Lessons of Resilience from Our Founding Mothers: An Examination of Women from 1776 to 1830

The role of women in American society during its first 50 years (1776-1830) varied. Women, however, built and maintained the Republic but were not granted access to the Academy (Nash, 2005, Kerber, 1997). At the threshold of the Revolutionary War, women served not only their home, family, and husbands, they began to serve the broader country. In the first third of the 19th century, white women of wealth engaged in political acts of service and in acts of disruption (Kerber, 1997). The rest of this paper examines how women leaders of early America laid the foundation for women’s access to chartered institutions of higher education and the influences of this foundation. I assert that the women of 1776-1830, through their resilience and what I have coined the capacity- social capital-finance framework, paved a path for the women to come (e.g., Catherine Beecher, Mary Lyon, Harriet Tubman, Ida B. Wells). Through historical research, I explore the philosophical underpinnings of 1776 through 1830 and explain women’s capacity, their social capital, and the eventual access to their own money. I also apply this framework to current day standards

FAK-inhibition opens the door to checkpoint immunotherapy in Pancreatic Cancer

Immunotherapy has had remarkable success in the treatment of some cancer types. However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors. Recently, Jiang and colleagues identified a key role for FAK in regulating the composition of the fibrotic and immuno-suppressive pancreatic tumour niche, and showed that FAK inhibitors can be used in combination with immune checkpoint blockade and gemcitabine chemotherapy to significantly delay pancreatic tumour progression. This study further supports the use of FAK inhibitors in combination with immunotherapy

Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines : a case report

Abstract Background Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing. Methods Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization. Results A peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now. Conclusions Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Differential unroofing within the central metasedimentary Belt of the Grenville Orogen: constraints from 40 Ar/ 39 Ar thermochronology

An 40 Ar/ 39 Ar thermochronological investigation of upper greenschist to granulite facies gneiss, amphibolite and marble was conducted in the Central Metasedimentary Belt (CMB), Ontario, to constrain its cooling history. Incremental 40 Ar/ 39 Ar release spectra indicate that substantial differential unroofing occurred in the CMB between ∼ 1000 and ∼ 600 Ma. A consistent pattern of significantly older hornblende and phlogopite 40 Ar/ 3 Ar cooling ages on the southeast sides of major northeast striking shear zones is interpreted to reflect late displacement due to extensional deformation. Variations in hornblende 40 Ar/ 39 Ar age plateaus exceeding 200 Ma occur over distances less than 50 km with major age discontinuities occurring across the Robertson Lake shear zone and the Sharbot Lake mylonite zone which separate the Sharbot Lake terrane from the Elzevir and Frontenac terranes. Extensional displacements of up to 14 km are inferred between the Frontenac and Elzevir terranes of the CMB. No evidence for significant post argon-closure vertical displacement is indicated in the vicinity of the Perth Road mylonite within the Frontenac terrane. Variations of nearly 100 Ma in phlogopite 40 Ar/ 39 Ar plateau ages occur in undeformed marble on either side of the Bancroft Shear Zone. Phlogopites from sheared and mylonitized marble within the shear zone yield 40 Ar/ 39 Ar diffusional loss profiles, but have older geologically meaningless ages thought to reflect incorporation of excess argon. By ∼ 900 Ma, southeast directed extension was occurring throughout the CMB, possibly initiated along previous zones of compressional shearing. An easterly migration of active zones of extension is inferred, possibly related to an earlier, overall easterly migration of active zones of regional thrusting and easterly migration of an ancient subduction zone. The duration of extensional shearing is not well constrained, but must have ceased before ∼ 600 Ma as required by the deposition of overlying undeformed Cambrian and/or Ordovician sedimentary rocks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47297/1/410_2004_Article_BF00310739.pd

Environmental Influences on Disabled Students\u27 Cocurricular Involvement

Involvement of students in the cocurriculum is critical to the development of desired outcomes in college. However, the literature on disabled college students centers academic experiences, largely overlooking cocurricular experiences. In this study, we explored the cocurricular involvement of disabled students, examining factors that created barriers for their involvement, how students responded to barriers, factors that made involvement possible, and those that encouraged involvement. Grounded in a critical realist approach to disability, augmented by environmental theories, and employing a descriptive-interpretive design, we used both individual interviews and focus groups to obtain data from 33 disabled students at a midwestern, comprehensive, land-grant university. We found that (a) other people\u27s behaviors and attitudes created more barriers to disabled students\u27 involvement than did physical or organizational factors; (b) participants reported a wide variety of emotional and behavioral responses to the barriers; (c) accessible physical design, flexible organizational policies, and assistance from others made involvement possible; (d) universally designed elements of the physical and organizational environment as well as active support from staff and peers encouraged involvement; and (e) barriers to and encouragers of involvement varied by impairment. We offer implications for further research and practice