type 2 diabetes mellitus (T2DM) is a complicated disease that can affect bone health, but the change in bone biochemical markers caused by T2DM was controversial, so the aim of this study was to investigate whether there was a discrepancy in the levels of bone biochemical markers between postmenopausal women with T2DM and non-diabetic women and to explore the relationship between the level of glycosylated hemoglobin A1c (HbA1c) and bone biochemical markers in these subjects. A total of 237 type 2 diabetic postmenopausal women visiting the First Affiliated Hospital of Anhui Medical University from January 2017 to October 2018 and 93 healthy postmenopausal women were retrospectively enrolled. The differences in the levels of bone biochemical markers between patients and controls were analyzed by one-way ANOVA or chi-square test. The relationship between HbA1c and bone biochemical markers was analyzed by multivariate regression, forest plot and fitted curve. Bone formation markers including N-MID osteocalcin and procollagen type 1 amino-terminal pro-peptide (PINP) were decreased in postmenopausal women with T2DM compared to controls (17.42 ± 9.50 vs 23.67 ± 7.58, p < 0.001; 48.47 ± 27.27 vs 65.86 ± 21.06, p < 0.001, respectively), but the bone resorption markers β-crossLaps (β-CTX) was no difference between the two groups (0.57 ± 0.28 vs 0.55 ± 0.21, p = 0.868). Multivariate regression showed that HbA1c was inversely associated with N-MID osteocalcin and PINP after adjusting for age, BMI, menopause's years, diabetic duration, TC, TG, HDL-c, LDL-c, creatinine, UA and eGFR. The adjusted coefficients for N-MID osteocalcin and PINP per 1% HbA1c decrease were − 0.71 (− 1.19, − 0.22) and − 1.79 (− 3.30, − 0.28), respectively. A segmentation effect was seen in the fitted curve between HbA1c and β-CTX with an inflection point at 7.4% of HbA1c, the highest quartile of β-CTX (> = 0.74 ng/ml) showed a significantly negative with HbA1c. No significant association was seen between HbA1c and other biochemical markers. Our study found that bone formation was inhibited in postmenopausal women with T2DM, but bone resorption was not affected, and poor glycemic control was related to lower levels of bone formation, may increase the risk of bone fracture in postmenopausal women with T2DM.
T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution in vivo. Here, optically clear immunocompromised zebrafish were engrafted with fluorescent-labeled human cancers along with chimeric antigen receptor T (CAR T) cells, bispecific T cell engagers (BiTEs), and antibody peptide epitope conjugates (APECs), allowing real-time single-cell visualization of T cell–based immunotherapies in vivo. This work uncovered important differences in the kinetics of T cell infiltration, tumor cell engagement, and killing between these immunotherapies and established early endpoint analysis to predict therapy responses. We also established EGFR-targeted immunotherapies as a powerful approach to kill rhabdomyosarcoma muscle cancers, providing strong preclinical rationale for assessing a wider array of T cell immunotherapies in this disease.
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood and is comprised of two major molecular subtypes. Here, we identify common developmental stages and hierarchies in this disease.
Activation of hepatic stellate cells (HSC) plays a crucial role in the liver disease progression from liver fibrosis/cirrhosis to cancer. Here, we found a rapid change of microenvironment after kras V12 -induction in zebrafish liver with progressively increased stromal cell number and enlarged liver size. Neutrophils and macrophages exhibited a faster response than HSCs. By manipulating the numbers of neutrophils and macrophages through morpholino knockdown, we found that macrophages contributed to both HSC survival and activation while neutrophils appear to be only required for HSC activation. Serotonin, which is essential for HSC survival and activation, was found up-regulated in hepatocytes and macrophages, but not in neutrophils after kras V12 induction. Serotonin receptor was highly expressed in HSCs; increase of the receptor activity by an agonist stimulated HSCs and oncogenic growth of the liver while an opposite effect was observed with an antagonist. Activated HSCs promoted the pro-tumorigenesis functions of neutrophils and macrophages through secretion of Tgfb1. Overall, these observations elucidated a cellular interaction in microenvironment where that upregulated serotonin in hepatocytes and macrophages activated HSCs. Since the microenvironment crosstalk plays a vital role in manipulation of liver carcinogenesis, the underlying mechanism may provide potential therapeutic targets for liver diseases.
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