Robust Institutional Support and Collaboration Between Summer Training Programs in Cancer and Biomedicine Drive the Pivot to a Virtual Format in Response to the COVID Pandemic.

Summer internships serve important roles in training the next generation of biomedical researchers and healthcare providers through laboratory and clinical experiences that excite trainees about these fields and help them make informed decisions about career paths. The SARS-CoV-2 (COVID) pandemic and associated physical distancing restrictions precluded implementation of traditional in-person summer curricula and led to the cancellation of many internships across the USA. COVID-related disruptions also created opportunities for trainees to engage in remote research, become proficient in online learning platforms, and explore multidisciplinary topics. These skills are highly relevant to trainees as virtual interfaces occupy an increasingly mainstream role in their professional paths. The response to the COVID pandemic required real-time adaptations at all levels for major biomedical institutions including the University of Maryland Baltimore (UMB). Pivoting summer programs to a virtual format as part of this response provided a "teachable moment" to expose trainees to the innovation and resilience that are essential components of the biomedical profession. UMB summer programs, which span diverse biomedical disciplines from cancer research to diabetes, consolidated resources and identified mentors with online research projects to develop a robust virtual curriculum. Herein, data from a cancer-focused internship illustrate the collaborative adaptations to established components and creation of new learning modules in the transition to, and implementation of, online training. Outcomes are presented in the context of the COVID pandemic and significant societal issues that arose in the summer of 2020. The utility of virtual components and their impact on future programs is discussed.

Role of OATP transporters in steroid uptake by prostate cancer cells in vivo.

BACKGROUND: Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated. METHODS: We sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1-, 2B1- or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intratumor accumulation of administered steroids by mass spectrometry. RESULTS: OATP1B1- and 2B-expressing xenografts each showed a threefold increase in tritiated-DHEAS uptake vs vector controls (P=0.002 and P=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15 µg dl-1), OATP1B1- and 2B1-expressing xenografts showed a 3.9-fold (P=0.057) and 1.9-fold (P=0.048) increase in tumor accumulation of DHEAS and a 1.6-fold (P=0.057) and 2.7-fold (P=0.095) increase in DHEA, respectively. At the substantial circulating testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected. CONCLUSIONS: OATP transporters measurably alter DHEAS uptake and intratumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.

Assessing substitution patterns, rates and homoplasy at HVRI of Steller sea lions, Eumetopias jubatus.

Despite the widely recognized incidence of homoplasy characterizing this region, the hypervariable region I (HVRI) of the mitochondrial control region is one of the most frequently used genetic markers for population genetic and phylogeographic studies. We present an evolutionary analysis of HVRI and cytochrome b sequences from a range-wide survey of 1031 Steller sea lions, Eumetopias jubatus, to quantify homoplasy and substitution rate at HVRI. Variation in HVRI was distributed across 41 variable sites in the 238-bp segment examined. All variants at HVR1 were found to be transitions. However, our analyses suggest that a minimum of 101 changes have actually occurred within HVRI with as many as 18 substitutions occurring at a single site. By including this hidden variation into our analyses, several instances of apparent long-range dispersal were resolved to be homoplasies and 8.5-12% of observed HVRI haplotypes were found to have geographic distributions descriptive of convergent molecular evolution rather than identity by descent. We estimate the rate of substitution at HVRI in Steller sea lions to be approximately 24 times that of cytochrome b with an absolute rate of HVRI substitution estimated at 27.45% per million years. These findings have direct implications regarding the utility of HVRI data to generate a variety of evolutionary genetic hypotheses.

Potential effects of environmental contaminants on P450 aromatase activity and DNA damage in swallows from the Rio Grande and Somerville, Texas.

