Vegetation boundaries on ERTS-1 imagery

There are no author-identified significant results in this report

Design, Synthesis, and Biological Activity of O-phenyl-N-(9’-acridinyl)-hydroxylamines

DNA intercalates, such as derivatives of 9-aminoacridine, can be effective anti-tumor agents. These compounds associate strongly with DNA, which can lead to cell cycle arrest and apoptosis; however, they can also have a similar effect on healthy cells. O-phenyl-N-(9’-acridinyl)-hydroxylamine, a novel anti-tumor compound, should be less susceptible to hydrolysis in vivo than existing 9-aminoacridine derivatives. The result would be a decrease in required effective dose in patients and a wider therapeutic window. The goal of this research is to synthesize O-phenyl-N-(9’-acridinyl)-hydroxylamine via the condensation of chloroacridine and an appropriately substituted O-phenylhydroxylamine. This compound will be isolated from the reaction mixture and extensively purified to prepare the target DNA intercalator. In addition, a series of related compounds can be prepared by selection of different arenes and aryl iodides in the first step of the synthesis. Once these O-phenyl-N-(9’-acridinyl)-hydroxylamines have been prepared, their properties, including binding affinity for genomic DNA, will be characterized

Extent of cyclic and changing ecological phenomena and semipermanent vegetation-ecosystem interface: Ecological applications of ERTS-A imagery

There are no author-identified significant results in this report

Unwilling Pilgrimage: Vikings, Relics, and the Politics of Exile during the Carolingian era (c. 830-940).

This dissertation investigates the flight and exile of Christian clergy during the Viking attacks along Europe’s Atlantic coasts during the ninth and early tenth centuries. These displaced clerics invariably brought the relics of their saints with them as they fled into exile. Because of this, these flights into exile carried broad repercussions in societies that looked on relics as healers, guarantors, patrons, and protectors. This dissertation argues that the movements of churchmen and their relics had vast religious, political, economic, and ideological significance that resounded far beyond churches and monasteries. The wanderings of dislocated Carolingian relic cults have been overlooked as a coherent phenomenon, but studied as a group, relic transfers c. 830-c. 930 offer a counterpoint to the triumphal narrative of Christian expansion in Europe. The unwilling movements of relics also help chart the political changes that unfolded in the West Frankish Kingdom as Carolingian hegemony gave way to the feudal age. The dissertation examines the literary traditions surrounding the movements of relics in three key Atlantic provinces of the Carolingan empire (Brittany, Neustria, and Aquitaine), and argues that relics, in addition to being material objects of devotion, provided a stable source of “spiritual capital” during the Viking attacks. Such "capital" could be leveraged by monks and clerics seeking to recoup losses sustained during the Viking raids, and also by local political leaders eager to legitimize themselves through protection of cult institutions threatened by the attacks. The dislocation of West Francia’s relic cults facilitated widespread re-localization of cult patronage relationships, weakening central Carolingian authority and empowering new groups of aristocrats to replace them.Ph.D.HistoryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62247/1/ddeselm_1.pd

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach

Cancer immunotherapy has gained traction in recent years owing to remarkable tumor clearance in some patients. Despite the notable success of immune checkpoint blockade (ICB) in multiple malignancies, engagement of the immune system for targeted prostate cancer (PCa) therapy is still in its infancy. Multiple factors contribute to limited response, including the heterogeneity of PCa, the cold tumor microenvironment, and a low number of neoantigens. Significant effort is being invested in improving immune-based PCa therapies. This review is a summary of the status of immunotherapy in treating PCa, with a discussion of multiple immune modalities, including vaccines, adoptively transferred T cells, and bispecific T cell engagers, some of which are undergoing clinical trials. In addition, this review also focuses on emerging mechanism-based small-molecule tyrosine kinase inhibitors with immune modulatory properties that, either as single agents or in combination with other immunotherapies, have the potential to improve clinical outcomes

Emergency Department Visits by Patients with Mental Health Disorders — North Carolina, 2008–2010

