Static wind imaging Michelson interferometer for the measurement of stratospheric wind fields.

The stratospheric wind field provides significant information on the dynamics, constituent, and energy transport in the Earth's atmosphere. The measurement of the atmospheric wind field on a global basis at these heights is still lacking because few wind imaging interferometers have been developed that can measure wind in this region. In this paper, we describe an advanced compact static wind imaging Michelson interferometer (SWIMI) developed to measure the stratospheric wind field using near-infrared airglow emissions. The instrument contains a field widened and thermal compensated interferometer with a segmented reflective mirror in one arm, which replace the moving mirror in a conventional Michelson interferometer, to provide interference phase steps. The field widened, achromatic, temperature compensated scheme has been designed and manufactured. The characterization, calibration, inversion software, and test of the instrument have been completed. The capacity of two-dimensional wind, temperature, and ozone measurement of the instrument has been verified in the lab experiment and model simulation. What we believe to be the novel principle, modeling, design, and experiment demonstrated in this paper will offer a significant reference to the static, simultaneous and real-time detection and inversion of the global wind field, temperature, and ozone.

Wind imaging using simultaneous fringe sampling with field-widened Michelson interferometers.

The first, to our knowledge, successful laboratory implementation of an approach to image winds using simultaneous (as opposed to sequential) fringe imaging of suitable isolated spectral emission lines is described. Achieving this in practice has been a long-standing goal for wind imaging using airglow. It avoids the aliasing effects of source irradiance variations that are possible with sequential fringe sampling techniques. Simultaneous fringe imaging is accomplished using a field-widened Michelson interferometer by depositing phase steps on four quadrants of one of the mirrors and designing an optical system so that four images of the scene of interest, each at a different phase, are simultaneously produced. In this paper, the instrument characteristics, its characterization, and the analysis algorithms necessary for use of the technique for this type of interferometer are described for the first time, to the best of our knowledge. The large throughput associated with field-widened Michelson interferometers is sufficient for the spatial resolutions and temporal cadences necessary for ground based imaging of gravity waves in wind and irradiance to be achieved. The practical demonstration of this technique also validates its use for proposed monolithic satellite instruments for wind measurements using airglow on the Earth and Mars.

Lethal and sublethal effects of five common herbicides on the wolf spider, Pardosa milvina (Araneae: Lycosidae).

We tested lethal and sublethal effects of five commonly applied herbicides on the agrobiont wolf spider Pardosa milvina. Pardosa were collected from two agricultural fields; one kept under continuous crop rotation and sprayed for over twenty years, the other had no pesticide application for the last twelve years. Male and female Pardosa from each site were exposed to one of seven herbicide treatments (atrazine, glyphosate, mesotrione, S-metolachlor, rimsulfuron, a combination of all five herbicides, or a distilled water control; N = 1201) and maintained for 52 days on the treated soil substrate. We recorded mortality, prey capture behavior, weight change, courtship behavior, and egg sac production across treatments. Mesotrione and the five-herbicide combination showed significantly higher mortality than control substrates while atrazine, glyphosate and S-metolachlor showed significantly higher survival than the control. Both male spiders and spiders collected from the conventional field had reduced survival under some herbicide treatments. Prey capture behavior varied significantly by herbicide treatment, sex, and site. We observed significant weight change differences in males and differences in egg sac production in females, with, compared to the control, significant male weight loss in the rimsulfuron treatment collected from the no herbicide field, and a decrease in egg sac production in rimsulfuron and S-metolachlor treatments among females collected from the no herbicide field. Our results show some herbicides may have modest but significant fitness benefits (atrazine, glyphosate, and S-metolachlor) while others strongly increase the mortality of a generalist predator (mesotrione and the combination herbicide treatment).

Two-Year Clinical and Radiographic Evaluation of Scheker Prosthesis (Aptis) Distal Radioulnar Joint Arthroplasty.

