136 research outputs found
Design and synthesis of benzosuberene and tetracyclic-based molecules inspired by natural products as inhibitors of tubulin polymerization and preparation of drug-linker constructs to facilitate tumor selective targeted delivery.
No full textOne primary research interest of the Pinney Research Group centers on the design and synthesis (and biological evaluation through long-standing collaborations) of small-molecule inhibitors of tubulin polymerization and development of targeting strategies that facilitate selective delivery of therapeutic agents to tumors and the tumor microenvironment. The tubulin-microtubule protein has been established as a prime target for anti-cancer agents specifically with inhibitors of tubulin polymerization finding significant clinical relevance. Natural products such as combretastatin A-4 and colchicine that bind to the colchicine site (functioning as potent inhibitors of tubulin polymerization and antiproliferative agents) have been evaluated clinically and have inspired countless analogues and derivatives. The Pinney group has established a small library of bioactive molecules with benzosuberene, dihydronaphthalene, and indole-based molecular scaffolds as representative examples. Many of these compounds have demonstrated highly potent activity as both inhibitors of tubulin polymerization and cytotoxins. A subset of these molecules function through a unique dual-mechanism of action as potent cytotoxins and vascular disrupting agents (VDAs)(distinct from other tubulin-binding agents). VDAs result in selective blood flow shutdown to existing tumor vasculature, causing irreparable damage and rapid tumor necrosis. Ongoing efforts include diversifying the structure-activity relationship (SAR) knowledge of molecules that interact with tubulin, as well as improving selectivity of active compounds via prodrug and drug-linker strategies. A series of benzosuberene and tetracyclic analogues were designed and synthesized, structurally inspired by related molecules discovered and developed by the Pinney Laboratory as promising anti-cancer agents. These new analogues were assessed for their antiproliferative activity, inhibition of tubulin polymerization, and in vivo efficacy as VDAs for the most active molecules. Tetracyclic compounds were synthesized through treatment of benzosuberenes with chlorosulfonyl isocyanate (CSI), also leading to the discovery of a new application of this reagent. The substrate scope to synthesize these tetracycles with CSI was explored. Antibody-drug conjugates (ADCs) represent a prominent strategy for cancer therapeutics that selectively targets the tumors and/or the tumor microenvironment. Previously established lead molecules were incorporated into drug-linker constructs and evaluated for their enzymatic cleavage. To improve release of phenolic payloads, constructs with alternative self-immolative spacers were prepared and evaluated for their release
Introduction: special section on recent photography theory: the state in visual matters
No full textThis introduction to a special section on ‘Photography and the State’ reflects on trends in photography theory exemplified in essays by Jens Andermann, Ariella Azoulay, Andrea Noble, and Bronwyn Law-Viljoen. It suggests that the contributors make a powerful argument for photography’ s emergent contribution to theories of the state and of sovereignty. It situates this work in the context of a growing body of scholarship (by theorists such as Natalia Brizuela, Paula Cortes-Rocca, Clare Harris, Chris Pinney, and Karen Strassler) attuned to photography’ s role in political imagination in post-colonial and post-imperial spaces, and underscores movement of the field away from inter-subjective conceptions of photographic ethics and debates about indexicality
Exam Sequence and Timing as Predictors of COMLEX-USA and USMLE Performance in Osteopathic Medical Students
No full textMaurice Blodgett,1 Martin Schmidt,2 Jennifer S Beaty,3 Brian Pinney,4 Bryan Hays5 1Department of Primary Care, Des Moines University, West Des Moines, IA, USA; 2Department of Biochemistry and Nutrition, Des Moines University, West Des Moines, IA, USA; 3Department of Specialty Medicine, Des Moines University, West Des Moines, IA, USA; 4Center for Educational Enhancement, Des Moines University, West Des Moines, IA, USA; 5Registrar’s Office, Des Moines University, West Des Moines, IA, USACorrespondence: Maurice Blodgett, Email [email protected]: This study examined the impact of exam sequence and timing on the performance of osteopathic medical students on the COMLEX-USA Level 1 and Level 2 and USMLE Step 1 and Step 2 examinations.Methods: Two cohorts were analyzed: 364 osteopathic medical students who completed both COMLEX-USA Level 1 and USMLE Step 1 between 2020 and 2022 (prior to the implementation of pass/fail grading), and 734 osteopathic medical students who completed both COMLEX-USA Level 2 and USMLE Step 2 between 2021 and 2025. Student performance was evaluated based on the sequence of examinations and intervals between them. Because the scores did not follow a normal distribution, as indicated by the Shapiro–Wilk test, the Mann–Whitney U-test was employed to compare the median scores between the groups.Results: Osteopathic medical students who undertook the USMLE examinations first consistently achieved higher scores than those who undertook the COMLEX-USA examinations first across most academic quartiles. Shorter exam intervals (1– 7 days) were associated with higher scores, whereas longer intervals (≥ 8 days) were correlated with significantly lower scores. The effects of exam order and timing varied across performance quartiles, with lower-performing students deriving the greatest benefit from taking the USMLE examinations first and maintaining shorter intervals between the exams.Conclusion: Strategic scheduling of exams may enhance performance on both the COMLEX-USA and USMLE examinations, particularly for lower-performing students. However, individual factors should be considered when implementing these strategies. These findings offer valuable insights for osteopathic medical students and educators in planning exam preparation and scheduling.Keywords: medical licensure assessment, standardized board examinations, test preparation strategies, score outcome correlatio
Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome
No full textBackground Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors.
