Academic literature on the topic 'Engle (C.H.) (Publisher)'

BackgroundThe clinical success of PD-1- and CTLA-4- immune checkpoint inhibitors highlights the key contribution of immunosuppression to limiting effective anti-tumor responses. However, as many patients do not respond to anti-PD1 or CTLA4 therapy1-3 novel therapeutics that target additional immune-suppressive mechanisms are needed. Regulatory T cells (Tregs) inhibit immune responses in the tumor microenvironment via multiple suppressive mechanisms.4 5 Existing Treg-targeting agents lack specificity for intratumoral Tregs and can also deplete effector cells, a property that has likely contributed to the lack of clinical activity observed to date. CCR8 (C-C chemokine receptor 8) is selectively expressed on highly activated intratumoral Tregs, its high expression correlates with poor prognosis in multiple human tumor types6 7 and depletion of CCR8+ Tregs in preclinical models elicited potent anti-tumor activity. These observations provided rationale for the development of a CCR8-specific human depleting antibody.MethodsHuman FOXP3 and CCR8 expression was correlated across multiple tumor types using TCGA datasets and expression of CCR8 evaluated in primary tumor explants and PBMCs by flow cytometry. The efficacy of anti-CCR8 antibody treatment was evaluated in the MC38 and CT26 murine tumor models. The depletion of Tregs following anti-CCR8 treatment was assessed by flow cytometry. Flow cytometric-based binding assays were performed using cell lines expressing human or cynomolgus CCR8. Purified human NK cells were co-cultured with CCR8+ target cells and flow cytometry used to evaluate antibody-dependent killing activity.ResultsCCR8 expression was highly correlated with FoxP3 across multiple cancer subtypes and was low to absent on effector T cells. Importantly, CCR8 was not detected on any peripheral human leukocyte subset. In murine tumor models, anti-CCR8 antibody treatment reduced tumor growth in a dose- and Fc-gamma-receptor-dependent manner and resulted in complete regressions and the development of memory. Tumor shrinkage was associated with a reduction in intratumoral Tregs and increased representation of intratumoral CD8 T cells. FPA157 is a highly specific human and cynomolgus crossreactive CCR8 antibody that does not bind closely related chemokine receptors. FPA157 was engineered to enhance antibody-dependent cell-mediated cytotoxicity (eADCC) and elicited potent NK-mediated killing of target cells expressing CCR8 at levels observed on human intratumoralTregs.ConclusionsFPA157 is a CCR8-specific monoclonal antibody with eADCC activity that is being developed for the treatment of cancer. Depletion of CCR8+ Tregs induced substantial anti-tumor activity in pre-clinical models, thus supporting the clinical evaluation of FPA157 as a novel approach to alleviate immune suppression in the microenvironment of human solid tumors.ReferencesHellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378(22):2093-2104.Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377(14):1345-1356.Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018 Apr 5;378(14):1277-1290.Teng MW, Ngiow SF, von Scheidt B, McLaughlin N, Sparwasser T, Smyth MJ. Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth [published correction appears in Cancer Res. 2010; 70(23):10014]. Cancer Res 2010;70(20):7800-7809.Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 2013;210(9):1695-710.Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM, Rudensky AY. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 2016;45(5):1122-1134.De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJP, Provasi E, Sarnicola ML, Panzeri I, Moro M, Crosti M, Mazzara S, Vaira V, Bosari S, Palleschi A, Santambrogio L, Bovo G, Zucchini N, Totis M, Gianotti L, Cesana G, Perego RA, Maroni N, Pisani Ceretti A, Opocher E, De Francesco R, Geginat J, Stunnenberg HG, Abrignani S, Pagani M. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 2016;45(5):1135-1147.

