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Wightman, Andrew, Geoffrey Smith, Kelci Mohrman, and Charles Mueller. "Trigger Rate Monitoring Tools at CMS." EPJ Web of Conferences 214 (2019): 01047. http://dx.doi.org/10.1051/epjconf/201921401047.
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One of the major challenges for the Compact Muon Solenoid (CMS)experiment, is the task of reducing event rate from roughly 40 MHz down to a more manageable 1 kHz while keeping as many interesting physics events as possible. This is accomplished through the use of a Level-1 (L1) hardware based trigger as well as a software based High-Level Trigger (HLT). Monitoring and understanding the output rates of the L1 and HLT triggers is of key importance for determining the overall performance of the trigger system and is intimately tied to what type of data is being recorded for physics analyses. We present here a collection of tools used by CMS to monitor the L1 and HLT trigger rates. One of these tools is a script (run in the CMS control room) that gives valuable real-time feedback of trigger rates to the shift crew. Another useful tool is a plotting library, that is used for observing how trigger rates vary over a range of beam and detector conditions, in particular how the rates of individual triggers scale with event pile-up.
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Koulouris, A., Y. Afik, A. Armbruster, et al. "Commissioning of the new muon-to-central-trigger-processor interface at ATLAS." Journal of Instrumentation 18, no. 03 (2023): C03020. http://dx.doi.org/10.1088/1748-0221/18/03/c03020.
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Abstract The ATLAS trigger system includes a Level-1 (L1) trigger based on custom electronics and firmware, and a high-level software trigger running on off-the-shelf hardware. The L1 trigger system uses information from the forward detectors, the calorimeters and the muon trigger detectors. Once information from all muon trigger sectors has been received, trigger candidate multiplicities are calculated by the Muon-to-Central-Trigger-Processor Interface (MUCTPI). Muon multiplicity information is sent to the Central-Trigger-Processor (CTP) and trigger objects are sent to the L1 Topological Trigger Processor (L1Topo). The CTP combines the information received from the MUCTPI with the trigger information from the forward detectors, the calorimeters and the L1Topo, and takes the L1 trigger decision. As part of the ATLAS L1 trigger system upgrade for Run-3 of the Large Hadron Collider (LHC) a new MUCTPI has been designed and commissioned. We discuss the commissioning and operation of the new MUCTPI used in ATLAS from the beginning of Run-3. In particular, we describe the integration tests which have been carried out for the commissioning and operation of the new MUCTPI.
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Ghete, V. M., and Cms Collaboration. "The CMS L1 Trigger emulation software." Journal of Physics: Conference Series 219, no. 3 (2010): 032009. http://dx.doi.org/10.1088/1742-6596/219/3/032009.
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Dordevic, Milos. "The CMS Trigger System." Journal of Physics: Conference Series 2375, no. 1 (2022): 012003. http://dx.doi.org/10.1088/1742-6596/2375/1/012003.
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Abstract The CMS experiment at CERN uses a two-stage triggering system composed of the Level-1 (L1), instrumented with custom-designed hardware boards with an output rate of 100 kHz, and the High Level Trigger (HLT), streamlined version of the offline software reconstruction that runs on the computing farm, allowing to store around 1.5 kHz of rate. New trigger algorithms and new features, as well as optimized trigger menus at both L1 and HLT are mandatory in order to be able to successfully record the events at higher data loads due to increasing luminosity and pileup at the LHC in Run 3. Many measurements and searches will profit from the updates implemented in the CMS trigger. The highlights of Run 2 CMS trigger results will be presented, together with the improvements for Run 3.
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Donato, Silvio. "CMS trigger performance." EPJ Web of Conferences 182 (2018): 02037. http://dx.doi.org/10.1051/epjconf/201818202037.
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During its second run of operation (Run 2), started in 2015, the LHC will deliver a peak instantaneous luminosity that may reach 2 · 1034 cm-2s-1 with an average pileup of about 55, far larger than the design value. Under these conditions, the online event selection is a very challenging task. In CMS, it is realized by a two-level trigger system: the Level-1 (L1) Trigger, implemented in custom-designed electronics, and the High Level Trigger (HLT), a streamlined version of the offine reconstruction software running on a computer farm. In order to face this challenge, the L1 trigger has been through a major upgrade compared to Run 1, whereby all electronic boards of the system have been replaced, allowing more sophisticated algorithms to be run online. Its last stage, the global trigger, is now able to perform complex selections and to compute high-level quantities, like invariant masses. Likewise, the algorithms that run in the HLT have been greatly improved; in particular, new approaches for the online track reconstruction lead to a drastic reduction of the computing time, and to much improved performances. This document will describe the performance of the upgraded trigger system in Run 2.
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Portalès, Louis. "L1 Triggering on High-Granularity Information at the HL-LHC." Instruments 6, no. 4 (2022): 71. http://dx.doi.org/10.3390/instruments6040071.
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The CMS collaboration is building a high-granularity calorimeter (HGCAL) for the endcap regions as part of its planned upgrade for the High-Luminosity LHC. The calorimetric data will form part of the Level-1 trigger (hardware) of the CMS experiment, reducing the event rate from the nominal 40 MHz to 750 kHz with a decision time (latency) of 12.5 microseconds. In addition to basic tracking information, which will also be available in the Level-1 trigger system, the use of particle-flow techniques will be facilitated as part of the trigger system. Around 1-million “trigger channels” are read at 40 MHz from the HGCAL, presenting a significant challenge in terms of data manipulation and processing for the trigger system: the trigger data volumes will be an order of magnitude above those currently handled at CMS. In addition, the high luminosity will result in an average of 140 (or more) interactions per bunch crossing that produce a huge background rate in the forward region and these will need to be efficiently rejected by the trigger algorithms. Furthermore, the reconstruction of particle clusters used for particle flow in high hit-rate events presents a complex computational problem associated with the trigger. We present the status of the trigger architecture and design, as well as the algorithmic concepts needed in order to tackle these major issues.
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Hoff, J., M. Johnson, R. Lipton, et al. "Design for a L1 tracking trigger for CMS." Journal of Instrumentation 8, no. 02 (2013): C02004. http://dx.doi.org/10.1088/1748-0221/8/02/c02004.
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Cieri, D., J. Brooke, M. Grimes, et al. "L1 track finding for a time multiplexed trigger." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 824 (July 2016): 268–69. http://dx.doi.org/10.1016/j.nima.2015.09.117.
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Kumar, Piyush, and Bhawna Gomber. "The CMS Level-1 Calorimeter Trigger for the HL-LHC." Instruments 6, no. 4 (2022): 64. http://dx.doi.org/10.3390/instruments6040064.
