Landmark Series: The Cancer Genome Atlas and the Study of Breast Cancer Disparities.

Race-related variation in breast cancer incidence and mortality are well-documented in the United States. The effect of genetic ancestry on disparities in tumor genomics, risk factors, treatment, and outcomes of breast cancer is less understood. The Cancer Genome Atlas (TCGA) is a publicly available resource that has allowed for the recent emergence of genome analysis research seeking to characterize tumor DNA and protein expression by ancestry as well as the social construction of race and ethnicity. Results from TCGA based studies support previous clinical evidence that demonstrates that American women with African ancestry are more likely to be afflicted with breast cancers featuring aggressive biology and poorer outcomes compared with women with other backgrounds. Data from TCGA based studies suggest that Asian women have tumors with favorable immune microenvironments and may experience better disease-free survival compared with white Americans. TCGA contains limited data on Hispanic/Latinx patients due to small sample size. Overall, TCGA provides important opportunities to define the molecular, biologic, and germline genetic factors that contribute to breast cancer disparities.

Suicidal ideation and sobriety: Should acute alcohol intoxication be taken into account for psychiatric evaluation?

BACKGROUND: When evaluating an emergency department (ED) patient who presents with suicidal ideation, it is a common practice to wait until the patient's ethanol level is known or calculated to be less than 80 mg/dl to evaluate patient safety. We know of no study that establishes an association between the degree of alcohol intoxication based on a blood alcohol level (BAL) and reported suicidal ideation (SI) upon recovery. METHODS: We conducted a retrospective review of patients evaluated in a Midwestern ED for the calendar year 2017. Cases were selected if they had a psychiatric social work consult and a blood alcohol level drawn while in the ED. Patients were selected on the same 2 days each week throughout the year to meet the sample size requirements of the study, resulting in 1084 cases for review. Chi-square analysis was used to evaluate the relationship between suicidal ideation and alcohol intoxication as defined by a BAL ≥80 mg/dl. RESULTS: Among patients presenting with suicidal ideation and a concurrent BAL ≥80 mg/dl, 69% no longer reported suicidal ideation when their BAL was <80 mg/dl, compared to 38% for patients without a positive BAL on presentation (chi-square, p = 0.000012). CONCLUSION: Our data show that patients presenting to the ED with complaints related to suicidal behavior who have a BAL ≥80 mg/dl are more likely to no longer endorse having suicidal ideation once their BAL is < 80 mg/dl than patients with similar presenting complaints and no alcohol intoxication. This finding supports the common ED practice of re-assessing suicidal ideation among individuals who are initially intoxicated once their BAL has decreased below 80 mg/dl.

Glans inflation morphology and female cloaca copulatory interactions of the male American alligator phallus†.

The phallic glans of the American alligator (Alligator mississippiensis) is the distal termination of the semen-conducting sulcus spermaticus and during copulation has the closest, most intimate mechanical interactions with the female urodeum, the middle cloacal chamber that contains the opening to the vaginal passages and oviducts. However, the details of this interface leading to insemination and gamete uptake are unclear. Here, we: (1) histologically characterize the underlying tissue types and morphologically quantify the shape changes associated with glans inflation into the copulatory conformation, (2) digitally reconstruct from MRI the 3D shape of functional tissue compartments, and (3) diffusible iodine-based contrast-enhanced computed tomography image the copulatory fit between male phallus and female cloaca. We discuss these results in relation to tissue type material properties, the transfer on intromittent forces, establishing potential copulatory lock, inflated glans volume scaling with body mass/length, the mechanics of semen targeting and insemination, and potential female cryptic choice impacting multiple clutch paternity. In part, this study further clarifies the phallic morphological variation observed among crocodylians and begins to investigate the role(s) these divergent male forms play during copulation interacting with female cloacal forms to increase reproductive success.

Investigating trace metal precipitation in highly concentrated cell culture media with Pourbaix diagrams.

