THERMAL ABLATION ALTERS THE TUMOR MICROENVIRONMENT ACTIVATING A ROBUST IMMUNE RESPONSE.

THERMAL ABLATION ALTERS THE TUMOR MICROENVIRONMENT ACTIVATING A ROBUST IMMUNE RESPONSE. Matthew T Campbell, M.D. Advisor Professor: Padmanee Sharma, M.D Ph.D Ablation techniques including radiofrequency ablation (RFA) and cryoablation have been shown to influence the immune system in animal models. Rare abscopal events, a distant metastatic response to a local procedure, have been observed in humans following both RFA and cryoablation. These rare observations have led to interest in further defining the impact of ablation procedures on the immune signature in the tumor microenvironment and in the systemic circulation. Retrospectively 9 patients with nephrectomy alone (control) were compared to 16 patients treated with ablation. Gene microarray analysis and immunohistochemistry (IHC) for presence of immune cell subtypes were performed on the tissue samples. Prospectively, blood was collected from patients 13 patients who underwent renal ablation for renal cell carcinoma for stage T1a (less than 4cm) at baseline and at day 1, day 28, and 6 months following the procedure. The blood was assessed by flow cytommetry and plasma cytokine levels at each time point following the procedure. GraphPad Prism version 6 was used to perform statistical analysis. The student’s t-test, Kruskal Wallis test, Friedman’s test, and Dunn’s multiple comparisons test were used when appropriate. IHC identified a significant difference (p=0.04) in programmed cell death 1 (PD-1) levels in the tumor invasive margin when comparing control to ablated tumors, while other tumor stains showed no significant differences between the two groups. Gene microarray analysis comparing control patients to three ablation specimens after RFA found significant differential gene expression in pathways and processes involving the immune system. Flow cytommetry markers consistent with previously characterized T regulatory populations of immune cell were found to trend upward at 24 hours following ablation compared to baseline levels. Cytokine analysis revealed elevated levels of IL-6 that increased at day 1 and returned toward baseline by day 28. RFA and cryoablation cause local tissue destruction and an inflammatory immune response that can be detected by gene microarray. Significant changes in tissue IHC, plasma cytokine levels, and immune cell populations in peripheral blood flow cytommetry analysis were not detected

Cold N+NH Collisions in a Magnetic Trap

We present an experimental and theoretical study of atom-molecule collisions in a mixture of cold, trapped atomic nitrogen and NH molecules at a temperature of $\sim 600$~mK. We measure a small N+NH trap loss rate coefficient of $k^{(\mathrm{N+NH})}_\mathrm{loss} = 8(4) \times 10^{-13}$~cm$^{3}$s$^{-1}$. Accurate quantum scattering calculations based on {\it ab initio} interaction potentials are in agreement with experiment and indicate the magnetic dipole interaction to be the dominant loss mechanism. Our theory further indicates the ratio of N+NH elastic to inelastic collisions remains large ($>100$) into the mK regime

Countdown to the Future

At the NASA Ames Research Center in California, the next generation of space biologists are working to understand the effects of long duration space flight on model organisms, and are developing ways to protect the health of future astronauts

Upper cenozoic chronostratigraphy of the southwestern Amazon Basin

The lack of numerical age dates for upper Cenozoic strata of the Amazon Basin has prevented resolution of its geologic history and accurate dating of important paleofaunas. Here we present results of magnetostratigraphy and 40Ar/39Ar dating of two volcanic ash deposits from the Madre de Dios Formation of eastern Peru. The two ash ages, 9.01 ± 0.28 Ma and 3.12 ± 0.02 Ma, provide the first numerical age data necessary for accurate interpretation of late Tertiary sedimentation in Amazonia and establish approximate time constraints for the last major cycle of Cenozoic deposition within the southwestern Amazon Basin. The older ash age also provides a minimum age for numerous Amazonian paleofaunas, which allows a more definitive correlation of these paleofaunas with those in other regions of South America