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The High-Luminosity LHC (HL-LHC) provides an opportunity for a pioneering physics program to harness an integrated luminosity of 4000 fb−1 of ten years of operations. This large volume of collision data will help in high precision measurements of the Standard Model (SM) and the search for new and rare physics phenomena. The harsh environment of 200 proton–proton interactions poses a substantial challenge in the collection of these large datasets. The HL-LHC CMS Level-1 (L1) trigger, including the calorimeter trigger, will receive a massive upgrade to tackle the challenge of a high-bandwidth and high pileup environment. The L1 trigger is planned to handle a very high bandwidth (∼63 Tb/s) with an output rate of 750 kHz, and the desired latency budget is 12.5 μs. The calorimeter trigger aims to process the high-granular information from the new end-cap detector called the high-granularity calorimeter (HGCAL) and the barrel calorimeter. The HL-LHC trigger prototyped boards are equipped with large modern-day FPGAs and high-speed optical links (∼28 Gb/s), which helps in the parallel and rapid computation of the calorimeter trigger algorithms. This article discusses the proposed design and expected performance of the upgraded CMS Level-1 calorimeter trigger system.
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Hoff, J., M. Johnson, R. Lipton, and G. Magazzu. "Readout chip for an L1 tracking trigger using asynchronous logic." Journal of Instrumentation 7, no. 08 (2012): C08004. http://dx.doi.org/10.1088/1748-0221/7/08/c08004.
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Bourrion, O., N. Arbor, G. Conesa-Balbastre, C. Furget, R. Guernane, and G. Marcotte. "The ALICE EMCal L1 trigger first year of operation experience." Journal of Instrumentation 8, no. 01 (2013): C01013. http://dx.doi.org/10.1088/1748-0221/8/01/c01013.
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Dong, Ling, Suzhen Chen, and Melitta Schachner. "Single chain Fv antibodies against neural cell adhesion molecule L1 trigger L1 functions in cultured neurons." Molecular and Cellular Neuroscience 22, no. 2 (2003): 234–47. http://dx.doi.org/10.1016/s1044-7431(02)00033-7.
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Ammendola, R., D. Battista, G. Paoluzzi, et al. "The NA62 level 0 calorimetric trigger fast readout implementation, commissioning and data taking performances." Journal of Instrumentation 18, no. 02 (2023): C02049. http://dx.doi.org/10.1088/1748-0221/18/02/c02049.
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Abstract The NA62 experiment at the CERN SPS aims to measure the branching ratio of the very rare kaon decay K + → π + ν ν ¯ . The Calorimetric Level 0 Trigger identifies clusters in the electromagnetic and hadronic calorimeters. Along with the trigger data sent to the L0 Trigger Processor, readout data is collected to be sent to the L1 software trigger. In this work we present the novel implementation of the readout data collection and forwarding system in the multiple layers of the calorimetric trigger structure. We will also present the commissioning of the system and the performance evaluation on current data taking.
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Perrella, S., Y. Afik, A. Armbruster, et al. "Integration and commissioning of the ATLAS Muon-to-Central-Trigger-Processor Interface for Run-3." Journal of Instrumentation 17, no. 04 (2022): C04006. http://dx.doi.org/10.1088/1748-0221/17/04/c04006.
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Abstract The Muon-to-Central Trigger Processor Interface was completely redesigned as part of the ATLAS Level-1 trigger upgrade for Run 3 of the Large Hadron Collider. The new system is implemented as a single AdvancedTCA module, using three large state-of-the-art FPGAs and high-density fiber-optic modules. Trigger information from the muon trigger detectors are received through 208 high speed links, while 60 links are used to send processed trigger information to the L1 Topological Trigger Processor and the Central Trigger Processor. Extensive integration tests with all input and output systems have shown that the data transfer is stable and reliable. We present results from integration tests with connected sub-systems as well as commissioning of the Muon-to-Central Trigger Processor Interface in the ATLAS experiment.
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Skambraks, Sebastian, Steffen Bähr, Jürgen Becker, et al. "A 3D track finder for the Belle II CDC L1 trigger." Journal of Physics: Conference Series 1525 (April 2020): 012102. http://dx.doi.org/10.1088/1742-6596/1525/1/012102.
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Barrio, J. A., O. Blanch, J. Boix, et al. "Analogue sum ASIC for L1 trigger decision in Cherenkov Telescope cameras." Journal of Instrumentation 10, no. 02 (2015): C02016. http://dx.doi.org/10.1088/1748-0221/10/02/c02016.
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PAVLENKO, ANETA, SCOTT JARVIS, SVITLANA MELNYK, and ANASTASIA SOROKINA. "Communicative relevance: Color references in bilingual and trilingual speakers." Bilingualism: Language and Cognition 20, no. 4 (2016): 853–66. http://dx.doi.org/10.1017/s1366728916000535.
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The study examined granularity of lexical partitioning of the blue area in speakers of English, which encodes the termblue; Russian, which encodes two terms, sinij[dark/navy blue] andgoluboj[light/sky blue]; and Ukrainian, which encodes the termssynij[dark/navy blue] andblakytnyjandgolubyj[light/sky blue]. Five groups of participants took part in the study: (1) 30 L1 speakers of English, (2) 30 L1 speakers of Russian, (3) 30 Russian–English bilinguals, (4) 30 English–Russian bilinguals, and (5) 25 Ukrainian–Russian–English trilinguals. Quantitative and qualitative analyses revealed that L1 Russian speakers referred to different types of blue significantly more frequently than all other groups, while bilinguals patterned with L1 English speakers. These findings suggest that classroom exposure to L2 Russian does not make the distinction betweensinijandgolubojcommunicatively relevant for L1 English speakers and that everyday use of L2 English may trigger attrition of the contrast in L1 Russian.
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Öhlschläger, Peter, Wolfram Osen, Kerstin Dell, et al. "Human Papillomavirus Type 16 L1 Capsomeres Induce L1-Specific Cytotoxic T Lymphocytes and Tumor Regression in C57BL/6 Mice." Journal of Virology 77, no. 8 (2003): 4635–45. http://dx.doi.org/10.1128/jvi.77.8.4635-4645.2003.
