NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route.

BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC. METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells. RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast. CONCLUSION: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

The Combined Effects of Short-Term Exposure to Multiple Meteorological Factors on Unintentional Drowning Mortality: Large Case-Crossover Study.

BACKGROUND: Drowning is a serious public health problem worldwide. Previous epidemiological studies on the association between meteorological factors and drowning mainly focused on individual weather factors, and the combined effect of mixed exposure to multiple meteorological factors on drowning is unclear. OBJECTIVE: We aimed to investigate the combined effects of multiple meteorological factors on unintentional drowning mortality in China and to identify the important meteorological factors contributing to drowning mortality. METHODS: Unintentional drowning death data (based on International Classification of Diseases, 10th Edition, codes W65-74) from January 1, 2013, to December 31, 2018, were collected from the Disease Surveillance Points System for Guangdong, Hunan, Zhejiang, Yunnan, and Jilin Provinces, China. Daily meteorological data, including daily mean temperature, relative humidity, sunlight duration, and rainfall in the same period were obtained from the Chinese Academy of Meteorological Science Data Center. We constructed a time-stratified case-crossover design and applied a generalized additive model to examine the effect of individual weather factors on drowning mortality, and then used quantile g-computation to estimate the joint effect of the mixed exposure to meteorological factors. RESULTS: A total of 46,179 drowning deaths were reported in the 5 provinces in China from 2013 to 2018. In an effect analysis of individual exposure, we observed a positive effect for sunlight duration, a negative effect for relative humidity, and U-shaped associations for temperature and rainfall with drowning mortality. In a joint effect analysis of the above 4 meteorological factors, a 2.99% (95% CI 0.26%-5.80%) increase in drowning mortality was observed per quartile rise in exposure mixture. For the total population, sunlight duration was the most important weather factor for drowning mortality, with a 93.1% positive contribution to the overall effects, while rainfall was mainly a negative factor for drowning deaths (90.5%) and temperature and relative humidity contributed 6.9% and -9.5% to the overall effects, respectively. CONCLUSIONS: This study found that mixed exposure to temperature, relative humidity, sunlight duration, and rainfall was positively associated with drowning mortality and that sunlight duration, rather than temperature, may be the most important meteorological factor for drowning mortality. These findings imply that it is necessary to incorporate sunshine hours and temperature into early warning systems for drowning prevention in the future.

Temperature-related mortality in China from specific injury.

Injury poses heavy burden on public health, accounting for nearly 8% of all deaths globally, but little evidence on the role of climate change on injury exists. We collect data during 2013-2019 in six provinces of China to examine the effects of temperature on injury mortality, and to project future mortality burden attributable to temperature change driven by climate change based on the assumption of constant injury mortality and population scenario. The results show that a 0.50% (95% confident interval (CI): 0.13%-0.88%) increase of injury mortality risk for each 1 °C rise in daily temperature, with higher risk for intentional injury (1.13%, 0.55%-1.71%) than that for unintentional injury (0.40%, 0.04%-0.77%). Compared to the 2010s, total injury deaths attributable to temperature change in China would increase 156,586 (37,654-272,316) in the 2090 s under representative concentration pathways 8.5 scenario with the highest for transport injury (64,764, 8,517-115,743). Populations living in Western China, people aged 15-69 years, and male may suffer more injury mortality burden from increased temperature caused by climate change. Our findings may be informative for public health policy development to effectively adapt to climate change.

Impact of ambient temperature on life loss per death from cardiovascular diseases: a multicenter study in central China.

