Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma

BackgroundMelanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.MethodsHuman as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.ResultsMCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.ConclusionThe SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients

Investigating Methods to Reduce the Burden of Cervical Cancer in Highly Impacted Countries

Cervical cancer, which primarily develops in middle-aged women, is a large public health issue in most low- and middle-income countries (LMICs), causing significant morbidity and mortality among women during peak working and child-rearing ages. In contrast, high-income countries, which tend to have comprehensive cytologic (e.g. Pap smear) screening programs, have low rates of cervical cancer, demonstrating the effectiveness of secondary prevention on incidence and mortality of this disease. Unfortunately, as of yet, LMICs have not effectively implemented screening programs; thus, it is critical to investigate non-traditional forms of cervical cancer interventions in low-resource settings. It is estimated that 90% of cervical cancers are caused by the human papillomavirus (HPV), so novel interventions focus on HPV detection and prevention. This dissertation investigates the impact of testing for and vaccinating against HPV among women in two LMICs: Guatemala and Thailand. First, we evaluate the acceptability of self-collection HPV testing as a primary form of cervical cancer screening among Buddhist and Muslim women in southern Thailand. We survey women to assess knowledge of cervical cancer and screening and offer self-collected HPV tests. We find high acceptability across both cultural groups, particularly among Muslim women, who report lower rates of prior cervical cancer screening. Second, we analyze barriers to cervical cancer screening among women in Guatemala, a country with about 50% indigenous population and over 25 spoken languages and dialects, using nationally representative cross-sectional data from 2014-2015. Specifically, we explore the association between reported health barriers (e.g. needing permission, cost, distance, reluctance to travel alone, language barriers) and prior cervical cancer screening, using multivariate negative binomial regressions to estimate prevalence ratios. We find that up-to-date screening remains low, particularly among rural and indigenous women, and that all reported health barriers, particularly discordant languages between a woman and the healthcare personnel in her community, are inversely associated with past screening. Third, we investigate the impact of exposure to self-collection HPV testing on participation in cervical cancer screening programs. We replicate the study from Aim 1 in a cohort of Guatemalan women, finding similar acceptability of HPV testing, and follow the cohort for two years to identify further participation in screening programs. We find that women who participate in an HPV testing campaign are more likely to receive additional screening. Discrepancies in the data indicate that many women do not accurately report screening history, suggesting that reported screening rates could be misleading. Fourth, we develop computational models of HPV transmission and cervical cancer development among a simulated cohort of Guatemalan women. This is the first model developed for the country using local data. The model suggests that HPV vaccination and effective screening schedules similar to those currently in practice in the United States would produce considerable reductions in cervical cancer incidence. However, even a one-time screen around age 40 or vaccination of 10-14-year-old females would cause a significant reduction in cervical cancer cases and deaths. This model can be adjusted to imitate the population of other LMICs and can be used by policymakers to evaluate different strategies when deciding which cervical cancer intervention strategies might best fit their country-specific context. Overall, this dissertation provides much needed insight into the utility of culturally sensitive novel cervical cancer interventions in highly impacted regions of the world.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155295/1/annagott_1.pd

Morphological and genetic diversity within Pilosella hoppeana aggr. (Asteraceae) in Italy and taxonomic implications

Morphological variation, ploidy level and genetic diversity have been studied on 10 populations of the Pilosella hoppeana aggr. from the Alps, Abruzzo, Calabria and Sicily.Chromosome counts showed that the plants from Abruzzo and those from Sicily are tetraploid (2n = 36); they are assigned to P. hoppeana subsp. macrantha. The plants from the Alps (P. hoppeana subsp. hoppeana) and those from Calabria are diploid. The Calabrian populations, previously included in P. hoppeana subsp. macrantha, are shown to belong to a separate species, P. leucopsilon. The principal component analysis, based on 25 morphological characters, allowed distinguishing clearly four groups. An allozymes study using 10 enzyme systems revealed 7 polymorphic loci with a total of 20 alleles, some of them exclusive at regional level, others shared between populations showing similar morphological features. The genetic differentiation between populations was relatively high. The obtained dendrogram supports recognition of the morphologically defined taxa