Commercial production of therapeutic proteins using mammalian cells requires complex process solutions, and consistency of these process solutions is critical to maintaining product titer and quality between batches. Inconsistencies between process solutions prepared at bench and commercial scale may be due to differences in mixing time, temperature, and pH which can lead to precipitation and subsequent removal via filtration of critical solution components such as trace metals. Pourbaix diagrams provide a useful tool to model the solubility of trace metals and were applied to troubleshoot the scale-up of nutrient feed preparation after inconsistencies in product titer were observed between bench- and manufacturing-scale batches. Pourbaix diagrams modeled the solubility of key metals in solution at various stages of the nutrient feed preparation and identified copper precipitation as the likely root cause of inconsistent medium stability at commercial scale. Copper precipitation increased proportionally with temperature in bench-scale preparations of nutrient feed and temperature was identified as the root cause of copper precipitation at the commercial scale. Additionally, cell culture copper titration studies performed in bench-scale bioreactors linked copper-deficient mammalian cell culture to inconsistent titers at the commercial scale. Pourbaix diagrams can predict when trace metals are at risk of precipitating and can be used to mitigate risk during the scale-up of complex medium preparations.

Spiking Suppression Precedes Cued Attentional Enhancement of Neural Responses in Primary Visual Cortex.

Attending to a visual stimulus increases its detectability, even if gaze is directed elsewhere. This covert attentional selection is known to enhance spiking across many brain areas, including the primary visual cortex (V1). Here we investigate the temporal dynamics of attention-related spiking changes in V1 of macaques performing a task that separates attentional selection from the onset of visual stimulation. We found that preceding attentional enhancement there was a sharp, transient decline in spiking following presentation of an attention-guiding cue. This disruption of V1 spiking was not observed in a task-naïve subject that passively observed the same stimulus sequence, suggesting that sensory activation is insufficient to cause suppression. Following this suppression, attended stimuli evoked more spiking than unattended stimuli, matching previous reports of attention-related activity in V1. Laminar analyses revealed a distinct pattern of activation in feedback-associated layers during both the cue-induced suppression and subsequent attentional enhancement. These findings suggest that top-down modulation of V1 spiking can be bidirectional and result in either suppression or enhancement of spiking responses.

Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR.

Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha-beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients' tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.

Efficacy of vaporized hydrogen peroxide for repeated sterilization of a single-use single-incision laparoscopic surgery port.

OBJECTIVE: To determine the ability of vaporized hydrogen peroxide (VHP) to sterilize a single-use single-incision laparoscopic surgery port and its associated components after repeated simulated uses. STUDY DESIGN: Prospective in vitro experimental study. SAMPLE POPULATION: Six single-use single-incision laparoscopic surgery ports with associated cannulas and insufflation tubing. METHODS: Ports, cannulas, and tubing were subjected to 10 cycles of simulated use, bacterial inoculation with Staphylococcus pseudintermedius and Escherichia coli, decontamination and sterilization, and testing via culture based on their treatment group designation. Bacteriological scores were compared among the negative control, positive control, and 4 treated ports and components. RESULTS: There was no difference in bacteriological scores between treated ports, cannulas, and insufflation tubing and the negative control port and components. Bacteriological scores of ports and components undergoing 6-10 cycles were not significantly different from scores of ports and components undergoing 5 or fewer sterilization cycles. No difference was found in detection of bacteria from treated ports by biopsy of the foam versus sampling via wash. CONCLUSION: This study suggests that a single-use single-incision laparoscopic port and its associated components can be effectively sterilized after multiple simulated uses by using VHP. CLINICAL SIGNIFICANCE: Reuse of a single-use single-incision laparoscopic port is a safe and effective method of cost reduction in veterinary patients.

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model.

Mechanisms of self-tolerance often result in CD8(+) tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8(+) T cells became tolerized in <24 h in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8(+) T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first molecular profile of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells.

No Seasonal Changes in Cognitive Functioning Among High School Football Athletes: Implementation of a Novel Electrophysiological Measure and Standard Clinical Measures.