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ABSTRACT We analyzed capsomeres of human papillomavirus type 16 (HPV16) consisting of the L1 major structural protein for their ability to trigger a cytotoxic T-cell (CTL) response. To this end, we immunized C57BL/6 mice and used the L1165-173 peptide for ex vivo restimulation of splenocytes prior to analysis (51Cr release assay and enzyme-linked immunospot assay [ELISPOT]). This peptide was identified in this study as a Db-restricted naturally processed CTL epitope by HPV16 L1 sequence analysis, major histocompatibility complex class I binding, and 51Cr release assays following immunization of C57BL/6 mice with HPV16 L1 virus-like particles (VLPs). HPV16 L1 capsomeres were obtained by purification of HPV16 L1 lacking 10 N-terminal amino acids after expression in Escherichia coli as a glutathione S-transferase fusion protein (GST-HPV16 L1ΔN10). Sedimentation analysis revealed that the majority of the purified protein consisted of pentameric capsomeres, and assembled particles were not observed in minor contaminating higher-molecular-weight material. Subcutaneous (s.c.) as well as intranasal immunization of C57BL/6 mice with HPV16 L1 capsomeres triggered an L1-specific CTL response in a dose-dependent manner as measured by ELISPOT and 51Cr release assay. Significant reduction of contaminating bacterial endotoxin (lipopolysaccharide) from the capsomere preparation did not diminish the immunogenicity. Antibody responses (serum and vaginal) were less robust under the experimental conditions employed. In addition, s.c. vaccination with HPV16 L1 capsomeres induced regression of established tumors expressing L1 determinants (C3 tumor cells). Our data demonstrate that capsomeres are potent inducers of CTL responses similar to completely assembled T=7 VLPs. This result is of potential relevance for the development of (combined prophylactic and therapeutic) HPV-specific vaccines, since capsomeres can be produced easily and also can be modified to incorporate heterologous sequences such as early HPV proteins.
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Gonçalves, Perpétua. "The role of ambiguity in second language change: the case of Mozambican African Portuguese." Second Language Research 18, no. 4 (2002): 325–47. http://dx.doi.org/10.1191/0267658302sr209oa.
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In this article, my point of departure is that language change is driven by acquisition, and I argue that the triggers for establishing the properties of language-specific grammars differ according to whether first language (L1) or second language (L2) acquisition is involved. The reason for this is that in L2 acquisition evidence about the target grammar may be ambiguous in ways which do not occur in L1 acquisition. To illustrate the argument, I present two case studies of Mozambican African Portuguese, a nonnative variety of Portuguese acquired during childhood by L1 speakers of Bantu languages. These case studies show that strings generated by the grammar of European Portuguese may trigger ‘wrong/new’ parameter values which, although nonexistent in the original grammatical system, are perfectly legitimate from the point of view of the speakers’ L1 grammars. In both cases, although the new parameter settings (NPSs) are not convergent with the target grammar, resetting is blocked because the new parameter values successfully analyse the input. The nonresetting of the ‘wrong/new’ parameter values in the direction of the target European norm can be attributed to the social context of language acquisition, where the original European model is considerably diluted, and the surface effects they set off appear to be denser since the L2 speakers are in the majority.
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Chapellier, Marion, Evelina Martinenaite, Preeyam Patel, et al. "Abstract 4094: Immune modulatory cancer vaccines against IDO1 and PD-L1 trigger distinct pathways and cooperatively reduce tumor growth in preclinical models." Cancer Research 84, no. 6_Supplement (2024): 4094. http://dx.doi.org/10.1158/1538-7445.am2024-4094.
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Abstract While immune checkpoint inhibitors have shown clinical efficacy in many cancers, drug and immune resistance remain challenging. Indoleamine 2,3-dehydrogenase (IDO1) and Programmed Death Ligand 1 (PD-L1) both contribute to immunosuppression, leading to immune escape and cancer progression. In this context, vaccination to promote T-cell immunity against IDO1+ and PD-L1+ cells is an attractive strategy that demonstrated encouraging clinical results in melanoma (Kjeldsen et al. Nat Med 2021). Our study aims to further evaluate the efficacy and mode of action of combined IDO1 and PD-L1 peptide vaccines. Mice injected with tumor cells and treated with IDO1 or PD-L1 peptides were monitored for tumor growth. Vaccine activity was determined by IFNγ Elispot assay. Gene expression analysis was performed on tumors using Nanostring nCounter PanCancer IO360 Panel. IDO1 and PD-L1 expression were also examined via multiplex immunofluorescence in a human tumor tissue microarray (TMA) panel. Human IDO1 and PD-L1 specific CD4+ T cell clones were isolated and expanded from melanoma patients treated with IDO1/IO102 or PD-L1/IO103 peptide vaccines in combination with aPD1 therapy. Immunofluorescence analysis of murine tumor sections showed expression of IDO1 and PD-L1 by different cell populations. Vaccination against each target led to expansion of specific T cells in splenocytes and reduced tumor growth in MC38 and CT26 models. Combining IDO1 and PD-L1 treatments further enhanced the anti-tumor response. Gene expression analysis of tumors revealed distinct signatures following monotherapy and combination treatments. While PD-L1 vaccination predominantly enhanced the cytotoxic effector T cell function in the tumor microenvironment (TME) and concomitantly increased gene signatures associated with enhanced activation of T effector cells, IDO1 vaccine primarily exerted its effect via reduction in the immune suppression loop. TMA analysis of IDO1+ and PD-L1+ cells in human tumors also revealed that they represent largely distinct cell populations. Lastly, IDO1 and PDL1-specific CD4+ T cell clones from melanoma patients treated with IO102-IO103 vaccine could selectively target cells differentially expressing IDO1 or PDL1. Our data collectively show that cells expressing IDO1 and PD-L1 represent distinct populations in the TME thus targetable by the IDO1-PD-L1 vaccination approach. The vaccines targeting IDO1 and PD-L1 cooperatively reduce tumor outgrowth, and each contributes to the anti-tumor effect through distinct molecular programs regulating immunosuppression in the TME and T cell activation respectively. These data are supported by ex vivo functional assays using target specific T cells from vaccinated patients. Altogether, our data support the use of a dual antigen approach to reduce the immunosuppression and enhance anti-tumor effect. Citation Format: Marion Chapellier, Evelina Martinenaite, Preeyam Patel, Lea Svendsen, Shamaila Munir Ahmad, Hannah Jorinde Glöckner, Marco Carretta, Erika Sutanto-Ward, James DuHadaway, Souvik Dey, Shih-Chun Shen, Dema Ghaban, Marcos Iglesias, Megan Biller, Inés Lecoq, Alexander J. Muller, Mads Hald Andersen, Ayako Wakatsuki Pedersen. Immune modulatory cancer vaccines against IDO1 and PD-L1 trigger distinct pathways and cooperatively reduce tumor growth in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4094.
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Kelsey, Maxfield M. G. "Reconsidering LINE-1’s role in cancer: does LINE-1 function as a reporter detecting early cancer-associated epigenetic signatures?" Evolution, Medicine, and Public Health 9, no. 1 (2021): 78–82. http://dx.doi.org/10.1093/emph/eoab004.