Improving Fingerprint Alteration Detection

Fingerprint alteration is a type of presentation attack in which the attacker strives to avoid identification, e.g. at border control or in forensic investigations. As a countermeasure, fingerprint alteration detection aims to automatically discover the occurrence of such attacks by classifying fingerprint images as ’normal’ or ’altered’. In this paper, we propose four new features for improving the performance of fingerprint alteration detection modules. We evaluate the usefulness of these features on a benchmark and compare them to four existing features from the literature. © Copyright 2015 IEEE - All rights reserved.This work is carried out under the funding of the EU-FP7 INGRESS project (Grant No. SEC-2012-312792). C. Gottschlich also acknowledges the support of the Felix-Bernstein-Institute for Mathematical Statistics in the Bio-sciences and the Niedersachsen Vorab of the Volkswagen Foundation.INGRES

Acceptability of Human Papillomavirus Self-Sampling for Cervical Cancer Screening in an Indigenous Community in Guatemala

Purpose: Cervical cancer rates in Latin America are higher than those in developed countries, likely because of the lower prevalence of screening. Specifically, less than 40% of women in Guatemala are regularly screened and even fewer women are screened in indigenous communities. Current screening strategies—Pap smears and visual inspection with acetic acid—might not be the most effective methods for controlling cancer in these settings. We thus investigated the potential of self-collection of cervical samples with testing for human papillomavirus (HPV) to help prevent cervical cancer in an indigenous community in Guatemala. Patients and Methods: A community representative random sample of 202 indigenous women age 18 to 60 years residing in Santiago Atitlan, Guatemala, were surveyed to assess knowledge of and risk factors for HPV and cervical cancer. Women were then invited to self-collect a cervical sample using HerSwab collection kits to assess the prevalence of HPV and the acceptability of self-sampling. Results: Of 202 women who completed the survey, 178 (89%) provided a self-sample. In all, 79% of these women found the test comfortable, 91% found the test easy to use, and 100% reported they were willing to perform the test periodically as a screening method. Thirty-one samples (17%) were positive for at least one of 13 high-risk HPV types, and eight (4.5%) were positive for HPV 16/18. Conclusion: HPV testing by using self-collected samples was well accepted, suggesting that it is a plausible modality for cervical cancer screening in indigenous communities. Further studies are needed to assess rates of follow-up after a positive test and to determine whether these findings extend to other indigenous and nonindigenous communities in Guatemala and Latin America

Cervical cancer knowledge and barriers and facilitators to screening among women in two rural communities in Guatemala: a qualitative study

Background Approximately 80% of deaths due to cervical cancer occur in low- and middle-income countries. In Guatemala, limited access to effective screening and treatment has resulted in alarmingly high cervical cancer incidence and mortality rates. Despite access to free-of-cost screening, women continue to face significant barriers in obtaining screening for cervical cancer. Methods In-depth interviews (N = 21) were conducted among women in two rural communities in Guatemala. Interviews followed a semi-structured guide to explore knowledge related to cervical cancer and barriers and facilitators to cervical cancer screening. Results Cervical cancer knowledge was variable across sites and across women. Women reported barriers to screening including ancillary costs, control by male partners, poor provider communication and systems-level resource constraints. Facilitators to screening included a desire to know one’s own health status, conversations with other women, including community health workers, and extra-governmental health campaigns. Conclusions Findings speak to the many challenges women face in obtaining screening for cervical cancer in their communities as well as existing facilitators. Future interventions must focus on improving cervical cancer-related knowledge as well as mitigating barriers and leveraging facilitators to promote screening.Medicine, Faculty ofNon UBCReviewedFacultyResearche

Elevated Aggression and Reduced White Matter Integrity in Mild Traumatic Brain Injury: A DTI Study

Mild traumatic brain injury (mTBI) remains the most commonly reported head injury in the United States, and is associated with a wide range of post-concussive symptoms including physical, cognitive and affective impairments. Elevated aggression has been documented in mTBI; however, the neural mechanisms associated with aggression at the chronic stage of recovery remain poorly understood. In the present study, we investigated the association between white matter integrity and aggression in mTBI using diffusion tensor imaging (DTI). Twenty-six age-matched adults participated in the study, including 16 healthy controls (HCs) and 10 individuals in the chronic stage of recovery (either 6-months or 12 months post-mTBI). Psychological measures of aggression included the Buss-Perry Aggression Questionnaire and the Personality Assessment Inventory (PAI). Axonal pathways implicated in affective processing were studied, including the corpus callosum, anterior thalamic radiation, cingulum and uncinate fasciculus, and measures of white matter integrity included fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). We found that adults with mTBI in the chronic stage of recovery had higher levels aggression. Individuals with mTBI also had greater RD in the corpus callosum compared to HCs, indicating reduced fiber integrity. Furthermore, we observed a significant association between reduced white matter integrity in the corpus callosum and greater aggression. Our findings provide additional evidence for underlying neuroanatomical mechanisms of aggression, although future research will be necessary to characterize the specific relationship between aggression and the white matter pathways we identified.Office of the Assistant Secretary of Defense for Health Affairs; Defense Health Agency J9, Research and Development Directorate, through the US Army Medical Research and Materiel Command (USAMRMC) [W81XWH-12-0386]Open access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Women’s cellphone access and ownership in rural Uganda: implications for self-care interventions

