Persistent Abnormal Immunocytes Induced Systemic Bone Loss in Locally Irradiated Rats.

Chronic and systemic bone complications frequently occur in patients who undergo radiotherapy; however, the pathological mechanisms underlying these complications remain unclear. This study aimed to observe persistent and systemic changes in locally irradiated rats and to determine the systemic pathological changes that persistently affect bone metabolism. We examined the inflammatory and oxidative stress responses that occurred after local irradiation using enzyme immunoassays and biochemical analyses. Lymphocytes obtained from the blood, spleen, thymus, and bone marrow were evaluated using flow cytometry. The proliferation and apoptosis characteristics of co-cultured bone marrow-derived mesenchymal stem cells (BMSCs) were detected by MTT assay and PI/Annexin V-FITC staining, respectively, and the differentiation of BMSCs was measured according to alkaline phosphatase (ALP) staining, alizarin red staining, and Oil Red O staining and by evaluating the mRNA expression of ALP, osteocalcin (OCN), osteopontin (OPN), collagen I, Runx2, and PPARγ. Our results revealed that no significant or continuous differences were present in the inflammatory response or the oxidative stress response throughout the body after local irradiation. B lymphocyte levels increased continuously in the blood, spleen, and bone marrow after local irradiation. T lymphocyte levels were decreased at 2 weeks after local irradiation, and CD8+T lymphocyte levels were increased in the blood, thymus, and bone marrow at 12 weeks after local irradiation. The ratio of CD4+/CD8+T lymphocytes began to decrease during the early phase after local irradiation and became significantly decreased at 12 weeks after local irradiation. Normal BMSCs co-cultured with lymphocytes derived from irradiated rats exhibited decreased proliferation and increased apoptosis, and the ALP staining intensity, alizarin red staining intensity, and mRNA expression of related genes were all also decreased. Oil Red O staining intensity and mRNA expression of PPARγ were both increased. Lymphocyte levels contribute to chronic and systemic bone complications after radiotherapy by inhibiting the proliferation and osteoblastogenesis of BMSCs.

Comparing Patient-Controlled Analgesia Versus Non-PCA Hydromorphone Titration for Severe Cancer Pain: A Randomized Phase III Trial.

BACKGROUND: Opioid titration is necessary to achieve rapid, safe pain relief. Medication can be administered via patient-controlled analgesia (PCA) or by a healthcare provider (non-PCA). We evaluated the efficacy of intravenous PCA versus non-PCA hydromorphone titration for severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]). PATIENTS AND METHODS: Patients with severe cancer pain were randomized 1:1 to PCA or non-PCA titration, stratified by opioid-tolerant or opioid-naïve status. The PCA pump was set to no continuous dose, with a hydromorphone bolus dose 10% to 20% of the total previous 24-hour equianalgesic (for opioid-tolerant patients) or 0.5 mg (for opioid-naïve patients). For the non-PCA group, the initial hydromorphone bolus dose was identical to that in the PCA group, with the subsequent dose increased by 50% to 100% (for NRS unchanged or increased) or repeated at the current dose (for NRS 4-6). Hydromorphone delivery was initiated every 15 minutes (for NRS ≥4) or as needed (for NRS ≤3). The primary endpoint was time to successful titration (TST; time from first hydromorphone dose to first occurrence of NRS ≤3 in 2 consecutive 15-minute intervals). RESULTS: Among 214 patients (PCA, n=106; non-PCA, n=108), median TSTs (95% CI) were 0.50 hours (0.25-0.50) and 0.79 hours (0.50-1.42) for the PCA and non-PCA groups, respectively (hazard ratio [HR], 1.64; 95% CI, 1.23-2.17; P=.001). TSTs in opioid-tolerant patients were 0.50 hours (0.25-0.75) and 1.00 hours (0.50-2.00) for the PCA and non-PCA groups, respectively (HR, 1.92; 95% CI, 1.32-2.78; P=.003); in opioid-naive patients, TST was not significantly different for the PCA versus non-PCA groups (HR, 1.35; 95% CI, 0.88-2.04; P=.162). Pain score (median NRS; interquartile range) over 24 hours was significantly lower in the PCA group (2.80; 2.15-3.22) than in the non-PCA group (3.00; 2.47-3.53; P=.020). PCA administration produces significantly higher patient satisfaction with pain control than non-PCA administration (P<.001). CONCLUSIONS: Intravenous hydromorphone titration for severe cancer pain was achieved more effectively with PCA than with non-PCA administration.

Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression.

The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.

Sulforaphane ameliorates bisphenol A-induced hepatic lipid accumulation by inhibiting endoplasmic reticulum stress.

The aim of the present study was to investigate the role of endoplasmic reticulum (ER) stress in bisphenol A (BPA) - induced hepatic lipid accumulation as well as the protective effects of Sulforaphane (SFN) in this process. Human hepatocyte cell line (LO2) and C57/BL6J mice were used to examine BPA-triggered hepatic lipid accumulation and the underlying mechanism. Hepatic lipid accumulation, triglycerides (TGs) levels, the expression levels of lipogenesis-related genes and proteins in the ER stress pathway were measured. It was revealed that BPA treatment increased the number of lipid droplets, the levels of TG and mRNAs expression of lipogenesis-related genes, and activated the ER stress pathway. These changes were inhibited by an ER stress inhibitor 4-phenylbutyric acid. SFN treatment abrogated BPA-altered hepatic lipid metabolism and ameliorated BPA-induced ER stress-related markers. Together, these findings suggested that BPA activated ER stress to promote hepatic lipid accumulation, and that SFN reversed those BPA effects by alleviating ER stress.

Synergistic Effect Between Full-Term Pregnancy/Breastfeeding And Familial Susceptibility On Breast Cancer Risk.

BACKGROUND: Breast cancer is the most common cancer in women worldwide, and reproductive factors and family history of malignancy are considered as high risk factors. The present study aimed to evaluate the synergistic effect of reproductive factors and family history on breast cancer. METHOD: A total of 1215 breast cancer patients and 1215 control participants from two medical centers were enrolled, and reproductive factor history and family cancer history information was collected. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratio (OR), and synergy index (SI) was used to assess the combined effect of potential factors. RESULTS: Compared to the controls, a negative association between full-term pregnancy/breastfeeding and breast cancer was observed regardless of the status of family cancer history (OR: 0.675, 95% CI: 0.560-0.814 and OR: 0.631, 95% CI: 0.503-0.789 respectively) after adjustment of other confounders, while the risk effect of abortion was unproven. The synergistic effect of history of full-term pregnancy and family history of malignancy was indicated in the combined analyses with SI as 9.429 (95% CI:1.248-71.245). CONCLUSION: Full-term pregnancy/breastfeeding were protective factors against breast cancer and synergistic additive effect was demonstrated between no full-term pregnancy/breastfeeding and a family history of malignancy on the risk of breast cancer.

Association of ambient air pollutants and birth weight in Ningbo, 2015-2017.

Previous studies have suggested a change of birth weight linked with elevated ambient air pollutant concentrations during the pregnancy. However, investigations of the influence of higher pollutant levels on birth weight change are limited. The goal of this study is to evaluate whether the air pollution of Ningbo is associated with birth weight, and which trimester could be a window period for maternal exposure to air pollution. A total of 170,008 live births were selected in the Ningbo city of Zhejiang, China, from 2015 to 2017. We estimated the association between the decreased birth weight and the increased air pollutant concentrations in the three trimesters and full gestation. The effects of interaction among pollutants were identified using a co-pollutant adjustment model. An interquartile range increases in PM2.5 (10.55 µg/m3), SO2(4.6 µg/m3), CO (125.59 µg/m3), and O3 (14.54 µg/m3) concentrations during the entire gestation were associated with 3.65 g (95% confidence interval: -6.02 g, -1.29 g), 5.02 g (-6.89 g, -3.14 g), 2.64 g (-4.65 g, -0.63 g) and 2.9 g (-4.8 g, 1 g) decreases, respectively, in birth weight. With each interquartile range increment in NO2 concentration was associated with an 8.05 g (6.24 g, 9.85 g) increase in birth weight. In the first trimester, only the PM2.5 exposure seemed to be associated with the greatest decline in birth weight. After adjustment for co-pollutant, both PM2.5 and SO2 were still associated with birth weight, except for CO for O3 adjustment, O3 for SO2 adjustment, and O3 for NO2 adjustment. Maternal exposure to air pollution may be associated with a decrease of birth weight, but the contribution of various pollutants is necessary to verify by future research.