Differentiating the impact of fine and coarse particulate matter on cause-specific cerebrovascular mortality: An individual-level, case-crossover study.

BACKGROUND AND OBJECTIVES: Many studies suggested that short-term exposure to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) was linked to elevated risk of cerebrovascular disease. However, little is known about the potentially differential effects of PM2.5 and PM2.5-10 on various types of cerebrovascular disease. METHODS: We collected individual cerebrovascular death records for all residents in Shanghai, China from 2005 to 2021. Residential daily air pollution data were predicted from a satellite model. The associations between particulate matters (PM) and cerebrovascular mortality were investigated by an individual-level, time-stratified, case-crossover design. The data was analyzed by the conditional logistic regression combined with the distributed lag model with a maximum lag of 7 days. Furthermore, we explored the effect modifications by sex, age and season. RESULTS: A total of 388,823 cerebrovascular deaths were included. Monotonous increases were observed for mortality of all cerebrovascular diseases except for hemorrhagic stroke. A 10 µg/m3 rise in PM2.5 was related to rises of 1.35% [95% confidence interval (CI): 1.04%, 1.66%] in mortality of all cerebrovascular diseases, 1.84% (95% CI: 1.25%, 2.44%) in ischemic stroke, 1.53% (95% CI: 1.07%, 1.99%) in cerebrovascular sequelae and 1.56% (95% CI: 1.08%, 2.05%) in ischemic stroke sequelae. The excess risk estimates per each 10 µg/m3 rise in PM2.5-10 were 1.47% (95% CI: 1.10%, 1.84%), 1.53% (95% CI: 0.83%, 2.24%), 1.93% (95% CI: 1.38%, 2.49%) and 2.22% (95% CI: 1.64%, 2.81%), respectively. The associations of both pollutants with all cerebrovascular outcomes were robust after controlling for co-pollutants. The associations were greater in females, individuals > 80 years, and during the warm season. CONCLUSIONS: Short-term exposures to both PM2.5 and PM2.5-10 may independently increase the mortality risk of cerebrovascular diseases, particularly of ischemic stroke and stroke sequelae.

Short-term association of particulate matter and cardiovascular disease mortality in Shanghai, China between 2003 and 2020.

Objective: Evidence regarding the effects of particulate matter (PM) pollutants on cardiovascular disease (CVD) mortality remains limited in Shanghai, China. Our objective was to thoroughly evaluate associations between PM pollutants and CVD mortality. Methods: Daily data on CVD mortality, PM (PM10 and PM2.5) pollutants, and meteorological variables in Shanghai, China were gathered from 2003 to 2020. We utilized a time-series design with the generalized additive model to assess associations between PM pollutants and CVD mortality. Additionally, we conducted stratified analyses based on sex, age, education, and seasons using the same model. Results: We found that PM pollutants had a significant association with CVD mortality during the study period. Specifically, there was a 0.29% (95%CI: 0.14, 0.44) increase in CVD mortality for every 10 µg/m3 rise in a 2-day average (lag01) concentration of PM10. A 0.28% (95% CI: 0.07, 0.49) increase in CVD mortality was associated with every 10 µg/m3 rise in PM2.5 concentration at lag01. Overall, the estimated effects of PM10 and PM2.5 were larger in the warm period compared with the cold period. Furthermore, males and the older adult exhibited greater susceptibility to PM10 and PM2.5 exposure, and individuals with lower education levels experienced more significant effects from PM10 and PM2.5 than those with higher education levels. Conclusion: Our findings suggested that PM pollutants have a substantial impact on increasing CVD mortality in Shanghai, China. Moreover, the impacts of air pollution on health may be altered by factors such as season, sex, age, and educational levels.

Effects of GHRH Deficiency and GHRH Antagonism on Emotional Disorders in Mice.

Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the endocrine system and mood disorders. In this context, the effects induced by MIA-602 were also analyzed in comparison to vehicle-treated mice with GH deficiency due to generalized ablation of the GHRH gene (GHRH knock out (GHRHKO)). We show that the chronic subcutaneous administration of MIA-602 to wild type (+/+) mice, as well as generalized ablation of the GHRH gene, is associated with anxiolytic and antidepressant behavior. Moreover, immunohistochemical and Western blot analyses suggested an evident activation of Nrf2, HO1, and NQO1 in the prefrontal cortex of both +/+ mice treated with MIA-602 (+/+ MIA-602) and homozygous GHRHKO (-/- control) animals. Finally, we also found significantly decreased COX-2, iNOS, NFkB, and TNF-α gene expressions, as well as increased P-AKT and AKT levels in +/+ MIA-602 and -/- control animals compared to +/+ mice treated with vehicle (+/+ control). We hypothesize that the generalized ablation of the GHRH gene leads to a dysregulation of neural pathways, which is mimicked by GHRH antagonist treatment.

Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.

COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-hACE2tg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-hACE2tg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.

Growth hormone-releasing hormone antagonist MIA-602 inhibits inflammation induced by SARS-CoV-2 spike protein and bacterial lipopolysaccharide synergism in macrophages and human peripheral blood mononuclear cells.

COVID-19 is characterized by an excessive inflammatory response and macrophage hyperactivation, leading, in severe cases, to alveolar epithelial injury and acute respiratory distress syndrome. Recent studies have reported that SARS-CoV-2 spike (S) protein interacts with bacterial lipopolysaccharide (LPS) to boost inflammatory responses in vitro, in macrophages and peripheral blood mononuclear cells (PBMCs), and in vivo. The hypothalamic hormone growth hormone-releasing hormone (GHRH), in addition to promoting pituitary GH release, exerts many peripheral functions, acting as a growth factor in both malignant and non-malignant cells. GHRH antagonists, in turn, display potent antitumor effects and antinflammatory activities in different cell types, including lung and endothelial cells. However, to date, the antinflammatory role of GHRH antagonists in COVID-19 remains unexplored. Here, we examined the ability of GHRH antagonist MIA-602 to reduce inflammation in human THP-1-derived macrophages and PBMCs stimulated with S protein and LPS combination. Western blot and immunofluorescence analysis revealed the presence of GHRH receptor and its splice variant SV1 in both THP-1 cells and PBMCs. Exposure of THP-1 cells to S protein and LPS combination increased the mRNA levels and protein secretion of TNF-α and IL-1ß, as well as IL-8 and MCP-1 gene expression, an effect hampered by MIA-602. Similarly, MIA-602 hindered TNF-α and IL-1ß secretion in PBMCs and reduced MCP-1 mRNA levels. Mechanistically, MIA-602 blunted the S protein and LPS-induced activation of inflammatory pathways in THP-1 cells, such as NF-κB, STAT3, MAPK ERK1/2 and JNK. MIA-602 also attenuated oxidative stress in PBMCs, by decreasing ROS production, iNOS and COX-2 protein levels, and MMP9 activity. Finally, MIA-602 prevented the effect of S protein and LPS synergism on NF-кB nuclear translocation and activity. Overall, these findings demonstrate a novel antinflammatory role for GHRH antagonists of MIA class and suggest their potential development for the treatment of inflammatory diseases, such as COVID-19 and related comorbidities.

Secular trends of low birth weight, preterm birth, and small for gestational age in Shanghai from 2004 to 2020: an age-period-cohort analysis.