Ultradian glucocorticoid exposure directs gene-dependent and tissue-specific mRNA expression patterns in vivo

In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex (PFC). We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary. We have explored a potential mechanism for differences in the induction dynamics of the same transcript (Sgk1) between the PFC and pituitary. Glucocorticoid receptor (GR) activation profiles were strikingly different in pituitary and prefrontal cortex, with a significantly greater dynamic range and shorter duration of GR activity detected in the pituitary, consistent with the more pronounced gene pulsing effect observed. In the prefrontal cortex, expression of Gilz mRNA was also non-pulsatile and exhibited a significantly delayed timecourse of increase and decrease when compared to Sgk1, additionally highlighting gene-specific regulatory dynamics during ultradian glucocorticoid treatment

The promise and peril of intensive-site-based ecological research: insights from the Hubbard Brook ecosystem study

Abstract. Ecological research is increasingly concentrated at particular locations or sites. This trend reflects a variety of advantages of intensive, site-based research, but also raises important questions about the nature of such spatially delimited research: how well does site based research represent broader areas, and does it constrain scientific discovery?We provide an overview of these issues with a particular focus on one prominent intensive research site: the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Among the key features of intensive sites are: long-term, archived data sets that provide a context for new discoveries and the elucidation of ecological mechanisms; the capacity to constrain inputs and parameters, and to validate models of complex ecological processes; and the intellectual cross-fertilization among disciplines in ecological and environmental sciences. The feasibility of scaling up ecological observations from intensive sites depends upon both the phenomenon of interest and the characteristics of the site. An evaluation of deviation metrics for the HBEF illustrates that, in some respects, including sensitivity and recovery of streams and trees from acid deposition, this site is representative of the Northern Forest region, of which HBEF is a part. However, the mountainous terrain and lack of significant agricultural legacy make the HBEF among the least disturbed sites in the Northern Forest region. Its relatively cool, wet climate contributes to high stream flow compared to other sites. These similarities and differences between the HBEF and the region can profoundly influence ecological patterns and processes and potentially limit the generality of observations at this and other intensive sites. Indeed, the difficulty of scaling up may be greatest for ecological phenomena that are sensitive to historical disturbance and that exhibit the greatest spatiotemporal variation, such as denitrification in soils and the dynamics of bird communities. Our research shows that end member sites for some processes often provide important insights into the behavior of inherently heterogeneous ecological processes. In the current era of rapid environmental and biological change, key ecological responses at intensive sites will reflect both specific local drivers and regional trends

Health-Related Factors Associated with Mode of Travel to Work

Active commuting (AC) to the workplace is a potential strategy for incorporating physical activity into daily life and is associated with health benefits. This study examined the association between health-related factors and mode of travel to the workplace. Methods. A volunteer convenience sample of employed adults completed an online survey regarding demographics, health-related factors, and the number of times/week walking, biking, driving, and using public transit to work (dichotomized as no walk/bike/drive/PT and walk/bike/drive/PT 1 + x/week). Logistic regression was used to predict the likelihood of each mode of transport and meeting PA recommendations from AC according to demographics and health-related factors. Results. The sample was aged 43.5 11.4 years and was primarily White (92.7%) and female (67.9%). Respondents reported walking (7.3%), biking (14.4%), taking public transit (20.3%), and driving (78.3%) to work at least one time/week. Among those reporting AC, 9.6% met PA recommendations from AC alone. Mode of travel to work was associated with several demographic and health-related factors, including age, number of chronic diseases, weight status, and AC beliefs. Discussion. Mode of transportation to the workplace and health-related factors such as disease or weight status should be considered in future interventions targeting AC

A Systemically-Administered Small Molecule Antagonist of CCR9 Acts as a Tissue-Selective Inhibitor of Lymphocyte Trafficking