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Abstract Long interspersed nuclear element-1 (LINE-1 or L1) is the only autonomously active retrotransposon in humans. While L1 has been implicated in several pathologies and the aging process, I present a model which challenges an understanding of L1 as predominantly antagonistic to human health. I hypothesize that L1 serves as a reporter in an early cancer alert system: a tripwire strung throughout the genome poised to trigger p53 and a type I interferon (IFN-1) response when the epigenetic landscape portends cancer. Cell proliferation and a shift to aerobic glycolysis cause dramatic changes in the epigenome which are permissive to L1’s escape from suppression. L1 has several properties which make it particularly apt to fulfill this hypothesized sentinel function. Being present in many copies spread throughout the genome allows it to monitor many regions for epigenetic instability and renders it robust to deactivation by mutation. This proposed cancer alert system would alter the cancer cell fitness landscape discouraging the use of growth-favoring aerobic glycolysis by threatening the activation of tumor-suppressive mechanisms. It also imposes costs on a strategy of non-specific global transcriptional derepression aimed at activating oncogenes. Erroneous activations of this system are predicted to increase the rate of aging, suggesting this represents a case of antagonistic pleiotropy trading prolonged youth for cancer prevention. More research is needed to assess this model. Lay summary: During carcinogenesis the epigenome is remodeled by the Warburg effect and cellular proliferation. These processes globally relax chromatin. This epigenetic environment is permissive to the retrotransposon long interspersed nuclear element-1’s (LINE-1 or L1) escape from suppression. I hypothesize and present evidence for the notion that L1 has been co-opted to serve as a reporter in an early cancer alert system, poised to trigger tumor suppressive mechanisms when the epigenetic landscape portends cancer. This hypothesis describes a potentially major means by which transformation is thwarted early on.
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Brooke, Jim, Karol Bunkowski, Ivan Cali, Carlos Ghabrous Larrea, Christos Lazaridis, and Alessandro Thea. "SWATCH: common control SW for the uTCA-based upgraded CMS L1 Trigger." Journal of Physics: Conference Series 664, no. 8 (2015): 082012. http://dx.doi.org/10.1088/1742-6596/664/8/082012.
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Bortignon, P. "Design and performance of the upgrade of the CMS L1 muon trigger." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 824 (July 2016): 256–57. http://dx.doi.org/10.1016/j.nima.2015.11.065.
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Bystricky, J., D. Calvet, P. Le Du, et al. "Algorithms and architecture for the L1 calorimeter trigger at D0 run IIb." IEEE Transactions on Nuclear Science 51, no. 3 (2004): 351–55. http://dx.doi.org/10.1109/tns.2004.828513.
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Boss, Alan P., and Sandra A. Keiser. "WHO PULLED THE TRIGGER: A SUPERNOVA OR AN ASYMPTOTIC GIANT BRANCH STAR?" Astrophysical Journal 717, no. 1 (2010): L1—L5. http://dx.doi.org/10.1088/2041-8205/717/1/l1.
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Kuang, Dong-Ming, Qiyi Zhao, Chen Peng, et al. "Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1." Journal of Experimental Medicine 206, no. 6 (2009): 1327–37. http://dx.doi.org/10.1084/jem.20082173.
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Macrophages (Mϕ) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mϕ to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mϕ in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor α and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mϕ may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.
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Yan, Lingyan, Yanan Sun, Jihua Guo, and Rong Jia. "PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells." International Journal of Molecular Sciences 24, no. 9 (2023): 8193. http://dx.doi.org/10.3390/ijms24098193.
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The interaction between programmed cell death 1 ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) protects tumor cells from immune surveillance. PD-L1 exon 3 is a potential alternative exon and encodes an Ig variable (IgV) domain. Here, we found that a lack of exon 3 leads to the significant loss of cellular membrane locations and the dramatically reduced protein expression of PD-L1, indicating that PD-L1 exon 3 is essential for its protein expression and translocation to the cell membrane. Notably, oral cancer cells show almost no exon 3 skipping to ensure the expression of the full-length, functional PD-L1 protein. We discovered two key exonic splicing enhancers (ESEs) for exon 3 inclusion. Two efficient antisense oligonucleotides (ASOs) were identified to block these two ESEs, which can significantly trigger exon 3 skipping and decrease the production of full-length, functional PD-L1 on the surface of cancer cells. Treatment of oral cancer cells with these ASOs significantly enhanced immune cells’ suppression of cancer cell proliferation. Surprisingly, these two ASOs also significantly inhibited cell growth and induced cell pyroptosis in oral cancer cells. Altogether, the results of our study demonstrate the pivotal roles of exon 3 in PD-L1 expression and provide a novel anti-PD-L1 method.
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Huang, Kevin Chih-Yang, Shu-Fen Chiang, William Tzu-Liang Chen, et al. "Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer." Cancers 12, no. 2 (2020): 462. http://dx.doi.org/10.3390/cancers12020462.
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Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.
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Hou, Hanxi, Cheuk Wun Li, Yaron Tomer, Zhengzi Yi, Weijia Zhang, and Mihaela Stefan Lifshitz. "OR19-5 Dissecting Thyroidal Pathways Activated by PD-L1 Blockade Identifies New Mechanisms for Thyroiditis Triggered by Immune Checkpoint Inhibitors." Journal of the Endocrine Society 6, Supplement_1 (2022): A802. http://dx.doi.org/10.1210/jendso/bvac150.1660.
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Abstract Programmed death-ligand 1 (PD-L1) is a strong immunosuppressor that inhibits T-cell activation by binding to its receptor (PD-1) on T-cells. Blocking the PD-L1/PD-1 interaction by monoclonal antibodies (mAbs) is an effective therapy for several cancers via activation of T-cells. Destructive thyroiditis and hypothyroidism often develop during anti-PD-L1 (αPD-L1) therapy but the pathogenic mechanisms are not known. We evaluated in vivo, the role of PD-L1 and its interactions with inflammatory triggers in the development of autoimmune thyroiditis (AIT). NOD.H-2h4 mice were treated with either αPD-L1 or isotype control (CTR) for two weeks and AIT evaluated after six weeks. αPD-L1 treated mice showed significantly higher Abs (p = 6×10e-4) and T-cell responses (p = 0.02) to thyroglobulin (Tg) compared with CTR mice. Serum fT4 levels were lower (p = 0.01) and TSH higher (p = 0.05) in αPD-L1 treated vs. CTR mice. Seven of the eight αPD-L1 treated mice (and none of the CTR mice) developed thyroid lymphocytic infiltration characterized by the presence of the CD4+, CD8+, FoxP3+ T- cells and B220+ B- cells. To gain insight into the pathways regulated by PD-L1 in the thyroid we assessed gene expression in the thyroid of αPD-L1 treated mice using RNA-seq. PD-L1 blockade was associated with upregulation of pathways of lymphocyte activation (p = 1.3×10e-5), lymphocyte proliferation (p = 2×10e-5), chemotaxis (p = 3.8×10e-12), and inflammatory response (p = 7.9×10e-7). Specifically, blocking PD-L1 was associated with upregulation of cytokine/chemokine genes that have a critical role in Th1 differentiation: IFNγ, IL-12, IL-15, CCL1 to CCL5, CD300, CXCL10, CXCL11. Ingenuity Pathway Analysis identified IFNγ and TNF as the top regulators of these activated gene networks. These results indicate that blockade of PD-L1 in thyroid promoted the Th1 mediator, IFNγ, inducing activation and proliferation of thyroidal CD4+ and CD8+ T cells, triggering thyroid tissue damage and AIT. Since PD-L1 mediates immune responses to inflammatory stressors (e.g. viral infections), we evaluated PD-L1 interaction with a known inflammatory trigger of AIT, interferon alpha (IFNα). Treatment with αPD-L1 + IFNα accelerated AIT in NOD.H-2h4 mice that developed high Tg Ab and T-cell responses and thyroidal lymphocytic infiltration only two weeks after treatment. Moreover, thyroiditis was more severe in mice receiving αPD-L1 + IFNα than αPD-L1 alone, manifesting by higher T-cell responses (p = 5×10e-3), and significantly more profound hypothyroidism. These results suggest that PDL-1 has a protective role in the thyroid against inflammatory stressors, and that its blockade exposes the thyroid to inflammatory damage. Therefore, in patients undergoing αPD-L1 therapy, inflammatory conditions (e.g. infections) can be a "second hit" that accelerates the onset of thyroiditis and augments thyroidal inflammation. Presentation: Monday, June 13, 2022 12:00 a.m. - 12:15 a.m.