BACKGROUND: Although highly heterogeneous among countries, the incidence rates of low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) have been increasing globally over the past two decades. To better understand the cause of these secular trends, this study aimed to investigate the effects of age, period, and birth cohort on LBW, PTB, and SGA rates in Shanghai. METHODS: Data from 2,958,695 singleton live births at 24-41 gestational weeks between 2004 and 2020 were obtained for this study. Age-period-cohort models based on Poisson regression were used to evaluate the independent effects of maternal age, delivery period, and maternal birth cohort on the trends in LBW, PTB, and SGA. RESULTS: The overall prevalence rates of LBW, PTB, and SGA were 2.9%, 4.7%, and 9.3%, respectively, and significant changes were observed (average annual change: + 10.7‰, + 9.1‰, -11.9‰) from 2004 to 2020. Cohort effect increased steadily, from 1960 (risk ratio [RR] = 0.71, 95% confidence interval [CI]: 0.65-0.78) to 1993 (RR = 0.97, 95% CI: 0.94-1.01) for LBW and from 1960 (RR = 0.69, 95% CI: 0.64-0.75) to 2004 (RR = 1.02, 95% CI: 0.94-1.12) for PTB. A strong cohort effect was found with the highest risk of SGA (RR = 1.82, 95% CI: 1.72-1.93) in 1960 and the lowest risk (RR = 0.57, 95% CI: 0.54-0.61) in 2004, compared with the reference cohort of 1985. There was a "U-shaped" maternal age effect on LBW and PTB and a weak period effect on the three birth outcomes. CONCLUSIONS: Our findings suggested a significant independent effect of age, period, and birth cohort on the three birth outcomes. The increasing rates of LBW and PTB motivated us to focus on young and advanced pregnant women. Meanwhile, the prevalence of SGA decreased steadily, illustrating the need for further research on the mechanisms underlying these trends.

GHRH agonist MR-409 protects ß-cells from streptozotocin-induced diabetes.

Patients with type 1 diabetes (T1D) suffer from insufficient functional ß-cell mass, which results from infiltration of inflammatory cells and cytokine-mediated ß-cell death. Previous studies demonstrated the beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R), such as MR-409 on preconditioning of islets in a transplantation model. However, the therapeutic potential and protective mechanisms of GHRH-R agonists on models of T1D diabetes have not been explored. Using in vitro and in vivo models of T1D, we assessed the protective propertie of the GHRH agonist, MR409 on ß-cells. The treatment of insulinoma cell lines and rodent and human islets with MR-409 induces Akt signaling by induction of insulin receptor substrate 2 (IRS2), a master regulator of survival and growth in ß-cells, in a PKA-dependent manner. The increase in cAMP/PKA/CREB/IRS2 axis by MR409 was associated with decrease in ß-cell death and improved insulin secretory function in mouse and human islets exposed to proinflammatory cytokines. The assessment of the effects of GHRH agonist MR-409 in a model of T1D induced by low-dose streptozotocin showed that mice treated with MR-409 exhibited better glucose homeostasis, higher insulin levels, and preservation of ß-cell mass. Increased IRS2 expression in ß-cells in the group treated with MR-409 corroborated the in vitro data and provided evidence for the underlying mechanism responsible for beneficial effects of MR-409 in vivo. Collectively, our data show that MR-409 is a novel therapeutic agent for the prevention and treatment of ß-cells death in T1D.

Association between excessive fetal growth and maternal cancer in Shanghai, China: a large, population-based cohort study.

The prevalence of high birth weight or large for gestational age (LGA) infants is increasing, with increasing evidence of pregnancy-related factors that may have long-term impacts on the health of the mother and baby. We aimed to determine the association between excessive fetal growth, specifically LGA and macrosomia, and subsequent maternal cancer by performing a prospective population-based cohort study. The data set was based on the Shanghai Birth Registry and Shanghai Cancer Registry, with medical records from the Shanghai Health Information Network as a supplement. Macrosomia and LGA prevalence was higher in women who developed cancer than in women who did not. Having an LGA child in the first delivery was associated with a subsequently increased risk of maternal cancer (hazard ratio [HR] = 1.08, 95% confidence interval [CI] 1.04-1.11). Additionally, in the last and heaviest deliveries, there were similar associations between LGA births and maternal cancer rates (HR = 1.08, 95% CI 1.04-1.12; HR = 1.08, 95% CI 1.05-1.12, respectively). Furthermore, a substantially increased trend in the risk of maternal cancer was associated with birth weights exceeding 2500 g. Our study supports the association between LGA births and increased risks of maternal cancer, but this risk requires further investigation.