OBJECTIVE: To evaluate neuroelectric and cognitive function relative to a season of football participation. Cognitive and neuroelectric function declines are hypothesized to be present in football athletes. DESIGN: Observational. SETTING: Athletic fields and research laboratory. PATIENTS (OR PARTICIPANTS): Seventy-seven high school athletes (15.9 + 0.9 years, 178.6 + 7.2 cm, 74.4 + 14.7 kg, and 0.8 + 0.8 self-reported concussions) participating in football (n = 46) and noncontact sports (n = 31). INTERVENTIONS (OR ASSESSMENT OF RISK FACTORS): All athletes completed preseason, midseason, and postseason assessments of cognitive and neuroelectric function, self-reported symptoms, and quality of life. All athletes participated in their respective sports without intervention, while head impact exposure in football athletes was tracked using the Head Impact Telemetry System. MAIN OUTCOME MEASURES: Cognitive performance was based on Cogstate computerized cognitive assessment tool processing speed, attention, learning, working memory speed, and working memory accuracy scores. ElMindA brain network activation amplitude, synchronization, timing and connectivity brain network activation scores demarcated neuroelectric performance. Quality of life was assessed on the Health Behavior Inventory and Satisfaction with Life Scale and symptoms on the SCAT3 inventory. RESULTS: Football and control sport athletes did not show declines in cognitive or neuroelectric function, quality-of-life measures, or symptom reports across a season of sport participation. CONCLUSIONS: These findings refute the notion that routine football participation places athletes at risk for acute cognitive declines. The lack of impairment may be associated with no association with head impacts and cognitive function, increased physical activity offsetting any declines, and/or test sensitivity. How these findings are associated with long-term cognitive function is unknown.

Hydrogen peroxide plasma sterilization of a waterproof, high-definition video camera case for intraoperative imaging in veterinary surgery.

OBJECTIVE: To evaluate the safety and usability of a wearable, waterproof high-definition camera/case for acquisition of surgical images by sterile personnel. STUDY DESIGN: An in vitro study to test the efficacy of biodecontamination of camera cases. Usability for intraoperative image acquisition was assessed in clinical procedures. METHODS: Two waterproof GoPro Hero4 Silver camera cases were inoculated by immersion in media containing Staphylococcus pseudointermedius or Escherichia coli at ≥5.50E+07 colony forming units/mL. Cases were biodecontaminated by manual washing and hydrogen peroxide plasma sterilization. Cultures were obtained by swab and by immersion in enrichment broth before and after each contamination/decontamination cycle (n = 4). The cameras were then applied by a surgeon in clinical procedures by using either a headband or handheld mode and were assessed for usability according to 5 user characteristics. RESULTS: Cultures of all poststerilization swabs were negative. One of 8 cultures was positive in enrichment broth, consistent with a low level of contamination in 1 sample. Usability of the camera was considered poor in headband mode, with limited battery life, inability to control camera functions, and lack of zoom function affecting image quality. Handheld operation of the camera by the primary surgeon improved usability, allowing close-up still and video intraoperative image acquisition. CONCLUSION: Vaporized hydrogen peroxide sterilization of this camera case was considered effective for biodecontamination. Handheld operation improved usability for intraoperative image acquisition. CLINICAL SIGNIFICANCE: Vaporized hydrogen peroxide sterilization and thorough manual washing of a waterproof camera may provide cost effective intraoperative image acquisition for documentation purposes.

Symbol addition by monkeys provides evidence for normalized quantity coding.

Weber's law can be explained either by a compressive scaling of sensory response with stimulus magnitude or by a proportional scaling of response variability. These two mechanisms can be distinguished by asking how quantities are added or subtracted. We trained Rhesus monkeys to associate 26 distinct symbols with 0-25 drops of reward, and then tested how they combine, or add, symbolically represented reward magnitude. We found that they could combine symbolically represented magnitudes, and they transferred this ability to a novel symbol set, indicating that they were performing a calculation, not just memorizing the value of each combination. The way they combined pairs of symbols indicated neither a linear nor a compressed scale, but rather a dynamically shifting, relative scaling.

Closed loop control of lactate concentration in mammalian cell culture by Raman spectroscopy leads to improved cell density, viability, and biopharmaceutical protein production.

Accumulation of lactate in mammalian cell culture often negatively impacts culture performance, impeding production of therapeutic proteins. Many efforts have been made to limit the accumulation of lactate in cell culture. Here, we describe a closed loop control scheme based on online spectroscopic measurements of glucose and lactate concentrations. A Raman spectroscopy probe was used to monitor a fed-batch mammalian cell culture and predict glucose and lactate concentrations via multivariate calibration using partial least squares regression (PLS). The PLS models had a root mean squared error of prediction (RMSEP) of 0.27 g/L for glucose and 0.20 g/L for lactate. All glucose feeding was controlled by the Raman PLS model predictions. Glucose was automatically fed when lactate levels were beneath a setpoint (either 4.0 or 2.5 g/L) and glucose was below its own setpoint (0.5 g/L). This control scheme was successful in maintaining lactate levels at an arbitrary setpoint throughout the culture, as compared to the eventual accumulate of lactate to 8.0 g/L in the historical process. Automated control of lactate by restricted glucose feeding led to improvements in culture duration, viability, productivity, and robustness. Culture duration was extended from 11 to 13 days, and harvest titer increased 85% over the historical process. Biotechnol. Bioeng. 2016;113: 2416-2424. © 2016 Wiley Periodicals, Inc.