PURPOSE: To evaluate the clinical and radiographic outcomes of patients who underwent semiconstrained distal radioulnar joint arthroplasty. METHODS: A retrospective analysis was performed on a series of patients who underwent distal radioulnar joint arthroplasty with more than a 23-month follow up. The quantitative outcome variables included the visual analog scale for pain; Disability of the Arm, Shoulder, and Hand (DASH) score; Patient-Rated Wrist Evaluation (PRWE); and Mayo wrist score. The range of motion, grip strength, torque, and lifting capacity were measured at final follow up and compared with that of the nonsurgical extremity. Complications related to the prosthesis were assessed. RESULTS: Twenty-one patients (mean age 57 years) were assessed at an average 41-month follow up (23-73 months). Fifteen underwent prior hand, wrist, or elbow procedures. Four patients required 5 reoperations. The postoperative median visual analog scale pain score was 0.6 at rest and 2.1 with activity. The median postoperative DASH score was 26.7, PRWE 41, and Mayo wrist score was 65. Upon comparing the supination torque of the operative and intact sides, the operative side was found to average 87% of the intact side on a work simulator and 77% on the simulator's D-ring. Eight of 20 patients had lysis around the collar of the ulnar component (40%), as detected using radiography. Three of 21 (14%) radial plates were malpositioned, with 2 resulting in a fracture. The overall complication rate was 29%. CONCLUSIONS: Distal radioulnar joint arthroplasty using the Scheker prosthesis demonstrated good patient pain scores and the restoration of supination strength. The collar lysis resulted in weaker supination and grip strength. Still, the patients experienced mild levels of pain and moderate disability. A moderate complication rate persisted, as reported by other authors. Accurate radial component placement is important. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Rebound and overshoot of donor-specific antibodies to human leukocyte antigens (HLA) during desensitization with plasma exchanges in hematopoietic progenitor cell transplantation: A case report.

BACKGROUND: Donor-specific antibodies (DSA) to HLA have been associated with graft loss in hematopoietic progenitor cell (HPC) transplantation. Limited data associate therapeutic plasma exchange (TPE) with desensitization and successful engraftment. We report an attempt of desensitization and observed overshooting of DSA during transplantation. CASE REPORT AND RESULTS: A 27-year-old female with cutaneous T cell lymphoma was scheduled for HPC transplantation from her HLA-haploidentical half-sister, who carried the HLA-DRB1*13:03:01 allele. The patient had the corresponding DSA. Lacking an alternative donor option at the time, we attempted a desensitization approach by immunosuppression with tacrolimus and mycophenolate mofetil (MMF). Unexpectedly, DSA increased from a mean fluorescence intensity (MFI) of 1835 on day -63 to 9008 on day -7. The MFI increased further during 3 TPE procedures and intravenous immunoglobulin (IVIG) until day -1. After transplantation, the DSA remained elevated despite 2 more TPE/IVIG procedures and graft-versus-host disease prophylaxis with high-dose cyclophosphamide, sirolimus, and MMF. Flow cytometric crossmatch, initially negative, turned positive after transplantation. Primary graft failure occurred and was attributed to antibody-mediated rejection. A second transplantation from a 7/8 HLA-matched unrelated donor, not carrying DRB1*13:03 allele, resulted in successful engraftment. CONCLUSION: Unexpected and rapid increases of a DSA can occur despite the use of current desensitization approaches. This is problematic when conditioning has already started, as such increases are unlikely to be overcome by TPE or other interventions for desensitization. Overshoot of DSA in HPC transplantation has rarely been reported. Its cause remains unclear and can include underlying disease, immunotherapy, chemotherapy, or TPE.

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer.