Efficacy of a growth hormone-releasing hormone agonist in a murine model of cardiometabolic heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR-409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system and aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (l-NAME) for 9 wk. After 5 wk of HFD + l-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-wk period. Control animals received no HFD + l-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.NEW & NOTEWORTHY This randomized study used rigorous hemodynamic tools to test the efficacy of a synthetic GHRH agonist to improve cardiac performance in a cardiometabolic HFpEF. Daily injection of the GHRH agonist, MR-356, reduced the HFpEF-like effects as evidenced by improved diastolic dysfunction, reduced cardiac hypertrophy, fibrosis, and pulmonary congestion. Notably, end-diastolic pressure and end-diastolic pressure-volume relationship were reset to control levels. Moreover, treatment with MR-356 increased exercise capacity and reduced myocardial stress associated with metabolic inflammation in HFpEF.

Growth hormone-releasing hormone agonist attenuates vascular calcification in diabetic db/db mice.

Introduction: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. VC increases mortality of all-causes. VC is one of most common cardiovascular complications in type II diabetes. So far, no therapy has been proven to be effective in treatment of clinical VC. The present study investigated the therapeutic effects of MR409, an agonistic analog of growth hormone-releasing hormone (GHRH-A), on VC in diabetic db/db mice. Method and result: Diabetic mice were injected with MR409 subcutaneously every day for 8 weeks. Long-term treatment with MR409 improved serum lipid profile and endothelium-dependent relaxation to acetylcholine, and reduced vascular structural injury in diabetic mice without affecting serum growth hormone level. Echocardiography showed that calcium plaques present in heart valve of diabetic mice disappeared in diabetic mice after treatment with MR409. MR409 inhibited vascular calcium deposition associated with a marked reduction in the expressions of osteogenic-regulated alkaline phosphatase (ALP) and transcription osteogenic marker gene Runx2 in diabetic mice. MR409 also inhibited vascular reactive oxygen species (ROS) generation and upregulated the expressions of anti-calcifying protein Klotho in diabetic mice. Discussion: Our results demonstrate that GHRH-A MR409 can effectively attenuate VC and heart valve calcification, and protect against endothelial dysfunction and vascular injury in diabetic mice without significantly affecting pituitary-growth hormone axis. The mechanisms may involve upregulation of anti-calcifying protein Klotho and reduction in vascular ROS and the expression of redox sensitive osteogenic genes Runx2 and ALP. GHRH-A may represent a new pharmacological strategy for treatment of VC and diabetics associated cardiovascular complications.

Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice.

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (SMN1). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.

Synthetic growth hormone-releasing hormone agonist ameliorates the myocardial pathophysiology characteristic of heart failure with preserved ejection fraction.

AIMS: To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis. METHODS AND RESULTS: CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts. CONCLUSION: These findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.

Residential Nitrogen Dioxide Exposure and Cause-Specific Cerebrovascular Mortality: An Individual-Level, Case-Crossover Study.

BACKGROUND: Existing studies have already shown a connection between nitrogen dioxide (NO2) exposure and cerebrovascular mortality. However, the differential effects of NO2 on cerebrovascular disease and its subtypes remain unclear and require further exploration. METHODS: Daily stroke mortality data between 2013 and 2021 in Shanghai, China were collected. Residential daily air pollution data for each decedent were predicted from a satellite model. An individual-level, time-stratified, case-crossover design was applied to examine the relationship between NO2 exposure and cerebrovascular mortality. A combination of conditional logistic regression and distributed lag models with a maximum lag of 7 days was used for data analysis. RESULTS: A total of 219,147 cases of cerebrovascular mortality were recorded. Among them, the proportion of sequelae of cerebrovascular disease, hemorrhagic stroke and ischemic stroke was 50.7%, 17.1% and 27.5%, respectively. The monotonic increases in mortality risks of cerebrovascular diseases, sequelae of cerebrovascular disease and ischemic stroke were observed, without any discernible thresholds. Each 10 µg/m3 increase in NO2 concentration was associated with increments of 3.62% [95% confidence interval (CI): 2.56%, 4.69%] for total cerebrovascular mortality, 4.29% (95% CI: 2.81%, 5.80%) for sequelae of cerebrovascular disease mortality and 4.30% (95% CI: 2.30%, 6.33%) for ischemic stroke mortality. No positive associations between NO2 exposure and hemorrhagic stroke mortality were observed. A greater risk of NO2 was observed in the warm season, in patients with less than 9 years of education and in those with single marital status. The effects of NO2 were robust to mutual adjustment of co-pollutants. CONCLUSIONS: Short-term exposures to NO2 may increase the risk of cerebrovascular mortality, specifically for ischemic stroke and sequelae of cerebrovascular disease.

