Home in the Dharma: Transgender Buddhists on the West Coast of the U.S. and Canada, 1998-2019

Research on LGBTQ+ people and religion focuses on how religion has done harm. This violence is vital to recognize. But as a result, histories of how religion has benefitted transgender people are silenced. I will respond to this lack of scholarship on trans and queer religious history. I will analyze how transgender Buddhists on the West Coast of the U.S. and Canada negotiated gender identity with religion between 1998 and 2019. What factors led these individuals to Buddhism in this place and time? What aspects of the religion did they find (un)appealing? How did differences of identity—race, age, (dis)ability—affect how they related to and accessed Buddhism? I will add to the small but growing body of scholarship on trans religious history. In a broader context, this project continues the urgent work of decolonizing the cis-centric academic landscape, bringing trans epistemologies and subjectivities to the fore

Effect of single peak overloading on fatigue crack propagation

The macroscopic and electronmicroscopic crack propagation behavior of 2024-T3 aluminum alloy resulting from the application of a single 50% overload in an otherwise uniform alternating fatigue load is examined

Análisis automático en lo industria del cemento por espectrometría de rayos X y calculador asociado

No availableLa Sociedad de Ciments Français emplea desde hace tres años, en su Laboratorio Central de Levallois, un espectrómetro automático de rayos X, PW 1210. Las materias controladas son los productos empleados y fabricados corrientemente en la industria del cemento. Se han hecho patrones por fusión de mezclas puras. Estos patrones han permitido calcular para cada elemento la ecuación de una recta de referencia, a partir de la cual se efectúan los cálculos que dan la composición elemental de las muestras analizadas. Estos cálculos necesitan dos operadores, y los procesos verbales de análisis deben ser dactilografiados enseguida. Se ha considerado útil asociar al espectrómetro un calculador PR 8000, que realiza el conjunto de los cálculos y la redacción de los procesos verbales de análisis. Con este conjunto, se llega a un trabajo de análisis completamente automatizado entre la introducción de la muestra en el espectrómetro y la salida de los resultados imprimidos. Gracias al calculador a él asociado, el espectrómetro puede ser utilizado a pleno rendimiento

Cancer Vaccines in Ovarian Cancer: How Can We Improve?

Epithelial ovarian cancer (EOC) is one important cause of gynecologic cancer-related death. Currently, the mainstay of ovarian cancer treatment consists of cytoreductive surgery and platinum-based chemotherapy (introduced 30 years ago) but, as the disease is usually diagnosed at an advanced stage, its prognosis remains very poor. Clearly, there is a critical need for new treatment options, and immunotherapy is one attractive alternative. Prophylactic vaccines for prevention of infectious diseases have led to major achievements, yet therapeutic cancer vaccines have shown consistently low efficacy in the past. However, as they are associated with minimal side effects or invasive procedures, efforts directed to improve their efficacy are being deployed, with Dendritic Cell (DC) vaccination strategies standing as one of the more promising options. On the other hand, recent advances in our understanding of immunological mechanisms have led to the development of successful strategies for the treatment of different cancers, such as immune checkpoint blockade strategies. Combining these strategies with DC vaccination approaches and introducing novel combinatorial designs must also be considered and evaluated. In this review, we will analyze past vaccination methods used in ovarian cancer, and we will provide different suggestions aiming to improve their efficacy in future trials

Reconstructing Dryopteris “semicristata” (Dryopteridaceae): Molecular profiles of tetraploids verify their undiscovered diploid ancestor

This is the publisher's version, also available electronically from http://www.amjbot.org.• Premise of the study: Discovering missing ancestors is essential to understanding the evolutionary history of biodiversity on Earth. Evidence from extinct species can provide links for reconstructing intricate patterns of reticulate relationships among extant descendents. When fossils are unavailable and other evidence yields competing hypotheses to explain species ancestry, data from proteins and DNA can help resolve conflicts and generate novel perspectives. The identity of a parent shared by two tetraploid species in the cosmopolitan fern genus Dryopteris has remained elusive for more than 50 years. Based on available data, four hypotheses were developed previously, each providing a different resolution to this uncertainty. • Methods: New molecular evidence from studies of isozymes and restriction site analysis of chloroplast DNA tested the competing hypotheses about the diploid ancestors of these two extant Dryopteris polyploids. • Key results: The results falsify two of the hypotheses, resolve the uncertainty in the third, and support the fourth. • Conclusions: Our data validate the prior existence of Dryopteris “semicristata,” which was proposed 38 years ago as a diploid progenitor of the allotetraploids D. cristata and D. carthusiana but has never been collected. After developing a phylogeny using the new molecular data, we describe a plausible morphology for D. “semicristata” by extrapolating likely character states from related extant species

CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

<p>Abstract</p> <p>Background</p> <p>Th17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMC) were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients) and another together with autologous dendritic cells (DC) pulsed with the melanoma epitope MART-1_26–35(6 patients). Cytokines were quantified directly in plasma from patients and after <it>in vitro </it>stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS).</p> <p>Results</p> <p>There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated <it>in vitro</it>, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells.</p> <p>Conclusion</p> <p>The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.</p> <p>Trial Registration</p> <p><b>Clinical trial registration numbers</b>: NCT0090896 and NCT00471887</p

Monocyte-derived dendritic cells loaded with a mixture of apoptotic/necrotic melanoma cells efficiently cross-present gp100 and MART-1 antigens to specific CD8(+ )T lymphocytes

BACKGROUND: In the present study, we demonstrate, in rigorous fashion, that human monocyte-derived immature dendritic cells (DCs) can efficiently cross-present tumor-associated antigens when co-cultured with a mixture of human melanoma cells rendered apoptotic/necrotic by γ irradiation (Apo-Nec cells). METHODS: We evaluated the phagocytosis of Apo-Nec cells by FACS after PKH26 and PKH67 staining of DCs and Apo-Nec cells at different times of coculture. The kinetics of the process was also followed by electron microscopy. DCs maturation was also studied monitoring the expression of specific markers, migration towards specific chemokines and the ability to cross-present in vitro the native melanoma-associated Ags MelanA/MART-1 and gp100. RESULTS: Apo-Nec cells were efficiently phagocytosed by immature DCs (iDC) (55 ± 10.5%) at 12 hs of coculture. By 12–24 hs we observed digested Apo-Nec cells inside DCs and large empty vacuoles as part of the cellular processing. Loading with Apo-Nec cells induced DCs maturation to levels achieved using LPS treatment, as measured by: i) the decrease in FITC – Dextran uptake (iDC: 81 ± 5%; DC/Apo-Nec 33 ± 12%); ii) the cell surface up-regulation of CD80, CD86, CD83, CCR7, CD40, HLA-I and HLA-II and iii) an increased in vitro migration towards MIP-3β. DC/Apo-Nec isolated from HLA-A*0201 donors were able to induce >600 pg/ml IFN-γ secretion of CTL clones specific for MelanA/MART-1 and gp100 Ags after 6 hs and up to 48 hs of coculture, demonstrating efficient cross-presentation of the native Ags. Intracellular IL-12 was detected in DC/Apo-Nec 24 hs post-coculture while IL-10 did not change. CONCLUSION: We conclude that the use of a mixture of four apoptotic/necrotic melanoma cell lines is a suitable source of native melanoma Ags that provides maturation signals for DCs, increases migration to MIP-3β and allows Ag cross-presentation. This strategy could be exploited for vaccination of melanoma patients

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long-term BRAF inhibition

It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.Fil: Madorsky Rowdo, Florencia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Baron, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Gallagher, Stuart John. Centenary Institute; AustraliaFil: Hersey, Peter. Centenary Institute; AustraliaFil: Emran, Abdullah A. L.. Centenary Institute; AustraliaFil: Von Euw, Erika María. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mordoh, Jose. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations

<p>Abstract</p> <p>Background</p> <p>A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines.</p> <p>Materials and methods</p> <p>The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot.</p> <p>Results</p> <p>Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRAS^Q61Kmutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAF^V600Emutants, including highly synergistic effects in two BRAF^V600Emutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAF^V600Emutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways.</p> <p>Conclusions</p> <p>The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAF^V600Emutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination.</p