1.6Mb of human genome, respectively. An average sequencing depth of 1,000X and 10,000x were achieved for tissue and plasma samples, respectively. Tumor mutation burden: calculated as the ratio of mutation count to the size of coding region of the panel, excluding CNV, fusions, large genomic rearrangements and mutations occurring on the kinase domain of EGFR and ALK. Results Across the 11 cancer types included in the analysis, lung squamous cell carcinoma had the highest average TMB, whereas sarcoma has the lowest TMB. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB.The independent predictive power for TMB 26 biological pathways was tested in 11 cancer types. Mismatch repair, DNA damage response, homologous recombination repair, and PI3K-AKT signaling pathway were most commonly correlated with high-TMB. In contrast, ERBB signaling pathway, and adhesion-related pathways were most commonly correlated with low-TMB. Moreover, we developed a 23- and 16-gene signature for TMB prediction for LUAD and LUSC, respectively, with 12 genes shared by both signatures, indicating a histology- specific mechanism for driving high- TMB in lung cancer. Conclusions The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types. Legal entity responsible for the study The authors. Funding Burning Rock Biotech. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background KEYNOTE-181 (NCT02564263) was an open-label, randomized, phase 3 trial of pembrolizumab (pembro) vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (chemo) in advanced/metastatic esophageal AC or SCC. Pts were enrolled in partially overlapping periods, initially globally and then in China with an extension period. We present results from the global and China cohorts. Methods Pts were randomized 1:1 to receive pembro or chemo. Randomization was stratified by histology (SCC vs AC) and region (Asia vs rest of world). Primary end points were OS in the ITT, SCC, and PD-L1 CPS ≥10 populations. Results There were 628 and 123 pts in the global and China cohorts, respectively. In the global cohort, 314 pts were randomized to receive pembro (199 [63%] had SCC; 107 [34%] had CPS ≥10 tumors); 314 pts to chemo (204 [65%] had SCC; 115 [37%] had CPS ≥10 tumors). Median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). Median OS with pembro vs chemo was similar in the ITT group (7.1 vs 7.1 mo) and longer in the SCC (8.2 vs 7.1 mo) and CPS ≥10 groups (9.3 vs 6.7 mo). 12-month OS rates were higher with pembro in all groups (ITT 32% vs 24%; SCC 39% vs 25%; CPS ≥10 42% vs 20%). In the China cohort, 62 pts were randomized to pembro (60 had SCC; 25 had CPS ≥10 tumors); and 61 pts to chemo (59 had SCC; 29 had CPS ≥10 tumors). Median follow-up was 8.3 mo (pembro) vs 5.6 mo (chemo). Median OS was higher with pembro in the ITT (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.36-0.82), SCC (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.37-0.83), and CPS ≥10 groups (12.0 vs 5.3 mo; HR 0.34; 95% CI 0.17-0.69). 12-month OS rates were higher with pembro in all groups (ITT 36% vs 17%; SCC 36% vs 16%; CPS ≥10 53% vs 16%). Fewer pts had TRAEs with pembro than chemo (global 64% vs 86%; China 76% vs 83%). TRAE rates resulting in discontinuation with pembro vs chemo were comparable in the global cohort (6% each) and lower with pembro in the China cohort (6% vs 12%). Conclusions Pembro and chemo showed comparable OS as 2L therapy for esophageal AC/SCC in the global ITT cohort. Pembro showed favorable OS in SCC and CPS ≥10 groups in the global cohort and in all groups in the China cohort, in which most patients had SCC. Pembro showed favorable safety in both cohorts. Clinical trial identification NCT02564263. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Traci Stuve, MA, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Disclosure S-B. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Aventis; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): DongKook Pharmaceutical. T. Doi: Advisory / Consultancy: Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer; Research grant / Funding (institution): Taiho Pharmaceutical, Novartis, Merck Serono, MSD, Boehringer Ingelheim, Pfizer, Lilly Japan, Sumitomo Group, Kyowa Hakko Kirin, Daiichi Sankyo, Bristol-Myers Squibb, AbbVie, Quintiles, Eisai. K. Kato: Research grant / Funding (institution): MSD, ONO Pharmaceutical, Shionogi, Merck Serono. M. Shah: Research grant / Funding (institution): Merck, Roche, Boston Biomedical. A. Adenis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier. T. Kojima: Non-remunerated activity/ies, Other- Patents, Royalties, other Intellectual Property: Ono Pharmaceutical, MSD, Shionogi Pharma, Oncolys BioPharma, Astellas Amgen BioPharama; Honoraria (self): Oncolys BioPharma. J-P. Metges: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Honoraria (self): Bayer-Health; Honoraria (self): Lilly; Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Sanofi. E. Francois: Research grant / Funding (institution): MSD; Non-remunerated activity/ies, +Personal Fees: Roche; Non-remunerated activity/ies, +Personal Fees: Servier; Non-remunerated activity/ies, +Personal Fees: Merck; Non-remunerated activity/ies, +Personal Fees: Amgen; Non-remunerated activity/ies, +Personal Fees: Sanofi; Non-remunerated activity/ies, +Personal Fees: Novartis; Non-remunerated activity/ies, +Personal Fees: Bayer. K. Muro: Honoraria (self): Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, Taiho Pharmaceutical, Lilly, Ono Pharmaceutical, Bayer; Research grant / Funding (institution): Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Merck Serono, Pfizer, Sanofi. R. Wang: Full / Part-time employment: Merck & Co. Inc. Y. Cui: Full / Part-time employment: MSD China. P. Bhagia: Full / Part-time employment: Merck & Co. Inc. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Promising clinical activity has been reported in patients with MET-altered NSCLC treated with tepotinib, an oral, selective, potent MET tyrosine kinase inhibitor. To support clinical development, we aimed to further characterize the safety profile of tepotinib in patients with cancer. Methods In this analysis from 5 phase I and II studies of tepotinib administered 500 mg once daily, adverse events (AEs), graded by NCI CTCAE v4.03, were pooled and summarized for all patients and for the subgroup of Asian patients. Results As of 28 Sep 2018, 228 patients (81 [35.5%] Asian, 59 [25.9%] NSCLC, 121 [53.1%] HCC) had received tepotinib 500 mg/day for a median of 2.7 months (range 0–21.5); in the ongoing phase II VISION study (NCT02864992), median was 4.1 months. The most common treatment-related AE of any grade was peripheral edema occurring in 33.8% of patients overall and in 24.7% of Asian patients. Other common treatment-related AEs were diarrhea, fatigue, and nausea (Table). Dose reduction due to an AE regardless of causality occurred in 33 (14.5%) patients and discontinuation in 49 (21.5%) patients; peripheral edema led to a dose reduction in 12 (5.3%) patients and discontinuation in 7 (3.1%) patients. In the Asian population, 13 (16.0%) patients had a dose reduction and 13 (16.0%) patients discontinued due to an AE; peripheral edema led to a dose reduction in 4 (4.9%) Asian patients and to no discontinuations. Two AEs leading to death were considered by the investigator to be potentially treatment-related and occurred in patients with HCC (upper gastrointestinal hemorrhage [in an Asian patient] and hypoglycemic coma). Table: 67P   All patients (N = 228)   Asian patients (N = 81)     Any Grade  Grade ≥3  Any Grade  Grade ≥3  Treatment-related AE (≥10%), n (%)  172 (75.4)  52 (22.8)  64 (79.0)  26 (32.1)  Peripheral edema  77 (33.8)  8 (3.5)  20 (24.7)  0  Diarrhea  45 (19.7)  4 (1.8)  27 (33.3)  4 (4.9)  Fatigue  34 (14.9)  3 (1.3)  14 (17.3)  3 (3.7)  Nausea  29 (12.7)  0  9 (11.1)  0  Decreased appetite  27 (11.8)  0  12 (14.8)  0  Blood creatinine increased  18 (7.9)  1 (0.4)  11 (13.6)  0  Hypoalbuminemia  16 (7.0)  1 (0.4)  10 (12.3)  0  Amylase increased  13 (5.7)  4 (1.8)  9 (11.1)  2 (2.5)    All patients (N = 228)   Asian patients (N = 81)     Any Grade  Grade ≥3  Any Grade  Grade ≥3  Treatment-related AE (≥10%), n (%)  172 (75.4)  52 (22.8)  64 (79.0)  26 (32.1)  Peripheral edema  77 (33.8)  8 (3.5)  20 (24.7)  0  Diarrhea  45 (19.7)  4 (1.8)  27 (33.3)  4 (4.9)  Fatigue  34 (14.9)  3 (1.3)  14 (17.3)  3 (3.7)  Nausea  29 (12.7)  0  9 (11.1)  0  Decreased appetite  27 (11.8)  0  12 (14.8)  0  Blood creatinine increased  18 (7.9)  1 (0.4)  11 (13.6)  0  Hypoalbuminemia  16 (7.0)  1 (0.4)  10 (12.3)  0  Amylase increased  13 (5.7)  4 (1.8)  9 (11.1)  2 (2.5)  Table: 67P   All patients (N = 228)   Asian patients (N = 81)     Any Grade  Grade ≥3  Any Grade  Grade ≥3  Treatment-related AE (≥10%), n (%)  172 (75.4)  52 (22.8)  64 (79.0)  26 (32.1)  Peripheral edema  77 (33.8)  8 (3.5)  20 (24.7)  0  Diarrhea  45 (19.7)  4 (1.8)  27 (33.3)  4 (4.9)  Fatigue  34 (14.9)  3 (1.3)  14 (17.3)  3 (3.7)  Nausea  29 (12.7)  0  9 (11.1)  0  Decreased appetite  27 (11.8)  0  12 (14.8)  0  Blood creatinine increased  18 (7.9)  1 (0.4)  11 (13.6)  0  Hypoalbuminemia  16 (7.0)  1 (0.4)  10 (12.3)  0  Amylase increased  13 (5.7)  4 (1.8)  9 (11.1)  2 (2.5)    All patients (N = 228)   Asian patients (N = 81)     Any Grade  Grade ≥3  Any Grade  Grade ≥3  Treatment-related AE (≥10%), n (%)  172 (75.4)  52 (22.8)  64 (79.0)  26 (32.1)  Peripheral edema  77 (33.8)  8 (3.5)  20 (24.7)  0  Diarrhea  45 (19.7)  4 (1.8)  27 (33.3)  4 (4.9)  Fatigue  34 (14.9)  3 (1.3)  14 (17.3)  3 (3.7)  Nausea  29 (12.7)  0  9 (11.1)  0  Decreased appetite  27 (11.8)  0  12 (14.8)  0  Blood creatinine increased  18 (7.9)  1 (0.4)  11 (13.6)  0  Hypoalbuminemia  16 (7.0)  1 (0.4)  10 (12.3)  