BACKGROUND: Although treatment delays have been associated with survival impairment for invasive breast cancer, this has not been thoroughly investigated for ductal carcinoma in situ (DCIS). With trials underway to assess whether DCIS can remain unresected, this study was performed to determine whether longer times to surgery are associated with survival impairment or increased invasion. METHODS: A population-based study of prospectively collected national data derived from women with a clinical diagnosis of DCIS between 2004 and 2014 was conducted using the National Cancer Database. Overall survival (OS) and presence of invasion were assessed as functions of time by evaluating five intervals (≤ 30, 31-60, 61-90, 91-120, 121-365 days) between diagnosis and surgery. Subset analyses assessed those having pathologic DCIS versus invasive cancer on final pathology. RESULTS: Among 140,615 clinical DCIS patients, 123,947 had pathologic diagnosis of DCIS and 16,668 had invasive ductal carcinoma. For all patients, 5-year OS was 95.8% and unadjusted median delay from diagnosis to surgery was 38 days. With each delay interval increase, added relative risk of death was 7.4% (HR 1.07; 95% CI 1.05-1.10; P < 0.001). On final pathology, 5-year OS for noninvasive patients was 96.0% (95% CI 95.9-96.1%) versus 94.9% (95% CI 94.6-95.3%) for invasive patients. Increasing delay to surgery was an independent predictor of invasion (OR 1.13; 95% CI 1.11-1.15; P < 0.001). CONCLUSIONS: Despite excellent OS for invasive and noninvasive cohorts, invasion was seen more frequently as delay increased. This suggests that DCIS trials evaluating nonoperative management, which represents infinite delay, require long term follow up to ensure outcomes are not compromised.

Does the Surgical Apgar Score predict serious complications after elective major cancer surgery?

BACKGROUND: Major cancer surgery is associated with significant risks of perioperative morbidity and mortality, resulting in delayed adjuvant therapy, higher recurrence rates, and worse overall survival. Previous retrospective studies have used the Surgical Apgar Score (SAS) for perioperative risk assessment. This study prospectively evaluated the predictive value of SAS to predict serious complication (SC) after elective major cancer surgery. METHODS: Demographic, comorbidity, procedure, and intraoperative data were collected prospectively for 405 patients undergoing elective major cancer surgery between 2014-17. The SAS was calculated immediately postoperative and outcome data were collected prospectively. Rates of SC according to SAS risk category were compared using Cochran-Armitage trend test. Receiver operating characteristic curves and area under the receiver operating characteristic curves were generated and 95% confidence intervals were calculated. RESULTS: Eighty percent, 17.3%, and 2.7% of patients were low (SAS 7-10), intermediate (SAS 5-6), and high risk (SAS 0-4), respectively, for SC based on their SAS. Forty-six (11.4%) had an SC within 30 days; 3.7% returned to the operating room, 3.7% experienced a urinary tract infection, 3.2% experienced a respiratory complication, 2.7% experienced a wound complication, and 1.2% experienced a cardiac complication. Overall, 9.3%, 18.6%, and 27.3% of patients with SAS 7-10, 5-6, and 0-4 experienced an SC, respectively (P = 0.005). The overall discriminatory ability of the SAS was modest (area under the receiver operating characteristic curves 0.661; 95% confidence intervals, 0.582-0.740). CONCLUSIONS: Although there was an overall association between SAS and higher risk of subsequent postoperative SC in our cohort, the ability of the SAS to accurately predict risk of postoperative SC at the patient level was limited.

Predictive Value of Leukocyte- and Platelet-Derived Ratios in Rectal Adenocarcinoma.