Cliff swallows (Petrochelidon pyrrhonota) and cave swallows (P. fulva) were sampled during the breeding season at several locations in the Rio Grande, Texas, to evaluate the potential effects of environmental contaminants on P450 aromatase activity in brain and gonads and DNA damage in blood cells. The tritiated water-release aromatase assay was used to measure aromatase activity and flow cytometry was used to measure DNA damage in nucleated blood cells. There were no significant differences in brain and gonadal aromatase activities or in estimates of DNA damage (HPCV values) among cave swallow colonies from the Lower Rio Grande Valley (LRGV) and Somerville. However, both brain and gonadal aromatase activities were significantly higher (P < 0.05) in male cliff swallows from Laredo than in those from Somerville. Also, DNA damage estimates were significantly higher (P < 0.05) in cliff swallows (males and females combined) from Laredo than in those from Somerville. Contaminants of current high use in the LRGV, such as atrazine, and some of the highly persistent organochlorines, such as toxaphene and DDE, could be potentially associated with modulation of aromatase activity in avian tissues. Previous studies have indicated possible DNA damage in cliff swallows. We did not observe any differences in aromatase activity or DNA damage in cave swallows that could be associated with contaminant exposure. Also, the differences in aromatase activity and DNA damage between male cliff swallows from Laredo and Somerville could not be explained by contaminants measured at each site in previous studies. Our study provides baseline information on brain and gonadal aromatase activity in swallows that could be useful in future studies.

Deep genetic subdivision within a continuously distributed and highly vagile marine mammal, the Steller's sea lion (Eumetopias jubatus).

The Steller's sea lion Eumetopias jubatus is an endangered marine mammal that has experienced dramatic population declines over much of its range during the past five decades. Studies using mitochondrial DNA (mtDNA) have shown that an apparently continuous population includes a strong division, yielding two discrete stocks, western and eastern. Based on a weaker split within the western stock, a third Asian stock has also been defined. While these findings indicate strong female philopatry, a recent study using nuclear microsatellite markers found little evidence of any genetic structure, implying extensive paternal gene flow. However, this result was at odds with mark-recapture data, and both sample sizes and genetic resolution were limited. To address these concerns, we increased analytical power by genotyping over 700 individuals from across the species' range at 13 highly polymorphic microsatellite loci. We found a clear phylogenetic break between populations of the eastern stock and those of the western and Asian stocks. However, our data provide little support for the classification of a separate Asian stock. Our findings show that mtDNA structuring is not due simply to female philopatry, but instead reflects a genuine discontinuity within the range, with implications for both the phylogeography and conservation of this important marine mammal.

Consequences of polluted environments on population structure: the bank vole (Clethrionomys glareolus) at Chornobyl.

The accident at the Chornobyl Nuclear Power Plant in April 1986, released 100-200 million Curies of radioactive material into the surrounding environment. To investigate the possible genetic and population effects resulting from chronic exposure to this environmental radiation, we have examined mitochondrial DNA (control region) sequences from bank voles, Clethrionomys glareolus, inhabiting contaminated sites. Our analysis indicates genetic diversity is elevated in the contaminated sites when compared to relatively uncontaminated reference sites. This may be attributed to either an increased mutation rate in the mtDNA control region or immigration of individuals from surrounding areas into the contaminated environment. Although our observations do indicate that the contaminated areas represent sink populations, we cannot statistically discriminate between these two alternatives at this time. In addition, we have been unable to attribute any significant detrimental effects to bank vole populations inhabiting the contaminated Chornobyl environment based on these data. This is particularly paradoxical considering bank voles in the contaminated areas harbor the highest radiocesium (137Cs) body burdens and external dose rates of any mammal ever measured. Our long-term research on the bank vole indicates that several factors, including contaminants, may affect haplotype dynamics both spatially and temporally. These multifarious influences subsequently affect population genetic estimates typically used to address the effects of environmental pollution on animal populations. Finally, we provide a general framework for designing experiments investigating the role contaminants play in altering the genetic characteristics of exposed populations.

DNA sequence variation in the mitochondrial control region of red-backed voles (Clethrionomys).

The complete mitochondrial DNA (mtDNA) control region was sequenced for 71 individuals from five species of the rodent genus Clethrionomys both to understand patterns of variation and to explore the existence of previously described domains and other elements. Among species, the control region ranged from 942 to 971 bp in length. Our data were compatible with the proposal of three domains (extended terminal associated sequences [ETAS], central, conserved sequence blocks [CSB]) within the control region. The most conserved region in the control region was the central domain (12% of nucleotide positions variable), whereas in the ETAS and CSB domains, 22% and 40% of nucleotide positions were variable, respectively. Tandem repeats were encountered only in the ETAS domain of Clethrionomys rufocanus. This tandem repeat found in C. rufocanus was 24 bp in length and was located at the 5' end of the control region. Only two of the proposed CSB and ETAS elements appeared to be supported by our data; however, a "CSB1-like" element was also documented in the ETAS domain.