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Migliorini, M., J. Pazzini, A. Triossi, and M. Zanetti. "40 MHz triggerless readout of the CMS Drift Tube muon detector." Journal of Instrumentation 19, no. 02 (2024): C02050. http://dx.doi.org/10.1088/1748-0221/19/02/c02050.
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Abstract The Level-1 trigger scouting system of the CMS experiment aims at intercepting the intermediate data produced by the L1 trigger processors before the final trigger decision. This system can be complemented by adding the raw stream of data collected from the detector front-end, whenever the throughput is manageable. In this work, the triggerless readout of the CMS Drift Tubes (DT) detector is presented. This is realized by reading a sector of the DT which has been equipped with the preproduction of Phase-2 upgrade front-end boards. A Xilinx VCU118 acts as a concentrator of the Phase-2 demonstrator lpGBT links and transmits data to a server via 100G TCP/IP. First results coming from a test-stand mimicking the sector demonstrator are shown.
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Baur, Rebecca, Franziska Karl, Romy Böttcher-Loschinski, et al. "Accumulation of T-cell-suppressive PD-L1highextracellular vesicles is associated with GvHD and might impact GvL efficacy." Journal for ImmunoTherapy of Cancer 11, no. 3 (2023): e006362. http://dx.doi.org/10.1136/jitc-2022-006362.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for a number of hemato-oncological disorders. In fact, allo-HSCT is considered as one of the most successful immunotherapies as its clinical efficacy is based on the donor T-cells’ capacity to control residual disease. This process is known as the graft-versus-leukemia (GvL) reaction. However, alloreactive T-cells can also recognize the host as foreign and trigger a systemic potentially life-threatening inflammatory disorder termed graft-versus-host disease (GvHD). A better understanding of the underlying mechanisms that lead to GvHD or disease relapse could help us to improve efficacy and safety of allo-HSCT. In recent years, extracellular vesicles (EVs) have emerged as critical components of intercellular crosstalk. Cancer-associated EVs that express the immune checkpoint molecule programmed death-ligand 1 (PD-L1) can suppress T-cell responses and thus contribute to immune escape. At the same time, it has been observed that inflammation triggers PD-L1 expression as part of a negative feedback network.Here, we investigated whether circulating EVs following allo-HSCT express PD-L1 and tested their efficacy to suppress the ability of (autologous) T-cells to effectively target AML blasts. Finally, we assessed the link between PD-L1 levels on EVs to (T-)cell reconstitution, GvHD, and disease relapse.We were able to detect PD-L1+EVs that reached a peak PD-L1 expression at 6 weeks post allo-HSCT. Development of acute GvHD was linked to the emergence of PD-L1highEVs following allo-HSCT. Moreover, PD-L1 levels correlated positively with GvHD grade and declined (only) on successful therapeutic intervention. T-cell-inhibitory capacity was higher in PD-L1highEVs as compared with their PD-L1lowcounterparts and could be antagonized using PD-L1/PD-1 blocking antibodies. Abundance of T-cell-suppressive PD-L1highEVs appears to also impact GvL efficacy as patients were at higher risk for relapse. Finally, patients of PD-L1highcohort displayed a reduced overall survival.Taken together, we show that PD-L1-expressing EVs are present following allo-HSCT. PD-L1 levels on EVs correlate with their ability to suppress T-cells and the occurrence of GvHD. The latter observation may indicate a negative feedback mechanism to control inflammatory (GvHD) activity. This intrinsic immunosuppression could subsequently promote disease relapse.
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Venturin, Beatrice. "“I Don’t Fit in Here and I Don’t Fit in There:” Understanding the Connections between L1 Attrition and Feelings of Identity in 1.5 Generation Russian Australians." Heritage Language Journal 16, no. 2 (2019): 238–68. http://dx.doi.org/10.46538/hlj.16.2.6.
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The present study analyzes four adult Russian-Australian 1.5ers, heritage bilinguals whose first language is Russian, and who immigrated to Australia or New Zealand during their primary school years. Semi-structured interviews conducted with the case-study participants examined their attitudes toward their Russian, their L1, and English, their L2. The interviews explored the participants’ schooling history, language use, perceived language proficiency, dominance and use, perceived L1 attrition, and feelings about their identity. The aim of the study was to understand the connections between language, particularly L1 attrition, and identity for this cohort of 1.5 generation speakers, as well as factors that may influence their identity perception. The results emerging from the study’s data reconfirm the role played by language in identity construction. At the same time, they suggest that for 1.5ers the relationship between language and identity also needs to be considered in relation to L1 attrition. This factor, in fact, might contribute to identity conflicts and trigger the desire to return to one’s roots.
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Kciuk, Mateusz, Damian Kołat, Żaneta Kałuzińska-Kołat, et al. "PD-1/PD-L1 and DNA Damage Response in Cancer." Cells 12, no. 4 (2023): 530. http://dx.doi.org/10.3390/cells12040530.
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The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor’s susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.
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Sahler, J. M., C. R. Eade, C. Altier, and J. C. March. "Salmonella entericaSerovar Typhimurium Increases Functional PD-L1 Synergistically with Gamma Interferon in Intestinal Epithelial Cells viaSalmonellaPathogenicity Island 2." Infection and Immunity 86, no. 5 (2018): e00674-17. http://dx.doi.org/10.1128/iai.00674-17.