BACKGROUND: Advances in treatment of rectal cancer have improved survival, but there is variability in response to therapy. Recent data suggest the utility of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in predicting survival. Our aim was to examine these ratios in rectal cancer patients and determine whether any association exists with overall survival (OS). METHODS: Using prospectively maintained institutional data, a query was completed for clinical stage II-III rectal adenocarcinoma patients treated from 2002 to 2016. We included patients who had a complete blood count collected before neoadjuvant chemoradiation (pre-CRT) and again before surgery (post-CRT). The LMR, NLR, and PLR were calculated for the pre-CRT and post-CRT time points. Potential cutpoints associated with OS differences were determined using maximally selected rank statistics. Survival curves were compared using log-rank tests and were adjusted for age and stage using Cox regression. RESULTS: A total of 146 patients were included. Cutpoints were significantly associated with OS for pre-CRT ratios but not for post-CRT ratios. Within the pretreatment group, a "low" (<2.86) LMR was associated with decreased OS (log-rank P = 0.004). In the same group, a "high" (>4.47) NLR and "high" PLR (>203.6) were associated with decreased OS (log-rank P < 0.001). With covariate adjustment for age, and separately for final pathologic stage, the associations between OS and LMR, NLR, and PLR each retained statistical significance. CONCLUSIONS: If obtained before the start of neoadjuvant chemoradiation, LMR, NLR, and PLR values are accurate predictors of 5-y OS in patients with locally advanced rectal adenocarcinoma.

Pathologic response following treatment for locally advanced rectal cancer: Does location matter?

BACKGROUND: Despite advances in the treatment of rectal adenocarcinoma, the management of locally advanced disease remains a challenge. The standard of care for patients with stages II and III rectal cancer includes neoadjuvant chemoradiation followed by total mesorectal excision and postoperative chemotherapy. Much effort has been dedicated to the identification of predictive factors associated with pathologic complete response (pCR). The aim of our study was to examine our institutional experience and determine whether any association exists between anatomic tumor location and the rate of pCR. We hypothesized that lesions more than 6 cm from the anal verge are more likely to achieve a pCR. METHODS: Using data from our prospectively maintained tumor registry, a query was completed to identify all patients with locally advanced rectal adenocarcinoma who underwent treatment at Fox Chase Cancer Center from 2002 to 2015. Demographics, pretreatment, posttreatment, and final pathologic TNM staging data were collected as well as treatment intervals in days, recurrence status, overall survival, and disease-free survival. Patients with incomplete endoscopic data, staging information, survival, or recurrence status were excluded. The primary outcome measured was the degree of pathologic response. Logistic regression was used to adjust for covariates. RESULTS: Of the 135 patients eligible in the study cohort, 39% were female and 61% were male. Regarding initial clinical stage, 43% were stage II and 57% were stage III. A total of 29% had a pCR, 43% had partial pathologic response, and 28% had no response to neoadjuvant treatment. Tumor location ranged from 0 to 13 cm from the anal verge. Longitudinal tumor length was recorded in 111 patients, facilitating the calculation of mean tumor distance from the anal verge. This ranged from 0 to 15.5 cm. Univariate and multivariable analyses were completed using pCR as a primary outcome. No statistically significant difference was noted based on tumor location, regardless of measurement approach. CONCLUSIONS: Anatomic location of cancer of the rectum does not affect pCR after neoadjuvant therapy and subsequent surgical resection.

Marginal Skin Flap Advancement: A Technique to Optimize the Skin Graft Interface Following Tumor Resections.

Split-thickness skin graft (STSG) for soft tissue defects is often required following tumor resections. There is often a step-off with subcutaneous adipose tissue along the defect margins. This review of 20 years of experience was performed to determine the success of marginal skin flap advancement, a simple surgical technique addressing this issue. Seventy-one cases were identified that underwent sarcoma resection and this technique. Marginal skin flap advancement decreased the defect size from 217 s 162 cm2 to 128 s 101 cm2 (p < .001). STSG was successfully applied in 69 cases (97%) with a mean 96% take of the skin graft. Although 29 cases (41%) had wound healing complications of any nature, only 11 (15%) required a secondary operation. Marginal skin flap advancement, in conjunction with vacuum-assisted closure therapy, decreases the defect surface area requiring STSG by 41% and provides an excellent reconstructive option for soft tissue defects following sarcoma resections. (Journal of Surgical Orthopaedic Advances 27(2):102-108, 2018).

Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice.