How did we make the Interdisciplinary Generalist Curriculum Project work? School-level efforts to facilitate success.

This article examines how the schools funded by the Interdisciplinary Generalist Curriculum (IGC) Project handled the process of planning and implementing their proposals; incorporated the IGC requirements as templates for changes in educational programs and organizational infrastructures; and identified key educational and management issues that emerged over time. How collaboration flourished at each IGC school was the central functional ingredient for successful implementation. Shared power and support from the dean were essential for success. The need for excellent channels of communication among all constituencies in the process of curricular change cannot be overemphasized. The most common approach was the addition of the new interdisciplinary clinical curriculum to the existing, usually discipline-based, curriculum, with attempts to establish integrative horizontal connections among concurrent courses in years one and two. The integration, sequencing, and correlating of basic science and clinical material occupied much of the IGC course directors' time in the early stages. Several approaches were used to help ensure a beneficial initial clinical experience for medical students, while accepting that a uniform experience for all students was not attainable or necessary. Encouraging active learning on the part of students was a goal of IGC schools' planning in and of itself. The splash of establishing interdisciplinary communication structures and greater melding of disciplinary cultures that occurred at and among the IGC schools appeared to lead to ripple effects that were recognized within the first year of planning and early implementation.

The Interdisciplinary Generalist Curriculum Project at Eastern Virginia Medical School.

The proposed Interdisciplinary Generalist Curriculum (IGC) Project at Eastern Virginia Medical School (hereafter Eastern Virginia) intended to encourage students to select generalist disciplines by featuring generalist role models, focusing on patients' perspectives, teaching generalist skills early, providing care to indigent and other populations, and emphasizing students' personal and professional development. To do so, Eastern Virginia proposed that collaborative interdisciplinary groups of faculty plan and oversee the implementation of first- and second-year students' early clinical experiences in generalists' offices as integrated with new and revised first- and second-year courses, the coordination of generalist curricula longitudinally from year one through year four, and the provision of appropriate faculty development. With minor exceptions described, the project was implemented as proposed. The project did have desirable effects, both intended and unexpected. The curricular changes made in the project will remain.

Reflective tomography reconstruction of satellite features-field results.

We report on the first satellite feature reconstruction, to our knowledge, by use of range-resolved reflective tomography techniques from nonimaging laser radar data collected on an orbiting satellite. The reconstructed features were two retroreflectors mounted on a satellite. The data were collected with a coherent laser radar system located at the Maui Space Surveillance Site in Maui, Hawaii. We utilized a filtered backpropagation algorithm to reconstruct the images using intensity projections created from the raw data. Key components of the image reconstruction process included the calculation of tomographic angles, the alignment of the intensity projections to an appropriate center of rotation, and compensation for the lack of data for a full 360 degrees set of views.

Deconvolution-based spatial resolution in optical diffusion tomography.

The role that deconvolution plays in the achievable spatial resolution in optical diffusion tomography is examined for the case of imaging an inhomogeneity in an otherwise homogeneous medium. It is shown that, in the measured data, it is the shape of the turbid medium modulation transfer function that determines the maximum spatial resolution. When the turbid medium transfer function is deconvolved from the measured data, it is the signal-to-noise ratio properties of the Fourier-transformed measured data that determine the maximum spatial resolution. It is shown that deconvolution-based methods can improve the spatial resolution in measured data up to a factor of 5 for realistic noise levels. These results are demonstrated with computer-simulated data.

Relationship between clinical signs and lung function in horses with recurrent airway obstruction (heaves) during a bronchodilator trial.