In the framework of new materials and next-generation batteries, the acceleration and quantification of the improvements that these advances pose, have become a priority in the field. In this regard, rate performance sits in an interesting spot. It is gaining more and more importance due to the electrification of transportation but its quantitative analysis is usually overlooked. In this regard, recently, new methodologies have been developed to allow the quantification of the rate performance. [1] It has been shown that the parameters used for this quantification, can be linked to intrinsic properties of the electrodes and materials, becoming a tool to further improve their understanding and optimization.[2] However, the usefulness of this methodology is damped by the slow acquisition of the rate data by galvanostatic cycling, which at very low rates can take even weeks. This limitation leads to reduced data density hampering the building of solid statistics to feed models. To mitigate this problem, chronoamperometry has been proposed as an accelerated method to acquire rate-performance data.[3] It has been proved that the low current/rate section of the chronoamperometry indeed matches the data of the galvanostatic equivalent, and it has been used as a way to characterize materials and electrodes.[4, 5] However, the high current/rate section has proved much more challenging, showing inconsistent results across references and a not well-understood dependence on materials that manifest as another contribution that difficult the data interpretation. [6] In this work, we focus on the high-rate behavior of the chronoamperometric response of the electrodes. We show how this abnormal contribution can distort the fitting of the capacity-rate curves highly affecting the quantification of the rate performance parameters. To avoid this distortion, we have investigated the origin of the contribution by electrochemical impedance spectroscopy and simulations, and developed a methodology to isolate and mitigate it. This leads to more reliable datasets that permit very accurate fittings that match the galvanostatic data and works for all the common LIBs materials tested.[7] These advances will surely boost the usefulness and reliability of the technique as a way to characterize batteries. (1) Heubner, C.; L¨ammel, C.; Nickol, A.; Liebmann, T.; Schneider, M.; Michaelis, A. Journal of Power Sources 2018, 397, Publisher: Elsevier, 11–15. (2) Tian, R.; Park, S.-H. H.; King, P. J.; Cunningham, G.; Coelho, J.; Nicolosi, V.; Coleman, J. N. Nature Communications 2019, 10, Publisher: Nature Publishing Group, 1933. (3) Heubner, C.; Seeba, J.; Liebmann, T.; Nickol, A.; B¨ orner, S.; Fritsch, M.; Nikolowski, K.; Wolter, M.; Schneider, M.; Michaelis, A. Journal of Power Sources 2018, 380, 83–91. (4) Pinilla, S.; Ryan, S.; McKeon, L.; Lian, M.; Vaesen, S.; Roy, A.; Schmitt, W.; Coleman, J. N.; Nicolosi, V. Advanced Energy Materials 2023, 2203747. (5) Tian, R.; Alcala, N.; O’Neill, S. J.; Horvath, D.; Coelho, J.; Griffin, A.; Zhang, Y.; Nicolosi, V.; O’Dwyer, C.; Coleman, J. N. ACS Applied Energy Materials 2020, DOI: 10.1021/acsaem. 0c00034. (6) Tian, R.; King, P. J.; Coelho, J.; Park, S. H.; Horvath, D. V.; Nicolosi, V.; O’Dwyer, C.; Coleman, J. N. Journal of Power Sources 2020, 468, DOI: 10.1016/j.jpowsour.2020.228220. (7) Manuscript under preparation.

Abstract In a subset of patients suffering from myeloproliferative neoplasms (MPNs), calreticulin (CALR) exon 9 frameshift mutations are known to be responsible for the development of either essential thrombocythemia (ET) or primary myelofibrosis (PMF) (1, 2). The most prevalent mutations are a 52-bp deletion (del52, type-1 mutation) and a 5-bp TTGTC insertion (ins5, type-2 mutation). In these patients, the mutational status is almost always heterozygous. Our group and collaborators have recently shown that the pathogenic mutant CALR proteins require interaction with and activation of the thrombopoietin receptor (TpoR) for activation of the JAK-STAT pathway (3, 4). Until now, no knock-in mouse model of these diseases has been published. In this abstract, we show how we succeeded in creating such a model. We had shown that the murine CALR mutant proteins behave just like their human counterparts (5). Specifically, the del52, ins5 and del61 (61bp deletion, type-1) Calr mutations were able to transform Ba/F3 cells (murine pro-B lymphocytic cells normally dependent on IL-3 for growth) expressing the thrombopoietin receptor (TpoR) and render them cytokine-independent. Importantly, we also mutated the Ba/F3 genome using the widely adopted CRISPR/Cas9 system in order to create a 61-bp deletion of the exon 9 of Calr. This too successfully transformed the Ba/F3 cells, showing that endogenous levels of expression of a mutant CALR protein are sufficient to induce phenotype in vitro. Now, using the same approach, we injected C57BL/6J