The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant up-regulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53-ZMAT3-CD44 axis in growth suppression in CRC cells.
To report the current incidence of bronchopulmonary dysplasia (BPD) and to compare changes in weight and head circumference between infants who developed BPD and infants who did not.
Retrospective, whole-population study.
All neonatal units in England between 2014 and 2018.
All liveborn infants born <28 completed weeks of gestation.
The change in weight z-score (ΔWz) was calculated by subtracting the birthweight z-score from the weight z-score at 36 weeks postmenstrual age (PMA) and at discharge. The change in head circumference z-score (ΔHz) was calculated by subtracting the birth head circumference z-score from the head circumference z-score at discharge.
BPD was defined as the need for any respiratory support at 36 weeks PMA.
11 806 infants were included in the analysis. Selleck FHD-609 The incidence of BPD was 57.5%, and 18.9% of the infants died before 36 weeks PMA. The median (IQR) ΔWz from birth to 36 weeks PMA was significantly smaller in infants who developed BPD (-0.69 (-1.28 to -0.14), n=6105) than in those who did not develop BPD (-0.89 (-1.40 to -0.33), n=2390; adjusted p<0.001). The median (IQR) ΔHz from birth to discharge was significantly smaller in infants who developed BPD (-0.33 (-1.69 to 0.71)) than in those who did not develop BPD (-0.61 (-1.85 to 0.35); adjusted p<0.001).
Postnatal growth was better in infants diagnosed with BPD compared with infants without BPD possibly due to more aggressive nutrition strategies.
Postnatal growth was better in infants diagnosed with BPD compared with infants without BPD possibly due to more aggressive nutrition strategies.
Although systemic chemotherapy is often administered to patients with malignant bowel obstruction (MBO), its benefit remains unknown. This study assessed the outcomes of patients who received systemic chemotherapy as part of MBO treatment.
For this retrospective cohort study, data were extracted from records of patients hospitalised due to MBO in a tertiary cancer centre from 2008 to 2020. Eligible patients were not candidates for surgery and received systemic chemotherapy targeting the underlying malignancy causing MBO. Primary objective was to assess patient outcomes after chemotherapy; secondary objectives were rates of intestinal function recovery, hospital discharge and grade ≥3 toxicities. The primary endpoint was overall survival (OS).
A total of 167 patients were included median age was 55 (18-81) years, 91% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, 75.5% had gastrointestinal tumours and 70% were treatment-naive. The median OS after chemotherapy was 4.4 weeks (95% CI 3.4 to 5.5) in the overall population. No OS difference was observed according to treatment line (p=0.24) or primary tumour (p=0.13). Intestinal function recovery occurred in 87 patients (52%), out of whom 21 (24.1%) had a reobstruction. Hospital discharge was possible in 74 patients (44.3%). Grade≥3 adverse events occurred in 26.9% of the patients, and a total of 12 deaths (7%) attributed to toxicities were observed after chemotherapy.
MBO was associated with a dismal prognosis in this mostly treatment-naive population. The administration of chemotherapy yielded a significant risk of toxicities, whereas it did not appear to provide any relevant survival benefit in this scenario.
MBO was associated with a dismal prognosis in this mostly treatment-naive population. The administration of chemotherapy yielded a significant risk of toxicities, whereas it did not appear to provide any relevant survival benefit in this scenario.
To study the uptake of annual diabetic retinopathy screening and study the 5-year trends in the detection of screen-positive diabetic retinopathy and non-diabetes-related eye disease in a cohort of annually screened individuals.
Retrospective retinopathy screening attendance and retinopathy grading analysis.
Community-based retinopathy screening centres for the Diabetic RetinaScreen Programme.
171 557 were identified by the screening programme to be eligible for annual diabetic retinopathy screening. 120 048 individuals over the age of 12 consented to and attended at least one screening appointment between February 2013 to December 2018.
Detection rate per 100000 of any retinopathy, screen-positive referrable retinopathy and nondiabetic eye disease.
Uptake of screening had reached 67.2% in the fifth round of screening. Detection rate of screen-positive retinopathy reduced from 13229 to 4237 per 100000 screened over five rounds. Detection of proliferative disease had reduced from 2898 to 713 per 100000 screened.Selleck FHD-609
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