Methods and Results All patients with biopsy‐proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N‐terminal pro‐B‐type natriuretic peptide (NT pro‐BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro‐BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro‐BNP <1420 pmol/L.
Conclusions Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐BNP level can aid in distinguishing ATTRwt from AL amyloidosis
The wavewatcher's companion
No full textA humorous, original guide to the waves that surround us and throughwhich we experience the world, by the bestselling author of The Cloudspotter's Guide
Microvascular permeability and endothelial cell morphology associated with low-flow ischemia/reperfusion injury in the equine jejunum
No full textMicrovascular permeability of the jejunum of clinically normal equids and microvascular permeability associated with 60 minutes of ischemia (25% baseline blood flow) and subsequent reperfusion were investigated. Eight adult horses were randomly allotted to 2 equal groups: normal and ischemic/reperfusion injury. Lymphatic flow rates, mesenteric blood flow, and lymph and plasma protein concentrations were determined at 15-minute intervals throughout the study. Microvascular permeability was determined by estimates of the osmotic reflection coefficient, which was determined when the ratio of lymphatic protein to plasma protein concentration reached a constant minimal value as lymph flow rate increased (filtration-independent lymph flow rate), which occurred at venous pressure of 30 mm of Hg. Full-thickness jejunal biopsy specimens were obtained at the beginning and end of each experiment, and were prepared for light microscopy to estimate tissue volume (edema) and for transmission electron microscopy to evaluate capillary endothelial cell morphology. The osmotic reflection coefficient for normal equine jejunum was 0.19 +/- 0.06, and increased significantly (P < or = 0.0001) to 0.48 +/- 0.05 after the ischemia/reperfusion period. Microscopic evaluation revealed a significant increase (P < or = 0.0001) in submucosal and serosal volume and capillary endothelial cell damage in horses that underwent ischemia/reperfusion injury. Results indicate that ischemia/reperfusion of the equine jejunum caused a significant increase in microvascular permeability
A Feminist Journey
No full textUndergraduate project for WMNS 301 in Fall 2004 in which the author explores the
"significance of past and present feminist ideas to her own life as a spiritual woman who aspires to a career in the ministry" (quoting the instructor's nomination). Submitted by instructor Jane M. Pederson for student award in the 2005 award cycle
Development of a new method for measuring metamorphic kinetics
No full textBecause garnet strongly fractionates Mn, spessartine (XSps) content can be treated as a rock-wide proxy for time. By using Sm-Nd isotopic dating to discretely date cores and rims of garnet crystals, I associated an age with a XSps content, and used this association to indirectly date a set of garnets in a subvolume from the specimen, a Grt-Chl-Pg-Bt-Ms schist from the Pinney Hollow Formation collected at Townshend Dam, VT. Using high-resolution X-ray computed tomographic data, two garnets were selected based on size and accessibility for Sm-Nd dating. These garnets yielded rim ages of 372.8±5.7 Ma and 372.8±4.0 Ma (2σ); EPMA data for these gives rim XSps values of 0.02 and 0.03 respectively. Core ages were unsuccessful due to low Sm/Nd ratios in garnet indicating incomplete cleansing of REE-rich inclusions. Using the average of four published core ages from other Pinney Hollow garnets at this locality, the core age is estimated at 380 ± 3.5 Ma (2σ) paired with the core XSps values for the two garnets of 0.21 and 0.15. A linear relationship between garnet age and XSps has the equation: Age = (43.58 Ma)(XSps) + 376.96 Ma. Core XSps from 8 garnets within a 72 cm3 subvolume of the sample were analyzed, and yield Mn ages by reference to the age-XSps relationship ranging from 377.2 ±3.0 to 382.2±6.0 Ma. The estimated nucleation rate for this subvolume is 0.022 +0.032/-0.008 nuclei/cm3/Ma. The two dated garnets yield growth durations of 