Environmental exposures occurring early in life may have an important influence on cancer risk later in life. Here, we investigated carryover effects of dichloroacetic acid (DCA), a small molecule analog of pyruvate with metabolic programming properties, on age-related incidence of liver cancer. The study followed a stop-exposure/promotion design in which 4-week-old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0 or 3.5g/l) for 10 weeks followed by dH2O or PB (n = 20-30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared with controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (≥85% tumor incidence and number) to those seen after continuous lifetime exposure. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce persistent liver cytotoxicity or preneoplastic changes on histopathology or alter DNA sequence variant profiles within liver tumors compared with controls. Distinct changes in liver messenger RNA and micro RNA profiles associated with prior DCA treatment were not apparent at 98 weeks. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects related to cellular metabolism.

Visible Light Driven Nanosecond Bromide Oxidation by a Ru Complex with Subsequent Br-Br Bond Formation.

Visible light excitation of [Ru(deeb)(bpz)2](2+) (deeb = 4,4'-diethylester-2,2'-bipyridine; bpz = 2,2'-bipyrazine), in Br(-) acetone solutions, led to the formation of Br-Br bonds in the form of dibromide, Br2(•-). This light reactivity stores ∼1.65 eV of free energy for milliseconds. Combined (1)H NMR, UV-vis and photoluminescence measurements revealed two distinct mechanisms. The first involves diffusional quenching of the excited state by Br(-) with a rate constant of (8.1 ± 0.1) × 10(10) M(-1) s(-1). At high Br(-) concentrations, an inner-sphere pathway is dominant that involves the association of Br(-), most likely with the 3,3'-H atoms of a bpz ligand, before electron transfer from Br(-) to the excited state, ket = (2.5 ± 0.3) × 10(7) s(-1). In both mechanisms, the direct photoproduct Br(•) subsequently reacts with Br(-) to yield dibromide, Br(•) + Br(-) → Br2(•-). Under pseudo-first-order conditions, this occurs with a rate constant of (1.1 ± 0.4) × 10(10) M(-1) s(-1) that was, within experimental error, the same as that measured when Br(•) were generated with ultraviolet light. Application of Marcus theory to the sensitized reaction provided an estimate of the Br(•) formal reduction potential E(Br(•)/Br(-)) = 1.22 V vs SCE in acetone, which is about 460 mV less positive than the accepted value in H2O. The results demonstrate that Br(-) oxidation by molecular excited states can be rapid and useful for solar energy conversion.

Genotoxic effect of ethacrynic acid and impact of antioxidants.

It is known that ethacrynic acid (EA) decreases the intracellular levels of glutathione. Whether the anticipated oxidative stress affects the structural integrity of DNA is unknown. Therefore, DNA damage was assessed in EA-treated HCT116 cells, and the impact of several antioxidants was also determined. EA caused both concentration-dependent and time-dependent DNA damage that eventually resulted in cell death. Unexpectedly, the DNA damage caused by EA was intensified by either ascorbic acid or trolox. In contrast, EA-induced DNA damage was reduced by N-acetylcysteine and by the iron chelator, deferoxamine. In elucidating the DNA damage, it was determined that EA increased the production of reactive oxygen species, which was inhibited by N-acetylcysteine and deferoxamine but not by ascorbic acid and trolox. Also, EA decreased glutathione levels, which were inhibited by N-acetylcysteine. But, ascorbic acid, trolox, and deferoxamine neither inhibited nor enhanced the capacity of EA to decrease glutathione. Interestingly, the glutathione synthesis inhibitor, buthionine sulfoxime, lowered glutathione to a similar degree as EA, but no noticeable DNA damage was found. Nevertheless, buthionine sulfoxime potentiated the glutathione-lowering effect of EA and intensified the DNA damage caused by EA. Additionally, in examining redox-sensitive stress gene expression, it was found that EA increased HO-1, GADD153, and p21mRNA expression, in association with increased nuclear localization of Nrf-2 and p53 proteins. In contrast to ascorbic acid, trolox, and deferoxamine, N-acetylcysteine suppressed the EA-induced upregulation of GADD153, although not of HO-1. Overall, it is concluded that EA has genotoxic properties that can be amplified by certain antioxidants.

Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats.

Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.0ppm, 6h/day for two days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0ppm O3, 6h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h-post second exposure. O3 increased circulating metabolites of glycolysis, long-chain free fatty acids, branched-chain amino acids and cholesterol, while 1,5-anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, proteolysis and lipolysis. Liver gene expression increased for markers of glycolysis, TCA cycle and gluconeogenesis, and decreased for markers of steroid and fat biosynthesis. Genes involved in apoptosis and mitochondrial function were also impacted by O3. In conclusion, short-term O3 exposure induces global metabolic derangement involving glucose, lipid, and amino acid metabolism, typical of a stress-response. It remains to be examined if these alterations contribute to insulin resistance upon chronic exposure.

Effect of antioxidants on the genotoxicity of phenethyl isothiocyanate.

Isothiocyanates are plant-derived compounds that may be beneficial in the prevention of certain chronic diseases. Yet, by stimulating the production of reactive oxygen species (ROS), isothiocyanates can be genotoxic. Whether antioxidants influence isothiocyanate-induced genotoxicity is unclear, but this situation was clarified appreciably herein. In HCT116 cells, phenethyl isothiocyanate (PEITC) increased ROS production, which was inhibited by N-acetylcysteine (NAC) and deferoxamine (DFO) but not by ascorbic acid (ASC) and trolox (TRX) that were found to be more potent radical scavengers. Surprisingly, ASC and TRX each intensified the DNA damage that was caused by PEITC, but neither ASC nor TRX by themselves caused any DNA damage. In contrast, NAC and DFO each not only attenuated PEITC-induced DNA damage but also attenuated the antioxidant-intensified, PEITC-induced DNA damage. To determine if the DNA damage could be related to possible changes in the major antioxidant defence system, glutathione (GSH) was investigated. PEITC lowered GSH levels, which was prevented by NAC, whereas ASC, TRX and DFO neither inhibited nor enhanced the GSH-lowering effect of PEITC. The GSH synthesis inhibitor, buthionine sulphoxime, intensified PEITC-induced DNA damage, although by itself buthionine sulphoxime did not directly cause DNA damage. The principal findings suggest that ASC and TRX make PEITC more genotoxic, which might be exploited in killing cancer cells as one approach in killing cancer cells is to extensively damage their DNA so as to initiate apoptosis.

Signaling Pathways and MicroRNA Changes in Nano-TiO2 Treated Human Lung Epithelial (BEAS-2B) Cells.

The effect of titanium dioxide nanoparticles (nano-TiO2 Degussa p25) treatment of human lung epithelial cells (BEAS-2B) was examined by analyzing changes in messenger [mRNA] and microRNA [miRNA]. BEAS-2B cells were treated with 0, 3, 10, 30 or 100 µg/ml nano-TiO2 for 1 day (for mRNA analysis) or 3 days (for miRNA analysis). Differentially expressed mRNA and miRNA were analyzed using Affymetrix microarrays and Affymetrix miRNA microarrays, respectively. Although, the tested doses were not cytotoxic, there were alterations in both mRNA and miRNA expression. The expression of mRNA/miRNA changes were examined in MetaCore (GeneGo) and IPA (Ingenuity Pathway Analysis) to delineate associated canonical/signaling pathways. Canonical/signaling pathways altered by nano-TiO2 treatments included: cell cycle regulation, apoptosis, calcium signaling, translation, NRF2-mediated oxidative response, IGF1 signaling, RAS signaling, PI3K/AKT signaling, cytoskeleton remodeling, cell adhesion, BMP signaling, and inflammatory response. Many of the genes in these pathways are known to be regulated by the miRNAs whose expressions were altered by the nano-TiO2 treatment. The miRNA 17-92 cluster and let-7 miRNA family that are involved in lung cancer formation were altered by nano-TiO2 treatment. The miR-17-92 cluster, an oncogenic microRNA cluster, is induced while the tumor suppressor microRNA, let-7 family, is suppressed. The changes of let-7/KRAS signaling pathway was observed in all the doses treated. The observed changes in miRNA expression introduces an additional mechanistic dimension that supports the significance of the observed mRNA expression changes, and demonstrated that the nano-TiO2 in vitro treatment in human lung cells can cause diverse but coordinated pathway alterations associated with changes in in vivo response to tumorigenes.