mouse zygotes with the same CRISPR/Cas9 constructs to create the same 61-bp deletion in the murine Calr gene. Out of 46 pups born from the procedure, one male pup was heterozygous for the 61-bp deletion. By in vitro fertilization, we subsequently obtained heterozygous Calr del61/WT pups. After inter-breeding the mice, we analyzed the blood of 12 Calr del61/WT males and 12 Calr WT/WT males (littermates) at three different timepoints (15, 18 and 22 weeks old) and found that the Calr del61/WT mice showed significantly higher levels of circulating platelets. Conversely, red blood and white blood cell numbers were the same between both groups at all time points. We further show that expression of a mutant CALR protein, in a heterozygous state, is sufficient to induce abnormal proliferation of megakaryocytes and develop an ET phenotype in vivo in mice. Follow-up in dynamics of the phenotype and bone marrow and spleen pathology (examination of myeloproliferation and fibrosis) allow comparison with the retroviral murine models of CALR-mutant MPNs and with the known features of the human disease. The only limitation of our model is the fact that the Calr del61 mutation is parentally acquired and widespread throughout the organism. With this new model, we aim to test the efficiency of various drugs to prevent or cure the MPN phenotype, such as ruxolitinib, a JAK2 type-1 inhibitor that is already used in clinics in patients suffering from CALR-mutated MPNs. We also now have a means to generate a high number of Calr del61/WT bone marrow cells to extensively study the oncogenic properties of the Calr mutations at different stages of the hematopoeisis. It will also be of great interest to study, if generated, a homozygous mutational status of Calr del61 in vivo. Thus, our system will shed light on the importance of the negatively charged tail of CALR and on the effects of the novel positively charged tail on myeloproliferation. References 1. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. N Engl J Med. 2013 Dec 10;369(25):2379-90. 2. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. N Engl J Med. 2013 Dec 10;369(25):2391-405. 3. Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu RI, Marty C, et al. Blood. 2015 Dec 14;10.1182/blood-2015-11-681932. 4. Marty C, Pecquet C, Nivarthi H, Elkhoury M, Chachoua I, Tulliez M, et al. Blood. 2015 Nov 25;10.1182/blood-2015-11-679571. 5. Balligand T, Achouri Y, Pecquet C, Chachoua I, Nivarthi H, Marty C, et al. Leukemia. 2016 Feb 29;10.1038/leu.2016.47. Disclosures Constantinescu: Teva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Personal Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

BackgroundThe randomized controlled trial (RCT) remains a most important research as well as a tool for drug licensing. Informed consent also remains an integral component of this tool. The exact wording of this consent is not in the public domain and we had previously raised that concern and had pointed out it should [1, 2]. As we previously indicated such transparency was important from the point of an organized skepticism an essential element of scientific inquiry [3]. Moreover, we had also indicated that this transparency was even more important in safety outcome trials (SOT)s. We have the impression that such SOTs are becoming more frequent especially with the increasing popularity of pragmatic trials [4] where the safety outcome measures are not infrequently as severe as death.ObjectivesTo tabulate the frequency of RCTs with the primary outcome measure of safety in mainline general medicine journals at two time points, thirty years apart.MethodsRCTs published in 1990-1991 vs 2019-2020 in NEJM, JAMA, LANCET and BMJ were searched by 2 independent reviewers (AO and SNE). Phase 1-2 RCTs, post-hoc analyses of RCTs and RCTs reporting long term follow-up data were excluded. RCTs with an undisputable primary endpoint of efficacy were defined as an ‘A trial’. Those trials with declared or obvious primary endpoints of ‘safety’, ‘efficacy and safety’ or simply as ‘efficacy’ in which we unanimously considered the presence of serious harm to the patients in the control arms were defined as a ‘B trial’. Finally, the trials that we could not unanimously decide whether designate A or B, were designated as C. Discrepancies were resolved after discussion with the senior author (HY) and if, even then, there was no consensus the trial remained as a C. We then compared the frequencies of the types of RCTs which were published in 1990-1991 vs 2019-2020. Other salient features, like the type and the practice setting, of these patients were also tabulated.ResultsThere were 309 RCTs published in 1990-1991 and 600 RCTs published in 2019-2020. Nineteen RCTs on COVID-19 infection were excluded for fair comparisons. As seen in the Table 1 there was a significant increase in the number SOTs in the later years. Moreover, the number of intensive care unit (ICU) trials, a setting in which obtaining informed consents can often be problematic, significantly increased.ConclusionRecently, there is a significant increase in the number of SOTs. Moreover, they are more frequently conducted in the ICUs. We strongly re-emphasize that the informed consents of all RCTs, particularly, those related to SOTs should be public. We strongly consider that such action is necessary a. to continue receiving our patients’ vital consent to enable us to continue conducting RCTs and b. for justly addressing the organized skepticism of our peers.References[1] Yazici Y, Yazici H. Informed consent: time for more transparency. Arthritis Res Ther 2010;12: 121.