Stability of an ERP-based measure of brain network activation (BNA) in athletes: A new electrophysiological assessment tool for concussion.

PRIMARY OBJECTIVE: To determine test-re-test reliabilities of novel Evoked Response Potential (ERP)-based Brain Network Activation (BNA) scores in healthy athletes. RESEARCH DESIGN: Observational, repeated-measures study. METHODS AND DESIGN: Forty-two healthy male and female high school and collegiate athletes completed auditory oddball and go/no-go ERP assessments at baseline, 1 week, 6 weeks and 1 year. The BNA algorithm was applied to the ERP data, considering electrode location, frequency band, peak latency and normalized amplitude to generate seven unique BNA scores for each testing session. MAIN OUTCOMES AND RESULTS: Mean BNA scores, intra-class correlation coefficient (ICC) values and reliable change (RC) values were calculated for each of the seven BNA networks. BNA scores ranged from 46.3 ± 34.9 to 69.9 ± 22.8, ICC values ranged from 0.46-0.65 and 95% RC values ranged from 38.3-68.1 across the seven networks. CONCLUSIONS: The wide range of BNA scores observed in this population of healthy athletes suggests that a single BNA score or set of BNA scores from a single after-injury test session may be difficult to interpret in isolation without knowledge of the athlete's own baseline BNA score(s) and/or the results of serial tests performed at additional time points. The stability of each BNA network should be considered when interpreting test-re-test BNA score changes.

Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts.

AIMS: The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial-epicardial (Endo-Epi) mapping coupled with high-resolution 3D structural imaging. METHODS AND RESULTS: Coronary-perfused human right atria from explanted diseased hearts (n = 8, 43-72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo-Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7-6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30-100 µM) perfusion. Dual-sided sub-Endo-sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or 'breakthrough' patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. CONCLUSIONS: Integrated 3D structural-functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles.

Advanced process monitoring and feedback control to enhance cell culture process production and robustness.

It is a common practice in biotherapeutic manufacturing to define a fixed-volume feed strategy for nutrient feeds, based on historical cell demand. However, once the feed volumes are defined, they are inflexible to batch-to-batch variations in cell growth and physiology and can lead to inconsistent productivity and product quality. In an effort to control critical quality attributes and to apply process analytical technology (PAT), a fully automated cell culture feedback control system has been explored in three different applications. The first study illustrates that frequent monitoring and automatically controlling the complex feed based on a surrogate (glutamate) level improved protein production. More importantly, the resulting feed strategy was translated into a manufacturing-friendly manual feed strategy without impact on product quality. The second study demonstrates the improved process robustness of an automated feed strategy based on online bio-capacitance measurements for cell growth. In the third study, glucose and lactate concentrations were measured online and were used to automatically control the glucose feed, which in turn changed lactate metabolism. These studies suggest that the auto-feedback control system has the potential to significantly increase productivity and improve robustness in manufacturing, with the goal of ensuring process performance and product quality consistency.

Improving antigenic peptide vaccines for cancer immunotherapy using a dominant tumor-specific T cell receptor.

Vaccines that incorporate peptide mimics of tumor antigens, or mimotope vaccines, are commonly used in cancer immunotherapy and function by eliciting increased numbers of T cells that cross-react with the native tumor antigen. Unfortunately, they often elicit T cells that do not cross-react with or that have low affinity for the tumor antigen. Using a high affinity tumor-specific T cell clone, we identified a panel of mimotope vaccines for the dominant peptide antigen from a mouse colon tumor that elicits a range of tumor protection following vaccination. The TCR from this high affinity T cell clone was rarely identified in ex vivo evaluation of tumor-specific T cells elicited by mimotope vaccination. Conversely, a low affinity clone found in the tumor and following immunization was frequently identified. Using peptide libraries, we determined if this frequently identified TCR improved the discovery of efficacious mimotopes. We demonstrated that the representative TCR identified more protective mimotopes than the high affinity TCR. These results suggest that targeting a dominant fraction of tumor-specific T cells generates potent immunity and that consideration of the available T cell repertoire is necessary for targeted T cell therapy. These results have important implications when optimizing mimotope vaccines for cancer immunotherapy.