Abstract Background The World Health Organization (WHO) call for cervical cancer elimination includes increasing global cervical screening coverage. HPV-based self-collection (HPV-SC) is a promising screening model for low- and middle-income countries (LMICs), and while digital technology, such as cellphones, can be used to streamline HPV-SC, there is limited data on digital technology penetration in LMICs. Determining women’s cellphone access is critical to understanding the feasibility of using cellphones to support HPV-SC. Methods This study is a secondary analysis of a larger clinical trial. Participants of a cluster-randomized trial comparing HPV-SC models in Uganda completed a survey, including questions about demographics, cellphone access/ownership, prior cervical cancer screening (CCS), and willingness to receive CCS information by text. A logistic regression model was used to determine adjusted rates of cellphone ownership using survey variables as factors. Results Of 2019 participants, 76.1% owned a cellphone. In non-cellphone owners (n = 483), 82.4% had daily cellphone access and 7.3% had no access. Compared to non-cellphone owners, cellphone owners were significantly older, more educated, closer to major health centers, more likely to have prior CCS, and more willing to receive a CCS text. In the logistic regression model, the aforementioned variables were all significantly associated with the odds of owning a cellphone. Conclusions As health care systems consider adopting HPV-SC, it is imperative to understand digital technology penetration. The majority of participants were cellphone owners and were willing to receive CCS information by text; however, significant socioeconomic and demographic differences remain between cellphone owners and non-owners. Further investigation is needed to understand whether HPV-SC using cellphones is feasible in similar settings. Trial registration ISRCTN, 12767014 . ClinicalTrials.gov, NCT04000503

Using self-collection HPV testing to increase engagement in cervical cancer screening programs in rural Guatemala: a longitudinal analysis

Abstract Background Cervical cancer is a leading cause of death in low- and middle-income countries. Self-collection testing for human papillomavirus (HPV) is an alternative form of cervical cancer screening that can be completed privately and at home. Understanding how the use of HPV testing influences follow-up care in low-resourced settings is crucial before broad implementation. This study aimed to identify if access to self-collection HPV testing impacts participation in established cervical cancer screening programs among women in two rural communities in Guatemala. Methods A cohort of 956 women was recruited in 2016 and followed for 2 years for the HPV Multiethnic Study (HPV MES). At baseline, women answered a questionnaire assessing cervical cancer screening history and were offered self-collection HPV testing. Women were re-contacted yearly to determine receipt of additional screening. Statistical changes in screening behavior before and throughout study participation, stratified by self-collection status, were assessed using McNemar pair tests for proportions. Alluvial plots were constructed to depict changes in individual screening behavior. The odds of changes in Pap-compliance (screened in past 3 years), given collection status, were assessed using multivariate logistic regressions. Results Reported screening rates increased 2 years after enrollment compared to rates reported for the 3 years before study entry among women who collected a sample (19.1% increase, p < 0.05), received results of their test (22.1% increase, p < 0.05), and received positive (24.2% increase, p < 0.1) or negative results (21.7% increase, p < 0.05). However, most increases came from one community, with minimal changes in the other. The adjusted odds of becoming Pap compliant were higher for women who collected a sample vs. did not (OR: 1.48, 95% CI: 0.64, 3.40), received their result vs. did not (OR: 1.29, 95% CI: 0.52, 3.02), and received a positive result vs. negative (OR: 2.43, 95% CI: 0.63, 16.10). Conclusions Participation in self-collection HPV testing campaigns may increase likelihood of involvement in screening programs. However, results varied between communities, and reporting of screening histories was inconsistent. Future work should identify what community-specific factors promote success in HPV testing programs and focus on improving education on existing cervical cancer interventions.http://deepblue.lib.umich.edu/bitstream/2027.42/173485/1/12889_2020_Article_9478.pd