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ABSTRACTNontyphoidal serovars ofSalmonella entericaare pathogenic bacteria that are common causes of food poisoning. WhereasSalmonellamechanisms of host cell invasion, inflammation, and pathogenesis are mostly well established, a new possible mechanism of immune evasion is being uncovered. Programmed death ligand 1 (PD-L1) is an immunosuppressive membrane protein that binds to activated T cells via their PD-1 receptor and thereby halts their activation. PD-L1 expression plays an essential role in the immunological tolerance of self-antigens but is also exploited for immune evasion by pathogen-infected cells and cancer cells. Here, we show for the first time thatSalmonellainfection of intestinal epithelial cells causes the induction of PD-L1. The increased expression of PD-L1 throughSalmonellainfection was seen in both human and rat intestinal epithelial cell lines. We determined that cellular invasion by the bacteria is necessary for PD-L1 induction, potentially indicating thatSalmonellastrains are delivering mediators from inside the host cell that trigger the increased PD-L1 expression. Using knockout mutants, we determined that this effect largely originates from theSalmonellapathogenicity island 2. We also show for the first time in any cell type thatSalmonellacombined with gamma interferon (IFN-γ) causes a synergistic induction of PD-L1. Finally, we show thatSalmonellaplus IFN-γ induction of PD-L1 decreased the cytokine production of activated T cells. UnderstandingSalmonellaimmune evasion strategies could generate new therapeutic targets and help to manipulate PD-L1 expression in other diseases.
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Bachtis, M., D. Campos, J. Jones, and M. Tepper. "The Octopus processor for the CMS L1 muon trigger for High Luminosity LHC." Journal of Instrumentation 17, no. 03 (2022): C03025. http://dx.doi.org/10.1088/1748-0221/17/03/c03025.
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Abstract The upgraded L1 muon trigger system of the CMS experiment in the High Luminosity Large Hadron Collider is based on custom processors featuring large Field Programmable Gate Arrays (FPGAs) connected by large numbers of optical links. These provide the I/O bandwidth and power necessary to process the complex algorithms used during the collection of physics data. The design and performance requirements of these processors creates significant challenges in signal integrity, power delivery, and thermal management. In this paper we describe the Octopus processor, featuring a large Xilinx Virtex Ultrascale+ FPGA and up to 128 links interfaced to optics through high quality twin-ax copper cables. Results on signal integrity at 25 Gb/s and the first demonstration of 50+ Gb/s links with pluggable optics in CMS are also shown, demonstrating bit error rates below 10−15 at a 95% confidence level. The thermal performance is measured inside an Advanced-TCA crate with acceptable thermal margins up to 200 W of chip power. Future improvements are mentioned, potentially allowing operation at up to 300 W.
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Lanzolla, Giulia, Alberto Coppelli, Mirco Cosottini, Stefano Del Prato, Claudio Marcocci, and Isabella Lupi. "Immune Checkpoint Blockade Anti–PD-L1 as a Trigger for Autoimmune Polyendocrine Syndrome." Journal of the Endocrine Society 3, no. 2 (2019): 496–503. http://dx.doi.org/10.1210/js.2018-00366.
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Schwegler, P., O. Kortner, H. Kroha, and R. Richter. "Improvement of the L1 trigger for the ATLAS muon spectrometer at high luminosity." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 718 (August 2013): 245–47. http://dx.doi.org/10.1016/j.nima.2013.01.023.
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Moreau, F. "The low noise L1 trigger of the H1 lead/scintillating-fibre electromagnetic calorimeter." Nuclear Physics B - Proceedings Supplements 61, no. 3 (1998): 132–36. http://dx.doi.org/10.1016/s0920-5632(97)00551-3.
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Avgustinovich, Alexandra V., Olga V. Bakina, Sergey G. Afanas’ev, Liudmila V. Spirina, and Alexander M. Volkov. "Safety and Efficacy of Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients with a PD-L1 Positive Status: A Case Report." Current Issues in Molecular Biology 45, no. 9 (2023): 7642–49. http://dx.doi.org/10.3390/cimb45090481.
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Introduction: The landscape of gastric cancer treatment has changed owing to the widespread use of immune checkpoint inhibitors. Autophagy, involved in regulating the immune system, is a potential trigger of immunity in tumors. This study aims to find molecular-based evidence for the effectiveness of FLOT chemotherapy with immune checkpoint inhibitors in gastric cancer patients. Materials and Methods: Three patients with advanced gastric cancer received FLOT neoadjuvant chemotherapy with immunotherapy and surgery. IHC was used to determine the PD-L1 status. Real-time PCR was used to analyze expression patterns of transcriptional growth factors, AKT/mTOR signaling components, PD-1, PD-L1, PD-L2 and LC3B. The LC3B content was measured via Western blotting analysis. Results: The combination of FLOT neoadjuvant chemotherapy and immunotherapy was found to be efficient in patients with a PD-L1-positive status. Gastric tumors with a PD-L1-positive status exhibited autophagy activation and decreased PD-1 expression. Conclusions: FLOT chemotherapy combined with immune checkpoint inhibitors showed high efficacy in gastric cancer patients with a positive PD-L1 status. Autophagy was involved in activating the tumor immunity. Further research is needed to clarify the mechanism of effective anticancer treatment.
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Hu, Lujun, Wenjie Chen, Shurong Zhou, and Guizhi Zhu. "ExoHCR: a sensitive assay to profile PD-L1 level on tumor exosomes for immunotherapeutic prognosis." Biophysics Reports 6, no. 6 (2020): 290–98. http://dx.doi.org/10.1007/s41048-020-00122-x.
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AbstractCancer immunotherapy has made recent breakthrough, including immune checkpoint blockade (ICB) that inhibits immunosuppressive checkpoints such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). However, most cancer patients do not durably respond to ICB. To predict ICB responses for patient stratification, conventional immunostaining has been used to analyze the PD-L1 expression level on biopsied tumor tissues but has limitations of invasiveness and tumor heterogeneity. Recently, PD-L1 levels on tumor cell exosomes showed the potential to predict ICB response. Here, we developed a non-invasive, sensitive, and fast assay, termed as exosome-hybridization chain reaction (ExoHCR), to analyze tumor cell exosomal PD-L1 levels. First, using αCD63-conjugated magnetic beads, we isolated exosomes from B16F10 melanoma and CT26 colorectal cancer cells that were immunostimulated to generate PD-L1-positive exosomes. Exosomes were then incubated with a conjugate of PD-L1 antibody with an HCR trigger DNA (T), in which one αPD-L1-T conjugate carried multiple copies of T. Next, a pair of metastable fluorophore-labeled hairpin DNA (H1 and H2) were added, allowing T on αPD-L1-T to initiate HCR in situ on bead-conjugated exosome surfaces. By flow cytometric analysis of the resulting beads, relative to αPD-L1-fluorophore conjugates, ExoHCR amplified the fluorescence signal intensities for exosome detection by 3–7 times in B16F10 cells and CT26 cells. Moreover, we validated the biostability of ExoHCR in culture medium supplemented with 50% FBS. These results suggest the potential of ExoHCR for non-invasive, sensitive, and fast PD-L1 exosomal profiling in patient stratification of cancer immunotherapy.
