Tropospheric ozone: respiratory effects and Australian air quality goals.

OBJECTIVE--To review the health effects of tropospheric ozone and discuss the implications for public health policy. DESIGN--Literature review and consultation with scientists in Australia and overseas. Papers in English or with English language abstracts were identified by Medline search from the international peer reviewed published reports. Those from the period 1980-93 were read systematically but selected earlier papers were also considered. Reports on ozone exposures were obtained from environmental agencies in the region. RESULTS--Exposure to ozone at concentrations below the current Australian air quality goal (0.12 ppm averaged over one hour) may cause impaired respiratory function. Inflammatory changes in the small airways and respiratory symptoms result from moderate to heavy exercise in the presence of ozone at levels of 0.08-0.12 ppm. The changes in respiratory function due to ozone are short lived, vary with the duration of exposure, may be modified by levels of other pollutants (such as sulphur dioxide and particulates), and differ appreciably between individuals. Bronchial lavage studies indicate that inflammation and other pathological changes may occur in the airways before reductions in air flow are detectable, and persist after respiratory function has returned to normal. It is not known whether exposures to ozone at low levels (0.08-0.12 ppm) cause lasting damage to the lung or, if such damage does occur, whether it is functionally significant. At present, it is not possible to identify confidently population subgroups with heightened susceptibility to ozone. People with asthma may be more susceptible to the effects of ozone than the general population but the evidence is not consistent. Recent reports suggest that ozone increases airway reactivity on subsequent challenge with allergens and other irritants. Animal studies are consistent with the findings in human populations. CONCLUSION--A new one hour air quality ozone goal of 0.08 ppm for Australia, and the introduction of a four hour goal of 0.06 ppm are recommended on health grounds

Inhibition of Haspin Kinase Promotes Cell-Intrinsic and Extrinsic Antitumor Activity.

Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent activity against both RMi-sensitive (RMS) and -resistant (RMR) melanoma cell lines. Haspin kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei, recruitment of cGAS, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I IFN response in tumor cells, increased IFNγ-producing CD8 <sup>+</sup> T cells, and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared with healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo-expanded human tumor-infiltrating lymphocytes (TIL), proliferating TILs, and in vitro differentiated neurons, suggesting a potential therapeutic index for anticancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment, and target a vulnerability in different cancer lineages. SIGNIFICANCE: HASPIN inhibition by CX-6258 is a novel and potent strategy for RAF/MEK inhibitor-resistant melanoma and potentially other tumor types. HASPIN inhibition has direct antitumor activity and induces a favorable immune microenvironment

Time series analysis of air pollution and mortality: effects by cause, age and socioeconomic status

OBJECTIVE—To investigate the association between outdoor air pollution and mortality in São Paulo, Brazil.
DESIGN—Time series study
METHODS—All causes, respiratory and cardiovascular mortality were analysed and the role of age and socioeconomic status in modifying associations between mortality and air pollution were investigated. Models used Poisson regression and included terms for temporal patterns, meteorology, and autocorrelation.
MAIN RESULTS—All causes all ages mortality showed much smaller associations with air pollution than mortality for specific causes and age groups. In the elderly, a 3-4% increase in daily deaths for all causes and for cardiovascular diseases was associated with an increase in fine particulate matter and in sulphur dioxide from the 10th to the 90th percentile. For respiratory deaths the increase in mortality was higher (6%). Cardiovascular deaths were additionally associated with levels of carbon monoxide (4% increase in daily deaths). The associations between air pollutants and mortality in children under 5 years of age were not statistically significant. There was a significant trend of increasing risk of death according to age with effects most evident for subjects over 65 years old. The effect of air pollution was also larger in areas of higher socioeconomic level.
CONCLUSIONS—These results show further evidence of an association between air pollution and mortality but of smaller magnitude than found in other similar studies. In addition, it seems that older age groups are at a higher risk of mortality associated with air pollution. Such complexity should be taken into account in health risk assessment based on time series studies.


Keywords: air pollution; mortality; socioeconomic statu