BACKGROUND: In the context of global climate change, studies have focused on the ambient temperature and mortality of cardiovascular diseases (CVDs). However, little is known about the effect of ambient temperature on year of life lost (YLL), especially the life loss per death caused by ambient temperature. In this study, we aimed to assess the relationship between ambient temperature and life loss and estimate the impact of ambient temperature on life loss per death. METHODS: We collected daily time series of mortality and meteorological data from 70 locations in Hunan province, central China, in periods ranging from Jan. 1, 2013, to Dec. 31, 2017. Crude rates of YLL were calculated per 100,000 people per year (YLL/100,000 population) for each location. A distributed lag nonlinear model and multivariate meta-regression were used to estimate the associations between ambient temperature and YLL rates. Then, the average life loss per death attributable to ambient temperature was calculated. RESULTS: There were 711,484 CVD deaths recorded within the study period. The exposure-response curve between ambient temperature and YLL rates was inverted J or U-shaped. Relative to the minimum YLL rate temperature, the life loss risk of extreme cold temperature lasted for 10 to 12 days, whereas the risk of extreme hot temperature appeared immediately and lasted for 3 days. On average, the life loss per death attributable to non-optimum ambient temperatures was 1.89 (95% CI, 1.21-2.56) years. Life loss was mainly caused by cold temperature (1.13, 95% CI, 0.89­1.37), particularly moderate cold (1.00, 95% CI, 0.78­1.23). For demographic characteristics, the mean life loss per death was relatively higher for males (2.07, 95% CI, 1.44­2.68) and younger populations (3.72, 95% CI, 2.06­5.46) than for females (1.88, 95% CI, 1.21-2.57) and elderly people (1.69, 95% CI, 1.28-2.10), respectively. CONCLUSIONS: We found that both cold and hot temperatures significantly aggravated premature death from CVDs. Our results indicated that the whole range of effects of ambient temperature on CVDs should be given attention.

Temperature Change between Neighboring Days Contributes to Years of Life Lost per Death from Respiratory Disease: A Multicounty Analysis in Central China.

BACKGROUND: Many epidemiological studies have recently assessed respiratory mortality attributable to ambient temperatures. However, the associations between temperature change between neighboring days and years of life lost are insufficiently studied. Therefore, we assessed the attributable risk of temperature change between neighboring days on life loss due to respiratory disease. METHODS: We obtained daily mortality and weather data and calculated crude rates of years of life lost for 70 counties in Hunan Province, Central China, from 2013 to 2017. A time-series design with distributed lag nonlinear model and multivariate meta-regression was used to pool the relationships between temperature change between neighboring days and rates of years of life lost. Then, we calculated the temperature change between neighboring days related to average life loss per death from respiratory disease. RESULTS: The total respiratory disease death was 173,252 during the study period. The association between temperature change and years of life lost rates showed a w-shape. The life loss per death attributable to temperature change between neighboring days was 2.29 (95% CI: 0.46-4.11) years, out of which 1.16 (95% CI: 0.31-2.01) years were attributable to moderately high-temperature change between neighboring days, and 0.99 (95% CI: 0.19-1.79) years were attributable to moderately low-temperature change between neighboring days. The temperature change between neighboring days related to life loss per respiratory disease death for females (2.58 years, 95% CI: 0.22-4.93) and the younger group (2.97 years, 95% CI: -1.51-7.44) was higher than that for males (2.21 years, 95% CI: 0.26-4.16) and the elderly group (1.96 years, 95% CI: 0.85-3.08). An average of 1.79 (95% CI: 0.18-3.41) life loss per respiratory disease death was related to non-optimal ambient temperature. CONCLUSIONS: The results indicated that more attention should be given to temperature change, and more public health policies should be implemented to protect public health.

Future injury mortality burden attributable to compound hot extremes will significantly increase in China.

BACKGROUND: As climate change, compound hot extremes (CHEs), daytime and nighttime persistent hot extremes, are projected to become much more frequent and intense, which may pose a serious threat to human health. However, evidence on the impact of CHEs on injury is rare. METHODS: We collected injury death data and daily meteorological data from six Chinese provinces during 2013-2018. A time-stratified case-crossover design with two-stage analytic approach was applied to assess the associations of CHEs with injury mortality by intention, mechanism, age and gender. Using the projected daily temperatures of five General Circulation Models (GCMs), we projected the frequency of CHEs and CHEs-attributable mortality burden of injury under three Representative Concentration Pathway (RCP) scenarios. RESULTS: CHEs were significantly associated with increased injury mortality risk (RR = 1.14, 95%CI: 1.09-1.19), with strong effects on unintentional injuries (RR = 1.16, 95%CI:1.11,1.22) and intentional injuries (RR = 1.11, 95%CI:0.99,1.25). Female (RR = 1.21,95%CI: 1.13-1.29) and the elderly (RR = 1.30, 95%CI: 1.22-1.39) were more susceptible to CHEs. Both the frequency and injury mortality burden of CHEs showed a steep rising trend under RCP8.5 scenario, with a 7.37-fold and 8.22-fold increase respectively, by the end of the century, especially in southern, eastern, central and northwestern China. CONCLUSION: CHEs were associated with increased injury mortality risk, and the CHEs-attributable injury mortality burden was projected to aggravate substantially in the future as global warming. It is urgent to develop targeted adaptation policies to alleviate the health burden of CHEs.