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Adam, W., T. Bergauer, K. Damanakis, et al. "Beam test performance of a prototype module with Short Strip ASICs for the CMS HL-LHC tracker upgrade." Journal of Instrumentation 17, no. 06 (2022): P06039. http://dx.doi.org/10.1088/1748-0221/17/06/p06039.
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Abstract The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam.
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Fedi, Giacomo. "L1 track trigger for the CMS HL-LHC upgrade using AM chips and FPGAs." EPJ Web of Conferences 150 (2017): 00004. http://dx.doi.org/10.1051/epjconf/201715000004.
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Klinz, Stephan G., Melitta Schachner, and Patricia F. Maness. "L1 and N-CAM Antibodies Trigger Protein Phosphatase Activity in Growth Cone-Enriched Membranes." Journal of Neurochemistry 65, no. 1 (2002): 84–95. http://dx.doi.org/10.1046/j.1471-4159.1995.65010084.x.
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Tang, Tianyu, Xing Huang, Gang Zhang, et al. "Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis." Journal for ImmunoTherapy of Cancer 10, no. 3 (2022): e004129. http://dx.doi.org/10.1136/jitc-2021-004129.
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BackgroundLTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.MethodsBoth immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.ResultsLTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.ConclusionsLTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.
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Tanaka, Ryota, Yuki Ichimura, Manabu Fujimoto, and Naoko Okiyama. "Distinct roles of programmed cell death ligands 1 and 2, based on the type of immunity." Journal of Immunology 204, no. 1_Supplement (2020): 229.7. http://dx.doi.org/10.4049/jimmunol.204.supp.229.7.
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Abstract Programmed cell death-1 (PD-1) is an immuno-regulatory receptor binding to two ligands, PD-L1 and PD-L2, which are expressed on stimulated antigen presenting cells (APCs). Isolated APCs such as macrophages (Mϕ), dendritic cells (DC), and B cells were cultured with interferon (IFN)-γ, interleukin (IL)-4, and IL-17A, respectively, followed by PD-L1/L2 expression analysis using flow cytometry. Upon stimulation by IFN-γ on all APCs and IL-17A on Mϕ and B cells, respectively, strong and moderate upregulation of PD-L1 expression was observed over unstimulated controls. Only stimulation by IL-4 could upregulate PD-L2 expression on all APCs. Therefore, experiments were performed on murine models, causing 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS), fluorescein isothiocyanate (FITC)-induced CHS, and imiquimod (IMQ)-induced psoriasis-like dermatitis, in order to trigger IFN-γ-mediated T helper (Th)1, IL-4-mediated Th2, and IL-17A-mediated Th17-type responses, respectively. In both Th1 and Th17-type immunity models, ear thickness changes in PD-L1 deficient (PD-L1−/−) mice were more severe than in wild-type (WT) and PD-L2 deficient (PD-L2−/−) mice (PD-L1−/−: 26.6±3.0, WT: 12.0±1.8 and PD-L2−/−: 12.3±1.9 [μm] in DNFB-induced CHS; 9.5±0.7, 6.2±0.4 and 5.7±0.6 [μm] in IMQ-induced psoriasis-like dermatitis [P < 0.01 by the U test], respectively). Thickness changes in PD-L2−/− were more severe than those in the WT and PD-L1−/− mice in the Th2-type immunity model (PD-L2−/−: 10.8±1.0, WT: 3.8±0.6 and PD-L1−/−: 3.6±0.6 [μm], [P < 0.01 by the U test], respectively). Collectively, PD-L1 has predominant roles in Th1 and Th17-type immunity; similarly, PD-L2 for Th2-type immunity.
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Musial, Shawn C., Tyler G. Searles, Sierra A. Kleist, et al. "Brain resident memory CD8+ T cells trigger CNS immune activation and infiltration." Journal of Immunology 208, no. 1_Supplement (2022): 165.18. http://dx.doi.org/10.4049/jimmunol.208.supp.165.18.
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Abstract The shifting paradigm regarding immune surveillance of the central nervous system (CNS) has shed light on immune cell networks thought to be absent from healthy brain tissue. Resident memory T cells (TRM) are a unique subset of memory T cells that persist within non-lymphoid tissues to provide rapid onset protection against reinfection. Recently, brain TRM (bTRM) have been identified in humans, with CNS or peripheral infection, or vaccination leading to bTRM establishment in mice. While bTRM are important for protection of the CNS against reinfection, their regulation and involvement in shaping the neuroimmune landscape remains unknown. Here, we take a reductionist approach employing viral-derived peptides to show that CD8+ bTRM reactivation is sufficient to initiate a cascade of innate and adaptive immune activation in the brain. Specifically, bTRM reactivation triggered activation of NK cells, T cells, microglia, and induced dendritic cell (DC) maturation, including upregulation of lymph node homing molecules. Reactivated bTRM also promoted accumulation of DCs in draining lymph nodes, and macrophages, monocyte-derived DCs, T cells and NK cells in the brain. Our preliminary data suggests that PD-1:PD-L1 signaling regulates the magnitude of this response, as PD-L1 blockade led to enhanced bTRM activation and neuroinflammation. We anticipate our results to illuminate roles for PD-1 signaling on bTRM in the context of pathogen clearance, and neurologic toxicities seen in cancer patients following PD-1 inhibitor treatment. This study will also provide insight into the pathologic or protective capacity of bTRM in neurologic diseases where T cells are implicated, such as Alzheimer’s disease, multiple sclerosis, and brain cancer. Supported by grants from NIH (K22 AI148508-02, T32 AI007363)
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Ban, Masao, Konosuke Kawashima, Kae Tsunematsu, Takumi Imura, Kyoko S. Kataoka, and Tohru Yamanoi. "Geologic and Petrologic Characteristics of the Lahar Deposits at the Western Foot of Zao Volcano." Journal of Disaster Research 17, no. 5 (2022): 736–44. http://dx.doi.org/10.20965/jdr.2022.p0736.
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The lahars are one of the most hazardous volcanic phenomena causing the third greatest causalities among the volcanic hazards since the 16th century worldwide. Lahars can flow down a long distance and cause tremendous disaster at the foot of volcanoes often beyond the areas of primary volcanic impacts of pyroclastic fall and pyroclastic density currents. Therefore, the research on lahar history of active volcanoes approaching from an analysis of a geological record in distal volcanic regions is significant for lahar hazard risk evaluation. Zao volcano has high risks of future eruptions, because volcanic tremors have been detected since 2013. The presence of a crater lake at the summit area, and steep slopes at the high altitude of Zao indicates high potential energy for future lahars, if triggered by an eruption starting underneath the crater lake. This study firstly reports the existence of lahar deposits at the western foot of Zao and discusses the depositional features and the origin of these as well as the lahar hazard risk at this volcano. The lahar deposits were exposed during the archaeological excavation of the Fujiki ruin, western foot of the Zao volcano. Two major lahar units, L1 and L2, were recognized. Based on the 14C dating and stratigraphic relationships, the ages of units L1 and L2 were estimated to be <ca. 4.0 and ca. 4.6 cal ka, respectively. The lithology, granulometry, and componentry features of the lahar deposits revealed the depositional features and the source materials. The upper part of L1 (L1-1) unit and lower part of L2 (L2-2) unit were deposited from a hyperconcentrated flow, whereas, the lower part of L1 (L1-2) unit and upper part of L2 (L2-1) unit were formed by a debris flow. The sources of both units were phreatomagmatic eruption products that may have erupted shortly before the lahar events. This implies that these eruptions were the most plausible trigger for the lahars. These results suggest that lahar risk will increase especially after the phreatomagmatic eruptions as well as phreatic eruptions, even in the western foot of this volcano.