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma.

Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.

Age-dependent and sex-dependent differences in mortality from influenza-associated cardiovascular diseases among older adults in Shanghai, China: a population-based study.

OBJECTIVES: Influenza epidemics lead to substantial morbidity and mortality among older adults. This study aimed to analyse and assess the age-specific and sex-specific differences in mortality rates for cardiovascular disease (CVD) associated with influenza in older adults. DESIGN: We obtained weekly data on mortality from CVD in adults≥60 years, categorised into five age groups. We used a quasi-Poisson model and adjusted for long-term and seasonal trends and absolute humidity as confounding factors. The male-to-female ratio (M/F ratio) was an indicator for assessing sex differences. SETTING: Shanghai, China. PARTICIPANT: We analysed 440 107 CVD deaths in adults aged ≥60 years, including 44 913 cases positive for influenza and 1 927 487 outpatient visits for influenza-like illness from 2010 to 2019. MAIN OUTCOME MEASURES: Age-specific and sex-specific excess CVD mortality rates in older adults for various combinations of CVDs and influenza viruses. RESULTS: Variations were observed in the excess mortality from CVD, ischaemic heart disease (IHD) and stroke depending on the influenza types/subtypes in different age and sex categories. The ≥85 years group had the highest excess mortality rates per 100 000 persons for CVD, IHD and stroke, while influenza A (H3N2) virus accounted for the highest mortality from CVD, IHD and stroke in people aged ≥65 years. Older men had a significantly lower influenza-associated IHD mortality rate than women, with an M/F ratio of 0.77 (p<0.05). CONCLUSIONS: Excess mortality rates for CVDs associated with influenza increased with age in older adults. The risk for influenza-associated IHD mortality was significantly higher in older women than men. Our findings will help implement targeted health strategies, including the promotion of influenza vaccination and early therapeutic intervention for the older population with CVD, to curb the influenza burden effectively.

The reversing trend in suicide rates in Shanghai, China, from 2002 to 2020.

BACKGROUND: To explore changing patterns in suicides and provide suggestions for suicide prevention by reviewing all suicide deaths from 2002 to 2020 in Shanghai, China. METHODS: Suicide-death data were obtained from the Shanghai Death Surveillance System and analyzed in terms of year, sex, age group, area, suicide method, and depression diagnosis. Joinpoint regression analyses were conducted to examine time trends in suicide rates. RESULTS: The age-adjusted suicide rate was 6.15/100,000 in 2002 and 5.10/100,000 in 2020. The change in this rate was U-shaped, with a downward trend before 2009 followed by an upward trend. The rate initially decreased by 6.33% annually (95% confidence interval [95%CI]: 4.25-8.37%) but, after 2009, increased by 2.60% annually (95%CI: 1.49-3.71%). Similar trends were found for men and women, the 0-29y and 30-49y age groups, and residents of central and suburban areas, respectively. In 2020, jumping from a high place was the leading suicide method (39.54%), and 22.54% of suicide victims had a diagnosis of depression. LIMITATIONS: Suicides may be misclassified in coding (however, provided misclassification rates remain stable, this should not influence overall trends). Suicides among temporary residents were not included because of inadequate stratified population data. The finding of a higher prevalence of depression may have been impacted by a higher detection rate. CONCLUSIONS: The post-2002 decline in Shanghai suicide rates reversed in 2009, and the suicide pattern changed greatly from 2002 to 2020. With the current increasing trend in suicide rates, targeted suicide-prevention strategies featuring multi-departmental cooperation are necessary.

Association of adverse birth outcomes with in vitro fertilization after controlling infertility factors based on a singleton live birth cohort.