9.8±7.3 Ma and 8.0±6.6 Ma, consistent with durations calculated by other workers for this area. Incremental growth rates from dated and subvolume garnets exhibit sharp transitions and negative growth rates, but generally are higher in the core and lower in the rim. Attempts to fit predicted growth rate laws to the incremental growth rates are inconclusive in determining a kinetic control. Crude nearest neighbors analysis suggests diffusion controlled growth. These data represent the first application of a new method for measuring crystallization kinetics. As Sm-Nd isotopic age analysis for this garnet suite is refined, more detailed calibration of the XSps-age relationship will be possible, which will in turn result in more precise Mn ages for garnet subvolumes, and better estimates of instantaneous and time-averaged nucleation and growth rates. Nevertheless, as the first quantitative estimate of nucleation rate, these results represent a significant step toward a new technique for measuring crystallization kinetics
Quantification of myocardial extracellular volume fraction in systemic AL amyloidosis. an equilibrium contrast cardiovascular magnetic resonance study
No full textBACKGROUND: Cardiac involvement predicts outcome in systemic AL amyloidosis and influences therapeutic options. Current methods of cardiac assessment do not quantify myocardial amyloid burden. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) to quantify the cardiac interstitial compartment, measured as myocardial extracellular volume (ECV) fraction, hypothesizing it would reflect amyloid burden.
METHODS AND RESULTS: Sixty patients with systemic AL amyloidosis (65% men, median age 65 years) underwent conventional clinical cardiovascular magnetic resonance, including late enhancement, equilibrium contrast cardiovascular magnetic resonance, and clinical cardiac evaluation, including ECG, echocardiography, assays of N-terminal pro-brain natriuretic peptide and Troponin T, and functional assessment comprising the 6-minute walk test in ambulant individuals. Cardiac involvement in the amyloidosis patients was categorized as definite, probable, or none, suspected by conventional criteria. Findings were compared with 82 healthy controls. Mean ECV was significantly greater in patients than healthy controls (0.25 versus 0.40, P<0.001) and correlated with conventional criteria for characterizing the presence of cardiac involvement, the categories of none, probable, definite corresponding to ECV of 0.276 versus 0.342 versus 0.488, respectively (P<0.001). ECV was correlated with cardiac parameters by echocardiography (eg, Tissue Doppler Imaging [TDI] S-wave R=0.52, P<0.001) and conventional cardiovascular magnetic resonance (eg, indexed left ventricular mass R=0.56, P<0.001). There were also significant correlations with N-terminal pro-brain natriuretic peptide (R=0.69, P<0.001) and Troponin T (R=0.53, P=0.006). ECV was associated with smaller QRS voltages (R=0.57, P<0.001) and correlated with poorer performance in the 6-minute walk test (R=0.36, P=0.03).
CONCLUSIONS: Myocardial ECV measurement has potential to become the first noninvasive test to quantify cardiac amyloid burden
The River of Life: A Discussion of the Symbols of Water, Isolation, and Silence in the Works of Eduardo Mallea
No full textI owe the inspiration for this paper to an incident which occurred during my Junior Year at the University of Redlands. In a Spanish American Literature class, I was to give a report on a contemporary novel by Eduardo Mallea. I chose Chaves as the book I would read. After reading the novel, I had the strange feeling that the author had said something very profound, but I was not aware of what it was. I tried to find the symbolical significance of the novel. I was unsuccessful. [...]
The purpose of this paper, therefore, is to present an insight into the symbolism, content, and style of Mallea\u27s writing. It is in no way intended to be an analysis of his symbolism, but rather, a comprehensive description of the most outstanding symbols used, so that after reading this paper, a novel such as Chaves could be read and understood
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