The Impact of Non-optimum Ambient Temperature on Years of Life Lost: A Multi-county Observational Study in Hunan, China.

The ambient temperature-health relationship is of growing interest as the climate changes. Previous studies have examined the association between ambient temperature and mortality or morbidity, however, there is little literature available on the ambient temperature effects on year of life lost (YLL). Thus, we aimed to quantify the YLL attributable to non-optimum ambient temperature. We obtained data from 1 January 2013 to 31 December 2017 of 70 counties in Hunan, China. In order to combine the effects of each county, we used YLL rate as a health outcome indicator. The YLL rate was equal to the total YLL divided by the population of each county, and multiplied by 100,000. We estimated the associations between ambient temperature and YLL with a distributed lag non-linear model (DNLM) in a single county, and then pooled them in a multivariate meta-regression. The daily mean YLL rates were 22.62 y/(p·100,000), 10.14 y/(p·100,000) and 2.33 y/(p·100,000) within the study period for non-accidental, cardiovascular, and respiratory disease death. Ambient temperature was responsible for advancing a substantial fraction of YLL, with attributable fractions of 10.73% (4.36-17.09%) and 16.44% (9.09-23.79%) for non-accidental and cardiovascular disease death, respectively. However, the ambient temperature effect was not significantly for respiratory disease death, corresponding to 5.47% (-2.65-13.60%). Most of the YLL burden was caused by a cold temperature than the optimum temperature, with an overall estimate of 10.27% (4.52-16.03%) and 15.94% (8.82-23.05%) for non-accidental and cardiovascular disease death, respectively. Cold and heat temperature-related YLLs were higher in the elderly and females than the young and males. Extreme cold temperature had an effect on all age groups in different kinds of disease-caused death. This study highlights that general preventative measures could be important for moderate temperatures, whereas quick and effective measures should be provided for extreme temperatures.

Sputum bacteriology conversion and treatment outcome of patients with multidrug-resistant tuberculosis.

PURPOSE: Multidrug-resistant tuberculosis (MDR-TB) requires long-term treatment, has a high fatality rate, and constitutes a global threat. Earlier detection of treatment failure is required to predict therapeutic efficacy. PATIENTS AND METHODS: We enrolled MDR-TB patients consecutively from January 2011 through December 2012 in Lianyungang, China. Sputum smear microscopy tests and sputum cultures were performed once a month for the first 6 months following initiation of antituberculosis treatment and once every 2 months thereafter until the end of therapy. The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were used with a 95% CI to estimate the role of sputum bacteriology conversion in predicting treatment outcomes. RESULTS: Among the 92 MDR-TB patients enrolled in this study, 40.2% had poor treatment outcomes. The median initial sputum bacteriology conversion time was 1 month. Patients having 2-month sputum smear conversions (adjusted odds ratio [OR]: 7.19, 95% CI: 2.60-19.84) or culture conversions (adjusted OR: 2.88, 95% CI: 1.11-7.45) were more likely to experience good outcomes. The sensitivity and specificity obtained when using two-month sputum smear conversions to predict treatment outcomes were 67.6% (95% CI: 50.2-82.0) and 76.4% (95% CI: 63.0-86.8), respectively. The sensitivity and specificity obtained when using 2-month culture conversions to predict treatment outcomes were 48.6% (95% CI: 32.0-65.6) and 74.5% (95% CI: 61.0-85.3), respectively. The AUC for two-month smear conversions was 0.72 (95% CI: 0.62-0.81), significantly higher than that obtained for 2-month culture conversions (0.62, 95% CI: 0.52-0.72) (χ2 = 4.18, P = 0.041). CONCLUSION: The prognoses of MDR-TB patients displaying persistent sputum positivity were inferior to those for whom sputum bacteriology conversion was observed. Thus, sputum smear conversion results obtained 2 months after treatment initiation may provide a potential means for predicting MDR-TB treatment outcomes.