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Bajor, Malgorzata, Agnieszka Graczyk-Jarzynka, Katsiaryna Marhelava, et al. "PD-L1 CAR effector cells induce self-amplifying cytotoxic effects against target cells." Journal for ImmunoTherapy of Cancer 10, no. 1 (2022): e002500. http://dx.doi.org/10.1136/jitc-2021-002500.
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BackgroundImmune checkpoint inhibitors and chimeric antigen receptor (CAR)-based therapies have transformed cancer treatment. Recently, combining these approaches into a strategy of PD-L1-targeted CAR has been proposed to target PD-L1high tumors. Our study provides new information on the efficacy of such an approach against PD-L1low targets.MethodsNew atezolizumab-based PD-L1-targeted CAR was generated and introduced into T, NK, or NK-92 cells. Breast cancer MDA-MB-231 and MCF-7 cell lines or non-malignant cells (HEK293T, HMEC, MCF-10A, or BM-MSC) were used as targets to assess the reactivity or cytotoxic activity of the PD-L1–CAR-bearing immune effector cells. Stimulation with IFNγ or with supernatants from activated CAR T cells were used to induce upregulation of PD-L1 molecule expression on the target cells. HER2–CAR T cells were used for combination with PD-L1–CAR T cells against MCF-7 cells.ResultsPD-L1–CAR effector cells responded vigorously with degranulation and cytokine production to PD-L1high MDA-MB-231 cells, but not to PD-L1low MCF-7 cells. However, in long-term killing assays, both MDA-MB-231 and MCF-7 cells were eliminated by the PD-L1–CAR cells, although with a delay in the case of PD-L1low MCF-7 cells. Notably, the coculture of MCF-7 cells with activated PD-L1–CAR cells led to bystander induction of PD-L1 expression on MCF-7 cells and to the unique self-amplifying effect of the PD-L1–CAR cells. Accordingly, PD-L1–CAR T cells were active not only against MDA-MD-231 and MCF-7-PD-L1 but also against MCF-7-pLVX cells in tumor xenograft models. Importantly, we have also observed potent cytotoxic effects of PD-L1–CAR cells against non-malignant MCF-10A, HMEC, and BM-MSC cells, but not against HEK293T cells that initially did not express PD-L1 and were unresponsive to the stimulation . Finally, we have observed that HER-2–CAR T cells stimulate PD-L1 expression on MCF-7 cells and therefore accelerate the functionality of PD-L1–CAR T cells when used in combination.ConclusionsIn summary, our studies show that CAR-effector cells trigger the expression of PD-L1 on target cells, which in case of PD-L1–CAR results in the unique self-amplification phenomenon. This self-amplifying effect could be responsible for the enhanced cytotoxicity of PD-L1–CAR T cells against both malignant and non-malignant cells and implies extensive caution in introducing PD-L1–CAR strategy into clinical studies.
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Mu, Wei, Lei Jiang, Yu Shi, et al. "Non-invasive measurement of PD-L1 status and prediction of immunotherapy response using deep learning of PET/CT images." Journal for ImmunoTherapy of Cancer 9, no. 6 (2021): e002118. http://dx.doi.org/10.1136/jitc-2020-002118.
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BackgroundCurrently, only a fraction of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) experience a durable clinical benefit (DCB). According to NCCN guidelines, Programmed death-ligand 1 (PD-L1) expression status determined by immunohistochemistry (IHC) of biopsies is the only clinically approved companion biomarker to trigger the use of ICI therapy. Based on prior work showing a relationship between quantitative imaging and gene expression, we hypothesize that quantitative imaging (radiomics) can provide an alternative surrogate for PD-L1 expression status in clinical decision support.Methods18F-FDG-PET/CT images and clinical data were curated from 697 patients with NSCLC from three institutions and these were analyzed using a small-residual-convolutional-network (SResCNN) to develop a deeply learned score (DLS) to predict the PD-L1 expression status. This developed model was further used to predict DCB, progression-free survival (PFS), and overall survival (OS) in two retrospective and one prospective test cohorts of ICI-treated patients with advanced stage NSCLC.ResultsThe PD-L1 DLS significantly discriminated between PD-L1 positive and negative patients (area under receiver operating characteristics curve ≥0.82 in the training, validation, and two external test cohorts). Importantly, the DLS was indistinguishable from IHC-derived PD-L1 status in predicting PFS and OS, suggesting the utility of DLS as a surrogate for IHC. A score generated by combining the DLS with clinical characteristics was able to accurately (C-indexes of 0.70–0.87) predict DCB, PFS, and OS in retrospective training, prospective testing and external validation cohorts.ConclusionHence, we propose DLS as a surrogate or substitute for IHC-determined PD-L1 measurement to guide individual pretherapy decisions pending in larger prospective trials.
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Brandel, Noa. "The positive effect of explicit positive evidence." Instructed Second Language Acquisition 2, no. 2 (2018): 215–41. http://dx.doi.org/10.1558/isla.35105.
Full textAbstract:
The study investigates questions central to the field of second language (L2) acquisition and instruction: Does the first language (L1) influence the L2 grammar? Can wrong patterns be restructured? Is Universal Grammar accessible during L2 acquisition? And can L2 acquisition, rather than learning (in Krashen’s sense), be triggered by explicit positive evidence (EPE), combining input flood with explicit emphasis upon target forms? Three properties associated with the Null Subject Parameter were inspected in two sixth-grade groups (L1-Hebrew, L2-English): thematic subject omission, expletive subject omission, and post-verbal subjects. During teaching, both groups were exposed to input flood of expletive subjects, but only in one group were expletives explicitly emphasized (EPE). A Hebrew-toEnglish translation-choice task tested the abovementioned properties pre-teaching, immediately post-teaching, and four months post-teaching. Shortly after teaching, the group which was explicitly taught improved significantly in rejecting ungrammatical null expletives and post-verbal subjects, but not null thematic subjects, thus indicating (partial) clustering. However, the improvement attained was not fully preserved four months later. The results show that shortterm exposure to EPE concerning a single property can apparently trigger change in another property, suggesting that learned knowledge can affect L2 competence, and that Universal Grammar plays a role in L2 acquisition.