Patients with mental health disorders (MHDs) use the emergency department (ED) for acute psychiatric emergencies, for injuries and illnesses complicated by or related to their MHD, or when psychiatric or primary-care options are inaccessible or unavailable. An estimated 5% of ambulatory-care visits in the United States during 2007-2008 were made by patients with primary mental health diagnoses. To measure the incidence of ED visits in North Carolina with MHD diagnostic codes (MHD-DCs), the Carolina Center for Health Informatics (University of North Carolina at Chapel Hill) analyzed ED visits occurring during the period 2008-2010 captured by the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT). This report describes the results of that analysis, which indicated that nearly 10% of ED visits had one or more MHD-DCs assigned to the visit and the rate of MHD-DC-related ED visits increased seven times as much as the overall rate of ED visits in North Carolina during the study period. Those with an MHD-DC were admitted to the hospital from the ED more than twice as often as those without MHD-DCs. Stress, anxiety, and depression were diagnosed in 61% of MHD-DC-related ED visits. The annual rate of MHD-DC-related ED visits for those aged ≥65 years was nearly twice the rate of those aged 25-64 years; half of those aged ≥65 years with MHD-DCs were admitted to the hospital from the ED. Mental health is an important component of public health (4). Surveillance is needed to describe trends in ED use for MHDs to develop strategies to prevent hospitalization, improve access to ambulatory care, and develop new ways to provide ED care for the elderly with MHDs

Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient\u27s tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor\u27s intrinsic resistance may change under different circumstances. We find a transcriptional death receptor score that reflects a tumor\u27s intrinsic sensitivity to CAR T cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden

Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation

Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in bone homeostasis is not well understood. Here, we report that autophagy is activated during osteoblast differentiation. Ablation of focal adhesion kinase family interacting protein of 200 kD (FIP200), an essential component of mammalian autophagy, led to multiple autophagic defects in osteoblasts including aberrantly increased p62 expression, deficient LC3‐II conversion, defective autophagy flux, absence of GFP‐LC3 puncta in FIP200‐null osteoblasts expressing transgenic GFP‐LC3, and absence of autophagosome‐like structures by electron microscope examination. Osteoblast‐specific deletion of FIP200 led to osteopenia in mice. Histomorphometric analysis revealed that the osteopenia was the result of cell‐autonomous effects of FIP200 deletion on osteoblasts. FIP200 deletion led to defective osteoblast terminal differentiation in both primary bone marrow and calvarial osteoblasts in vitro. Interestingly, both proliferation and differentiation were not adversely affected by FIP200 deletion in early cultures. However, FIP200 deletion led to defective osteoblast nodule formation after initial proliferation and differentiation. Furthermore, treatment with autophagy inhibitors recapitulated the effects of FIP200 deletion on osteoblast differentiation. Taken together, these data identify FIP200 as an important regulator of bone development and reveal a novel role of autophagy in osteoblast function through its positive role in supporting osteoblast nodule formation and differentiation. © 2013 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100319/1/jbmr1971.pd

Is the combination of immunotherapy and radiotherapy in non-small cell lung cancer a feasible and effective approach?

For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small-cell lung cancer (NSCLC). The recent introduction of immunotherapy (IT) in clinical practice, especially strategies targeting negative regulators of the immune system, so-called immune checkpoint inhibitors, has led to a paradigm shift in lung cancer as in many other solid tumors. Although antibodies against programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) are currently on the forefront of the immuno-oncology field, the first efforts to eradicate cancer by exploiting the host's immune system date back to several decades ago. Even then, researchers aimed to explore the addition of RT to IT strategies in NSCLC patients, attributing its potential benefit to local control of target lesions through direct and indirect DNA damage in cancer cells. However, recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Herein, the authors review the rationale of combining IT and RT across all NSCLC disease stages and summarize both historical and current clinical evidence surrounding these combination strategies. Furthermore, an overview is provided of active clinical trials exploring the IT-RT concept in different settings of NSCLC