The impact of weather changes on air quality and health in the United States in 1994–2012

Air quality is heavily influenced by weather conditions. In this study, we assessed the impact of long-term weather changes on air quality and health in the US during 1994–2012. We quantified past weather-related increases, or ‘weather penalty’, in ozone (O3) and fine particulate matter (PM2.5), and thereafter estimated the associated excess deaths. Using statistical regression methods, we derived the weather penalty as the additional increases in air pollution relative to trends assuming constant weather conditions (i.e., weather-adjusted trends). During our study period, temperature increased and wind speed decreased in most US regions. Nationally, weather-related 8 h max O3 increases were 0.18 ppb per year (95% CI: 0.06, 0.31) in the warm season (May–October) and 0.07 ppb per year (95% CI: 0.02, 0.13) in the cold season (November–April). The weather penalties on O3 were relatively larger than PM2.5 weather penalties, which were 0.056 µg m−3 per year (95% CI: 0.016, 0.096) in warm months and 0.027 µg m−3 per year (95% CI: 0.010, 0.043) in cold months. Weather penalties on O3 and PM2.5 were associated with 290 (95% CI: 80, 510) and 770 (95% CI: 190, 1350) excess annual deaths, respectively. Over a 19-year period, this amounts to 20 300 excess deaths (5600 from O3, 14 700 from PM2.5) attributable to the weather penalty on air qualit

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag[superscript −/−] mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag[superscript −/−] mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly(ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag[superscript −/−] liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.National Institutes of Health (U.S.) (Grant R01-CA055042)National Institutes of Health (U.S.) (Grant R01-CA149261)National Institutes of Health (U.S.) (Grant P30-ES02109)Ellison Medical Foundatio

Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study

Introduction: Level I evidence supports the use of cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer prior to radical cystectomy (RC). On average, 30–40% of patients achieve a complete pathologic response (i.e., stage pT0) after receiving NAC. Some centers risk-stratify patients, suggesting that there may be a higher-risk population that would derive the most benefit from NAC. Recently, a risk-stratification model developed at M.D. Anderson Cancer Center (MDACC) specified criteria for clinical staging and patient selection for NAC. We applied this model to our own RC patient cohort and evaluated our own experience with clinical risk stratification and the effect of NAC on post treatment risk categories. Methods: We retrospectively reviewed the charts of consecutive patients who underwent RC at two institutions between 2004 and 2014 and noted whether or not they received NAC. We determined the clinical stage by reviewing the exam under anesthesia, transurethral resection biopsy (TURBT) pathology, and preoperative imaging. Patients with cT2-T4a node-negative disease were included. Those with sarcomatoid features or adenocarcinoma were excluded. Patients were classified as high risk if they had tumor-associated hydronephrosis, clinical stage≥T3b-T4a disease, variant histology (i.e., micropapillary or small cell), or lymphovascular invasion (LVI), as specified by the MDACC model. Variables were examined for associations with cancer-specific survival (CSS), overall survival (OS), and risk-category reclassification. Results: We identified 166 patients with a median follow-up time of 22.2 months. In all, 117 patients (70.5%) did not receive NAC, 68 (58.1%) of whom we classified as high risk. Among patients not receiving NAC, CSS and OS were significantly decreased in high-risk patients (log-rank test p = 0.01 for both comparisons). The estimated age-adjusted hazard ratios of high-risk classification for cancer-specific and overall death were 3.2 (95% CI: 1.2 to 8.6) and 2.2 (95% CI: 1.1 to 4.4), respectively. On post-RC final pathology, 23 (46.9%) low-risk patients were up-classified to high risk and 17 (25.0%) high-risk patients were down-classified. Complete pathologic responses (pT0) were achieved in 7 (6.0%) patients and partial responses (pT1, pTa, pTis) were achieved in 28 (23.9%) patients. Of the 49 patients who did receive NAC, 43 (87.8%) received cisplatin-based and six (12.2%) received carboplatin-based regimens. Applying the MDACC model, we categorized 41 (83.7%) patients as high risk prior to NAC treatment. On final pathology, 3 (37.5%) low-risk patients were up-classified and 17 (41.5%) high-risk patients were down-classified. Complete pathologic responses (pT0) were seen in 13 (26.5%) patients and partial responses were seen in 10 (20.4%) patients. Although the utilization of NAC was not statistically significantly associated with CSS or OS (log-rank test p > 0.05 for both comparisons), it was associated with a 1.2 times increased odds (95% CI: 0.4 to 2.1) of post-RC reclassification from high to low risk on age-adjusted logistic regression. Conclusions: We found similar results using the clinical risk-stratification model in our cohort and showed that the high-risk category was associated with lower CSS and OS. NAC was associated with a higher probability of risk reclassification from high to low risk