Infants conceived with in vitro fertilization (IVF) are exposed to underlying infertility and the IVF process. High risks of adverse birth outcomes (ABOs) were observed among these infants, including preterm birth, low birth weight, macrosomia, being large/small for gestational age (LGA/SGA). It is unclear whether the specific etiology of the rise of ABOs among IVF infants is IVF technology itself or underlying infertility. A total of 9,480 singletons conceived with IVF and 1,952,419 singletons from the general population were obtained in this study. Multivariable logistic regression model was used to assess variations in risk of ABOs according to causes of infertility. Poisson distributions were applied to calculate standardized risk ratios of IVF infants vs. general population after controlling the causes of infertility. Higher risk of preterm birth and low birth weight were observed among parents with polycystic ovary syndrome, endometriosis, uterine and semen abnormalities. Compared to the general population, after excluding the influence of infertility causes, singletons conceived with IVF were at higher risk of macrosomia (SRR = 1.28, 95% CI 1.14-1.44) and LGA (SRR = 1.25, 95% CI 1.15-1.35). The higher risk of ABOs in IVF was driven by both IVF treatments and infertility, which is important for improving IVF treatments and the managing pregnancies and child development.

Synthesis of potent antagonists of receptors for growth hormone-releasing hormone with antitumor and anti-inflammatory activity.

The syntheses and biological evaluation of GHRH antagonists of AVR series with high anticancer and anti-inflammatory activities are described. Compared to our previously reported GHRH antagonist 602 of MIAMI series, AVR analogs contain additional modifications at positions 0, 6, 8, 10, 11, 12, 20, 21, 29 and 30, which induce greater antitumor activities. Five of nineteen tested AVR analogs presented binding affinities to the membrane GHRH receptors on human pituitary, 2-4-fold better than MIA-602. The antineoplastic properties of these analogs were evaluated in vitro using proliferation assays and in vivo in nude mice xenografted with various human cancer cell lines including lung (NSCLC-ADC HCC827 and NSCLC H460), gastric (NCI-N87), pancreatic (PANC-1 and CFPAC-1), colorectal (HT-29), breast (MX-1), glioblastoma (U87), ovarian (SK-OV-3 and OVCAR-3) and prostatic (PC3) cancers. In vitro AVR analogs showed inhibition of cell viability equal to or greater than MIA-602. After subcutaneous administration at 5 µg/day doses, some AVR antagonists demonstrated better inhibition of tumor growth in nude mice bearing various human cancers, with analog AVR-353 inducing stronger suppression than MIA-602 in lung, gastric, pancreatic and colorectal cancers and AVR-352 in ovarian cancers and glioblastoma. Both antagonists induced greater inhibition of GH release than MIA-602 in vitro in cultured rat pituitary cells and in vivo in rats. AVR-352 also demonstrated stronger anti-inflammatory effects in lung granulomas from mice with lung inflammation. Our studies demonstrate the merit of further investigation of AVR GHRH antagonists and support their potential use for clinical therapy of human cancers and other diseases.

Antagonist of growth hormone-releasing hormone MIA-690 attenuates the progression and inhibits growth of colorectal cancer in mice.

Colorectal cancer (CRC) is an aggressive tumor in which new treatment options deliver negative results on cure rates and long-term survival. The anticancer effects of growth hormone-releasing hormone (GHRH) antagonists have been reported in various experimental tumors, but their activity in CRC is unknown. In the present study, we demonstrated that chronic treatment with GHRH antagonist of MIAMI class, MIA-690, promoted survival and gradually blunted tumor progression in experimentally induced colitis-associated cancer in mice, paralleled by reduced inflammation in colon tissue. In particular, MIA-690 improved disease activity index score, and reduced loss of weight and mortality, by improving the survival rates, compared with vehicle-treated group. MIA-690 was also found to reduce various inflammatory and oxidative markers, such as serotonin, prostaglandin (PG)E2 and 8-iso-PGF2α levels, as well as COX-2, iNOS, TNF-α, IL-6 and NF-kB gene expression. Moreover, MIA-690 inhibited the protein expression of c-Myc, P-AKT and Bcl-2 and upregulated p53 protein expression. In conclusion, we showed that MIA-690 suppresses CRC progression and growth by reducing inflammatory and oxidative markers and modulating apoptotic and oncogenic pathways. Further investigations are required for translating these findings into the clinics.