0  Amylase increased  13 (5.7)  4 (1.8)  9 (11.1)  2 (2.5)  Conclusions Tepotinib demonstrated an acceptable safety profile in patients with advanced cancer, with a similar profile in Asian patients and in the overall population. Further characterization of the clinical relevance of peripheral edema is ongoing. Clinical trial identification NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992. Editorial acknowledgement Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Jen Lewis, PhD of Bioscript Science (Macclesfield, UK). Legal entity responsible for the study Merck KGaA. Funding Merck KGaA. Disclosure K. Yamazaki: Honoraria (self): Chugai; Honoraria (self): Takeda; Honoraria (self): Yakult; Honoraria (self): Daiichi‐Sankyo; Honoraria (self): Merck Serono; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Honoraria (self): Taiho; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. P.K. Paik: Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Honoraria (self): Takeda. R. Veillon: Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Merck. T. Decaens: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Travel / Accommodation / Expenses: Gilead; Honoraria (self), Travel / Accommodation / Expenses: AbbVie; Honoraria (self): Sanofi; Advisory / Consultancy: BTG; Advisory / Consultancy: Sirtex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Genoscience Pharma. S. Faivre: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. G.S. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Travel / Accommodation / Expenses: Fujifilm; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing ; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): American Society of Clinical Oncology; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, No. J. Scheele: Full / Part-time employment: Merck KGaA. R. Bruns: Full / Part-time employment: Merck KGaA. K. Berghoff: Full / Part-time employment: Merck KGaA. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

The non-classical correlations presented in quantum random access code experiment are a powerful diagnostic tool for semi-device-independent random number generator protocols. The idea behind it is that if the user observes the optimal non-classical correlations, he has the guarantee that the unknown quantum states and measurements in the devices have carefully calibrated (we say have global reference frame), in a relationship which can bring to random outcomes. This means, for observing the non-classical correlations, the devices must have that calibration in previous. However, that calibration can’t always be guaranteed in reality due to unintentional flaws or failures of the quantum apparatuses, thus the devices do not always occur the wanted non-classical correlations. In this paper, we show there will always have non-classical correlations by the proper operations, when the devices have local reference. The quantity of true randomness in the observed non-classical correlations is then quantified by the violation values of some inequality. Besides we also consider the devices without local reference and show the probability of non-classical correlations occurring in 100 trials. [ABSTRACT FROM AUTHOR]

A novel method to determine the total hydrogen density and, accordingly, a precise plasma temperature in a lowly ionized hydrogen plasma is described. The key to the method is to analyze the energy loss of swift heavy ions interacting with the respective bound and free electrons of the plasma. A slowly developing and lowly ionized hydrogen theta-pinch plasma is prepared. A Boltzmann plot of the hydrogen Balmer series and the Stark broadening of the Hß line preliminarily defines the plasma with a free electron density of (1.9±0.1)×1016 cm-3 and a free electron temperature of 0.8-1.3 eV. The temperature uncertainty results in a wide hydrogen density, ranging from 2.3×1016 to 7.8×1018 cm-3. A 108 MHz pulsed beam of 48Ca10+ with a velocity of 3.652 MeV/u is used as a probe to measure the total energy loss of the beam ions. Subtracting the calculated energy loss due to free electrons, the energy loss due to bound electrons is obtained, which linearly depends on the bound electron density. The total hydrogen density is thus determined as (1.9±0.7)×1017 cm-3, and the free electron temperature can be precisely derived as 1.01±0.04 eV. This method should prove useful in many studies, e.g., inertial confinement fusion or warm dense matter. [ABSTRACT FROM AUTHOR]

Plasma carbon monoxide (CO) concentrations were measured in 12 patients with sepsis syndrome. CO concentrations were found to be significantly increased in patients compared with those in 30 normal controls. Patients with septic shock had significantly higher plasma CO concentrations than those without shock. Results suggest that CO might play an important role in paediatric sepsis syndrome. [ABSTRACT FROM AUTHOR]