During a trial to determine the dose response to the beta2-adrenergic agonist pirbuterol, we judged the severity of airway obstruction by use of a clinical scoring system and compared this to objective data obtained by quantitative measures of lung function. Six horses affected by recurrent airway obstruction were used in this trial. Four hundred and sixty-eight measurements of lung function and clinical scores were obtained from 13 measurement periods when horses received each of 6 doses of pirbuterol. Scores of 1-4 were assigned to degree of nasal flaring and abdominal effort and summed for a total score. The veterinarian scoring the signs did not know the dose of pirbuterol received by the horse and was unaware of the lung function data. Nasal, abdominal and total scores were significantly related to changes in lung function and changes in breathing pattern. There were significant differences between total scores greater than 5 in indices that reflected changes in breathing strategy (peak inspiratory and expiratory flow), peripheral airway obstruction (dynamic elastance), and effort of breathing (maximal change in pleural pressure). Below a total score of 5, there were fewer significant differences in lung function even though measurements of pulmonary resistance and dynamic elastance indicated considerable airway obstruction. Failure of clinical score to reflect this low-grade airway obstruction suggests that airway disease is underdiagnosed and its detection would be helped by the availability of a convenient lung function test.

Pulmonary function and adrenal gland suppression with incremental doses of aerosolized beclomethasone dipropionate in horses with recurrent airway obstruction.

OBJECTIVE: To evaluate clinical response, pulmonary function, and adrenal gland response to incremental doses of beclomethasone dipropionate in horses with recurrent airway obstruction. DESIGN: Crossover trial. ANIMALS: 8 horses with recurrent airway obstruction. PROCEDURE: Horses randomly assigned to 4 groups were treated twice daily via aerosol administration of placebo or 500, 1,000, or 1,500 micrograms of beclomethasone dipropionate in a crossover design with a 10-day minimum washout period. Subjective assessment of airway obstruction, serum cortisol concentration, and maximum change in pleural pressure during tidal breathing (delta Pplmax) were determined daily prior to morning drug administration, and delta Pplmax was reevaluated 15 minutes after morning drug administration. Pulmonary resistance and dynamic compliance were determined at baseline and approximately 12 hours after the final treatment. RESULTS: An immediate treatment effect was not identified. Within 24 hours, delta Pplmax and airway obstruction were lower in horses receiving beclomethasone. Onset and magnitude of response was similar among the 3 beclomethasone dose regimens. Pulmonary resistance was improved only after administration of all 3 doses of beclomethasone, whereas dynamic compliance was improved after administration of 1,000 micrograms and 1,500 micrograms of beclomethasone. Reduction in serum cortisol concentration occurred with all 3 beclomethasone dose regimens; however, the magnitude of adrenal gland suppression was greater in horses receiving 1,000 or 1,500 micrograms of beclomethasone. CONCLUSIONS AND CLINICAL RELEVANCE: Low-dose (500 micrograms) beclomethasone administration caused similar, improvement in pulmonary function, compared with high-dose beclomethasone (1,000 and 1,500 micrograms), with the exception of dynamic compliance, and caused less suppression of endogenous cortisol production.

Cholecystokinin and leptin act synergistically to reduce body weight.

Leptin, the product of the obese gene, reduces food intake and body weight in rats and mice, whereas administration of the gut-peptide CCK reduces meal size but not body weight. In the current experiments, we report that repeated daily combination of intracerebroventricular leptin and intraperitoneal CCK results in significantly greater loss of body weight than does leptin alone. However, leptin plus CCK treatment does not synergistically reduce the size of individual 30-min sucrose meals during this period, and the effect of leptin-CCK combination on daily chow intake, while significant, is small compared with the robust effects on body weight loss. This synergistic effect on body weight loss depends on a peripheral action of CCK and a central action of leptin. These data suggest a previously unsuspected role for CCK in body weight regulation that may not depend entirely on reduction of feeding behavior and suggest a strategy for enhancing the effects of leptin in leptin-resistant obese individuals.

Image transfer through cirrus clouds. I. Ray trace analysis and wave-front reconstruction.

A new technique for modeling image transfer through cirrus clouds is presented. The technique uses a ray trace to model beam propagation through a three-dimensional volume of polydisperse, hexagonal ice crystals. Beyond the cloud, the technique makes use of standard Huygens-Fresnel propagation methods. At the air-cloud interface, each wave front is resolved into a ray distribution for input to the ray trace software. Similarly, a wave front is reconstructed from the output ray distribution at the cloud-air interface. Simulation output from the ray trace program is presented and the modulation transfer function for stars imaged through cirrus clouds of varying depths is discussed.