Approximate LD₅₀ of <i>Aag</i>^−/− and <i>Aag</i> transgenic mice to various genotoxic agents.

<p>MMS, Methyl methanesulfonate; MNU, N-methyl-N-nitrosourea; AOM, Azoxymethane; MMC, Mitomycin C; CAA, Chloroacetaldehyde.</p>*<p>Indicates that the <i>Aag</i> transgene is expressed in an <i>Aag^−/−</i> background.</p

MMS induces severe cerebellar lesions <i>AagTg</i> mice.

<p>(A) H&E stained image of cerebellar granule cells from WT, <i>Aag</i>^−/− and <i>AagTg</i> mice either in untreated conditions or 24 h following MMS treatment (150 mg/kg). Representative images are shown of n>6 experiments. Yellow arrows indicate pyknotic nuclei. Scale bar is 100 µm on low magnification images (black bar) and 15 µm on high-magnification images (white bar). Insets contain magnified images of area in dashed boxes. (B) Quantitation of cerebellar phenotype was performed on images from WT (n = 4), <i>Aag</i>^−/− (n = 3) and <i>AagTg</i> mice (n = 4). Representative images with identified objects (edema) colorized for visualization. Greater than 3 images/cerebella were quantitated per mouse, and the average sum of object area per image is presented. Data represent mean ± SEM. All the mice in this figure are on a pure C57BL/6 background.</p

MMS induces an Aag-dependent decrease in motor function.

<p>(A) Representations of gait are shown for WT (n = 3), <i>Aag</i>^−/− (n = 3) and <i>AagTg</i> (n = 3) mice three hours following MMS treatment (90 mg/kg). (B) Rotarod performance is shown for WT (n = 18), <i>Aag</i>^−/− (n = 17) and <i>AagTg</i> (n = 25) mice under untreated conditions and following MMS treatment (60 mg/kg). Data represent mean ± SEM. (C) Performance for the rotarod challenge is shown for WT (n = 17) and <i>Aag</i>^−/− (n = 22), 3 and 4 h following MMS treatment (140 mg/kg). Data represent mean ± SEM. All the mice in this figure are on a pure C57BL/6 background.</p

Human peripheral blood mononuclear cells (PBMCs) exhibit a wide range in AAG activity.

<p>An <i>in vitro</i> glycosylase assay determined AAG activity in PBMCs isolated from 80 healthy individuals.</p

Parp1 deficiency protects against Aag-dependent, MMS-induced motor dysfunction.

<p>(A) H&E stained cerebellar sections are shown from WT, <i>Aag</i>^−/−, <i>Parp1</i>^−/−, <i>AagTg</i>, and <i>AagTg</i>/<i>Parp1</i>^−/− under untreated conditions or 24 h following MMS treatment (150 mg/kg). Scale bar is 15 µm. Representative images for n = 5 mice/genotype are shown. (B) Quantitation of cerebellar phenotype is shown. Three or more images/cerebella were quantitated per mouse, and 3 mice per genotype analyzed for quantitation; the average sum of object area (edema) per image is presented. (C) Performance during the rotarod challenge in WT (n = 15), <i>AagTg</i> (n = 18), and <i>AagTg</i>/<i>Parp1</i>^−/− (n = 9) is illustrated under untreated conditions and following MMS treatment (60 mg/kg). (D) Performance for the rotarod challenge is shown for WT (n = 8), <i>Aag</i>^−/− (n = 11), and <i>Parp1</i>^−/− (n = 15) mice four hours following MMS treatment (140 mg/kg). All the mice used in this figure are mixed C57BL/6:129S background. All data represent mean ± SEM.</p