Left ventricular gene expression profile of healthy and cardiovascular compromised rat models used in air pollution studies.

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impairment, will reveal underlying disease processes that facilitate understanding of the mechanisms of air pollution susceptibility differences. Left ventricular gene expression was examined using Affymetrix rat 230A-gene arrays in male, age-matched (12-14 weeks old) healthy Wistar Kyoto (WKY) and CV-compromised spontaneously hypertensive (SH), stroke-prone SH (SHSP), obese SH heart failure (SHHF) and obese insulin-resistant (JCR) rats. Principle component analysis separated strains in three clusters: (1) WKY, (2) JCR and )3) SH, SHSP and SHHF. Gene expression pattern in JCR differed from all other CVD strains. Both SHHF and JCR strains presented the most differentially expressed genes from WKY, but generally with opposing directional pattern suggesting that the CVD in these strains arise through different mechanisms. Hierarchical clustering of nuclear factor-kappaB target genes indicated varying degrees of, but similar directional changes, in SH, SHSP and SHHF relative to WKY rats, which may relate to the severity of their CVD. The JCR strain had less pronounced expressions of these genes suggesting milder cardiac disease. No unique expression pattern could be identified for genes implicated in stroke and heart failure in SHSP and SHHF rats, respectively. The data show that the CVD pathophysiological mechanisms differ in models with different genetic backgrounds, and therefore, the mechanisms by which air pollutants affect the cardiopulmonary system are likely to vary.

Pulmonary transcriptional response to ozone in healthy and cardiovascular compromised rat models.

The genetic cardiovascular disease (CVD) and associated metabolic impairments can influence the lung injury from inhaled pollutants. We hypothesized that comparative assessment of global pulmonary expression profile of healthy and CVD-prone rat models will provide mechanistic insights into susceptibility differences to ozone. The lung expression profiles of healthy Wistar Kyoto (WKY) and CVD-compromised spontaneously hypertensive (SH), stroke-prone SH (SHSP), obese SH heart failure (SHHF) and obese, atherosclerosis-prone JCR rats were analyzed using Affymetrix platform immediately after 4-h air or 1 ppm ozone exposure. At baseline, the JCR exhibited the largest difference in the number of genes among all strains when compared with WKY. Interestingly, the number of genes affected by ozone was inversely correlated with genes different at baseline relative to WKY. A cluster of NFkB target genes involved in cell-adhesion, antioxidant response, inflammation and apoptosis was induced in all strains, albeit at different levels (JCR < WKY < SHHF < SH < SHSP). The lung metabolic syndrome gene cluster indicated expressions in opposite directions for SHHF and JCR suggesting different mechanisms for common disease phenotype and perhaps obesity-independent contribution to exacerbated lung disease. The differences in expression of adrenergic receptors and ion-channel genes suggested distinct mechanisms by which ozone might induce protein leakage in CVD models, especially SHHF and JCR. Thus, the pulmonary response to ozone in CVD strains was likely linked to the defining gene expression profiles. Differential transcriptional patterns between healthy and CVD rat strains at baseline, and after ozone suggests that lung inflammation and injury might be influenced by multiple biological pathways affecting inflammation gene signatures.