A goal for developers of immunomodulatory drugs has long been a systemically administered small molecule that can selectively inhibit inflammation in specific tissues. The chemokine receptor CCR9 is an attractive target for this approach, as entry of T cells into the small intestine from blood requires interaction between CCR9 and its ligand CCL25. We have tested the ability of a small molecule CCR9 antagonist, CCX8037, to inhibit antigen-mediated T cell accumulation in the intestine. This compound prevented accumulation of gut-imprinted antigen-specific CD8 T cells within epithelium of the small intestine. Interestingly, the antagonist did not affect the robust generation of gut-imprinted CD8 T cells within mesenteric lymph nodes. To distinguish “gut-selective” from “general” T cell inhibition, we tested the drug’s ability to influence accumulation of T cells within skin, a tissue in which CCR9 plays no known role, and we found no appreciable effect. This study demonstrates the feasibility of creating systemically-administered pharmaceuticals capable of tissue-selective immune modulation. This proof of concept is of utmost importance for designing effective treatments against various autoimmune disorders localized to a specific tissue

Central Blood Pressure and Peripheral Reactive Vasodilation in Plant-Based and Typical Dieting African Americans

African American individuals (AA) face higher mortality rates from cardiovascular disease than Americans from other racial/ethnic backgrounds. The cause of this health disparity is multifactorial and is in part related to impaired vascular function as well as other variables including diet and numerous socioeconomic factors. Diets rich in whole plant foods and low in animal products may protect blood vessels through their high antioxidant capacity and low inflammatory load. PURPOSE: The purpose of this study was to test the hypothesis that AA adhering to a 100% plant-based (vegan) diet (PBD) would have a more favorable dietary intake of several key nutrients and more optimal blood cholesterol, which would contribute to better blood pressure and peripheral reactive vasodilation relative to AA following a typical American diet (TAD). METHODS: Seventeen AA participated in the study. Of them, 8 (5 female; age: 25±2 years; BMI: 23.4±1.4 kg/m2) were following a PBD for 2.5±0.3 years and 9 (5 female; age: 21±1 years; BMI: 25.3±2.1 kg/m2) were following a TAD. A fasting venous blood draw was performed to assess blood lipids. Participants completed a comprehensive diet questionnaire (DHQIII, NIH). Peripheral and central blood pressures were measured via the SphygmoCor system (AtCor Medical). Brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH) were assessed via well-established procedures. Briefly, 2 min baseline measurements of brachial artery diameter and blood velocity were taken via Doppler ultrasound before a forearm cuff was inflated to 220 mmHg for 5 min. Post-occlusion data were recorded for 3 min. Measurement of baseline to peak post-occlusion brachial artery diameter and blood velocity were performed by pairing a video capture system (Elgato) with edge-detection and blood velocity-tracking software (Quipu). RESULTS: PBD AA consumed more dark green vegetables and whole grains and less cholesterol than TAD AA (p\u3c.05 for all). Consumption of sodium, potassium, and vitamins C & E was not different between groups (p\u3e.05 for all). Total (TC) and low-density lipoprotein (LDL-C) blood cholesterol concentrations were lower in PBD AA relative to TAD AA (TC: 136±9 vs. 174±12 mg/dl; LDL-C: 77±6 vs. 106±11 mg/dl; respectively; p\u3c.05 for both). Resting brachial (b) and central (c) mean arterial blood pressures (MAP) were lower in PBD AA relative to TAD AA (bMAP: 85±2 vs. 91±2 mmHg; cMAP: 80±2 vs. 87±2 mmHg; respectively; p\u3c.05 for both). There were no differences between groups in FMD nor RH (p\u3e.05 for all). FMD and FMD/shear rate were 7.7±0.8% and 0.33±0.05 au in PBD AA and 6.2±0.9% and 0.27±0.03 au in TAD AA, respectively. For RH, the percentage change in blood velocity and flow were 1441±479% and 1425±466% in PBD AA and 707±495% and 671±76% in TAD AA, respectively. CONCLUSION: These preliminary data suggest that a diet rich in whole plant foods but devoid of animal products may be associated with healthier blood cholesterol and peripheral and central blood pressures in AA but that these differences may not yet be translating to differences in peripheral reactive vasodilation