[2] Ozdede A, Yazici H. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022; 386(18):1766.[3] Merton, Robert K. Science and technology in a democratic order. Journal of Legal and Political Sociology 1942; 1:115–126.[4] Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci 2011; 13:217-24.Table 1.1990-1991 (n=309)2019-2020 (n=581)OR (95% CI)Total number of RCTs309581A trial284 (91.9%)501 (86.2%)0.6 (0.3-1.0)B trial9 (2.9%)39 (6.7%)2.4 (1.1-5.0)None-A trial*25 (8.1%)80 (13.8%)2.0 (1.1-2.1)ICU trial12 (3.8%)52 (8.9%)2.4 (1.3-4.6)* All non-A trials include trials designated B and C.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Setiap karya sastra mengandung nilai-nilai yang bersumber dari agama, tradisi, budaya, dan kebangsaan. Karya sastra berkaitan erat dengan pendidikan karakter. Karya sastra merupakan sarana yang efektif untuk memberikan nilai-nilai pendidikan karakter. Dalam hal ini penelitian anak meneliti karya sastra dalam kumpulan cerpen. Tujuan Penelitian berupa: (1) mendeskripsikan karakter religius yang terkandung dalam kumpulan Cerita Anak Banua, (2) mendeskripsikan karakter nasionalis yang terkandung dalam kumpulan Cerita Anak Banua, (3) mendeskripsikan karakter integritas yang terkandung dalam kumpulan Cerita Anak Banua. (4) mendeskripsikan karakter mandiri yang terkandung dalam kumpulan Cerita Anak Banua, dan (5) mendeskripsikan karakter gotong royong yang terkandung dalam kumpulan Cerita Anak Banua. Pendekatan yang digunakan adalah penndekatan sosiologis dengan jenis penelitian kepustakaan. Metode yang digunakan adalah metode analisis isi dengan sumber data berupa kumpulan Cerita Anak Banua. Diterbitkan oleh Zahra Publisher Grub, Kota Malang, Jawa Timur, pada tahun 2020. Adapun cerita yang diambil peneliti berjumlah 12 judul cerita. Peneliti menggunakan teknik pengumpulan data pustaka, baca, dan teknik catat. Teknik deskriptif analisis merupakan Teknik analisis data yang digunakan. Hasil penelitian diperoleh bahwa: (1) Karakter Religius berjumlah 16 kutipan, yang terdapat dalam 5 cerita sebagai berikut: (a) Oleh-oleh Acil, (b) Bedak Dingin Laila, (c) Julak Kaning dan Sarakap Ajaib, (d) Udin Si Monyet dan Jamal Si Bekantan, dan (e) Kelekai Ajaib. (2) Karakter Nasionalis berjumlah 5 kutipan, yang terdapat dalam 3 cerita antara lain: (a) Julak Kaning dan Sarakap Ajaib, (b) Sunatan, dan (c) Unta Kertas. (3) Karakter Integritas berjumlah 20 kutipan, yang terdapat dalam 9 cerita sebagai berikut: (a) Mandai Untuk Dayu, (b) Oleh-oleh Acil, (c) Bedak Dingin Laila, (d) Julak Kaning dan Sarakap Ajaib, (e) Raja Bakung dan Putri Salsa, (f) Cici dan Hujan, (g) Unta Kertas, (h) Lempeng Pisang, dan (i) Kelekai Ajaib. (4) Karakter Mandiri berjumlah 6 kutipan, yang terdapat dalam 5 cerita yaitu: (a) Mandai Untuk Dayu, (b) Oleh-oleh Acil, (c) Bedak Dingin Laila, (d) Raja Bakung dan Putri Salsa, dan (e) Si Ringsang. (5) Karakter Gotong Royong berjumlah 53 kutipan, yang terdapat dalam 12 cerita sebagai berikut: (a) Mandai Untuk Dayu, (b) Oleh-oleh Acil, (c) Bedak Dingin Laila, (d) Julak Kaning dan Sarakap Ajaib, (e) Sunatan, (f) Udin Si Monyet dan Jamal Si Bekantan, (g) Raja Bakung dan Putri Salsa, (h) Si Ringsang, (i) Cici dan Hujan, (j) Unta Kertas, (k) Lempeng Pisang, dan (l) Kelekai Ajaib. Kata Kunci: nilai karakter, cerita anak

This chapter focuses on Illinois Negroes who were engaged in business. In 1837, three of the seventy-seven included in Chicago's population of 4,170 were business men. Among them were Lewis Isabel, Abram Hall, John Johnson, Ambrose Jackson, and John Jones. In 1860, there were 1,500 Negroes in the city, and thirty-two of them were involved in business. There were sixteen hairdressers, five barbers, four draymen, three butchers, one hotel keeper, one blacksmith, and one whitewasher. Negro business suffered in the “panic” years of 1867, 1873, and 1876, with many ventures failing. One of the successful Negro businessmen of the following years was Charles H. Smiley, who arrived in 1885, and became one of the city's foremost caterers. Chicago's first Negro millionaire was William Henry Lee, a publisher who owned F. C. Laird. In 1885 there were 110 businesses in Chicago owned and operated by Negroes in twenty-seven fields.