A case of Burkitt Lymphoma discovered by digital rectal exam.

Burkitt Lymphoma (BL) is an aggressive B-cell lymphoma predominantly encountered in pediatrics. Sporadic type typically involves the abdomen and/or pelvis. We present an 8-year-old Caucasian male with vomiting, weight loss, fatigue, and abdominal pain. An abdominal X-ray was unremarkable without any acute findings. Pediatric gastroenterology was consulted and recommended esophagogastroduodenoscopy and colonoscopy. A digital rectal exam (DRE) was performed, and a firm lesion was palpated. The colonoscopy was normal. Subsequent magnetic resonance imaging and computed tomography scans revealed a lesion in the left lower quadrant with mass-like processes involving the porta hepatis and encasing the left distal ureter. Tissue biopsy confirmed BL. The patient completed chemotherapy and achieved remission. This case highlights DRE as a basic physical exam skill in the evaluation of patients with nonspecific gastrointestinal symptoms.

Arabidopsis Hexokinase-Like1 and Hexokinase1 form a critical node in mediating plant glucose and ethylene responses.

Arabidopsis (Arabidopsis thaliana) Hexokinase-Like1 (HKL1) lacks glucose (Glc) phosphorylation activity and has been shown to act as a negative regulator of plant growth. Interestingly, the protein has a largely conserved Glc-binding domain, and protein overexpression was shown previously to promote seedling tolerance to exogenous 6% (w/v) Glc. Since these phenotypes occur independently of cellular Glc signaling activities, we have tested whether HKL1 might promote cross talk between the normal antagonists Glc and ethylene. We show that repression by 1-aminocyclopropane-1-carboxylic acid (ACC) of the Glc-dependent developmental arrest of wild-type Arabidopsis seedlings requires the HKL1 protein. We also describe an unusual root hair phenotype associated with growth on high Glc medium that occurs prominently in HKL1 overexpression lines and in glucose insensitive 2-1 (gin2-1), a null mutant of Hexokinase1 (HXK1). Seedlings of these lines produce bulbous root hairs with an enlarged base after transfer from agar plates with normal medium to plates with 6% Glc. Seedling transfer to plates with 2% Glc plus ACC mimics the high-Glc effect in the HKL1 overexpression line but not in gin2-1. A similar ACC-stimulated, bulbous root hair phenotype also was observed in wild-type seedlings transferred to plates with 9% Glc. From transcript expression analyses, we found that HKL1 and HXK1 have differential roles in Glc-dependent repression of some ethylene biosynthesis genes. Since we show by coimmunoprecipitation assays that HKL1 and HXK1 can interact, these two proteins likely form a critical node in Glc signaling that mediates overlapping, but also distinct, cellular responses to Glc and ethylene treatments.

The accuracy of race & ethnicity data in US based healthcare databases: A systematic review.

BACKGROUND: The availability and accuracy of data on a patient's race/ethnicity varies across databases. Discrepancies in data quality can negatively impact attempts to study health disparities. METHODS: We conducted a systematic review to organize information on the accuracy of race/ethnicity data stratified by database type and by specific race/ethnicity categories. RESULTS: The review included 43 studies. Disease registries showed consistently high levels of data completeness and accuracy. EHRs frequently showed incomplete and/or inaccurate data on the race/ethnicity of patients. Databases had high levels of accurate data for White and Black patients but relatively high levels of misclassification and incomplete data for Hispanic/Latinx patients. Asians, Pacific Islanders, and AI/ANs are the most misclassified. Systems-based interventions to increase self-reported data showed improvement in data quality. CONCLUSION: Data on race/ethnicity that is collected with the purpose of research and quality improvement appears most reliable. Data accuracy can vary by race/ethnicity status and better collection standards are needed.

Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function.

Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.