OBJECTIVE: To investigate the correlation between the expression of PD-L1 and HIF-1α in hepatocellular carcinoma (HCC) tissue and further analyze the association with clinical parameters and the ...prognostic value of coexpression in HCC patients. METHODS: We assessed the expression of PD-L1 and HIF-1α by immunohistochemistry in tumor tissue from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: PD-L1 and HIF-1α exhibited in tumor tissue high expression rates of 41.11% (37/90) and 43.33% (43/90), respectively, and their expressions were positively correlated (r = 0.563, P < .01). High expression of PD-L1 was significantly associated with low albumin levels (P < .05); high expression of HIF-1α was significantly correlated with high alpha-fetoprotein (AFP) levels and low albumin levels (P < .05); high expression of both PD-L1 and HIF-1α was also significantly associated with high AFP levels and low albumin levels (P < .05). High expression of PD-L1, HIF-1α, as well as both PD-L1 and HIF-1 α was respectively significantly associated with worse overall survival (OS) and disease-free survival (DFS) (P < .05). Patients with co-overexpression of PD-L1 and HIF-1α had the worst prognosis compared with other groups. Additionally, multivariate Cox regression models suggested that high expression of PD-L1, HIF-1α, as well as both PD-L1 and HIF-1α was an independent prognostic factor for OS and DFS (P < .05). Furthermore, the positive correlation and prognostic values of PD-L1 and HIF-1α were validated in an independent data set. CONCLUSION: We demonstrated that HCC patients with co-overexpression of PD-L1 and HIF-1α in tumor tissue had a significantly higher risk of recurrence or metastasis and death compared with others. Therefore, more frequent follow-up is needed for patients with co-overexpression of PD-L1 and HIF-1α. At the same time, a combinational therapy with HIF-1α inhibitors in conjunction with PD-L1 blockade may be beneficial for HCC patients with co-overexpression in the future.
OBJECTIVE To examine trends in attention-deficit/hyperactivity disorder (ADHD) by race/ethnicity, age, sex, and median household income. DESIGN An ecologic study of trends in the diagnosis of ADHD ...using the Kaiser Permanente Southern California (KPSC) health plan medical records. Rates of ADHD diagnosis were derived using Poisson regression analyses after adjustments for potential confounders. SETTING Kaiser Permanente Southern California, Pasadena. PARTICIPANTS All children who received care at the KPSC from January 1, 2001, through December 31, 2010 (n = 842 830). MAIN EXPOSURE Period of ADHD diagnosis (in years). MAIN OUTCOME MEASURES Incidence of physician-diagnosed ADHD in children aged 5 to 11 years. RESULTS Rates of ADHD diagnosis were 2.5% in 2001 and 3.1% in 2010, a relative increase of 24%. From 2001 to 2010, the rate increased among whites (4.7%-5.6%; relative risk RR = 1.3; 95% CI, 1.2-1.4), blacks (2.6%- 4.1%; RR = 1.7; 95% CI, 1.5-1.9), and Hispanics (1.7%-2.5%; RR = 1.6; 95% CI, 1.5-1.7). Rates for Asian/Pacific Islander and other racial groups remained unchanged over time. The increase in ADHD diagnosis among blacks was largely driven by an increase in females (RR = 1.9; 95% CI, 1.5-2.3). Although boys were more likely to be diagnosed as having ADHD than girls, results suggest the sex gap for blacks may be closing over time. Children living in high-income households were at increased risk of diagnosis. CONCLUSIONS The findings suggest that the rate of ADHD diagnosis among children in the health plan notably has increased over time. We observed disproportionately high ADHD diagnosis rates among white children and notable increases among black girls.
ABSTRACT
Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride‐synthesis pathway and by regulating transcription factor ...activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole‐body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle‐specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1–deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1–mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.—Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.‐F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1–mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. FASEB J. 33, 652–667 (2019). www.fasebj.org
Estrogen and its receptors in cancer Chen, George G; Zeng, Qiang; Tse, Gary MK
Medicinal research reviews,
11/2008, Volume:
28, Issue:
6
Journal Article
The poor clinical outcome of hepatocellular carcinoma (HCC) patients is ascribed to the resistance of HCC cells to traditional treatments and tumor recurrence after curative therapies. Cancer stem ...cells (CSCs) have been identified as a small subset of cancer cells which have high capacity for self-renewal, differentiation and tumorigenesis. Recent advances in the field of liver CSCs (LCSCs) have enabled the identification of CSC surface markers and the isolation of CSC subpopulations from HCC cells. Given their central role in cancer initiation, metastasis, recurrence and therapeutic resistance, LCSCs constitute a therapeutic opportunity to achieve cure and prevent relapse of HCC. Thus, it is necessary to develop therapeutic strategies to selectively and efficiently target LCSCs. Small molecular inhibitors targeting the core stemness signaling pathways have been actively pursued and evaluated in preclinical and clinical studies. Other alternative therapeutic strategies include targeting LCSC surface markers, interrupting the CSC microenvironment, and altering the epigenetic state. In this review, we summarize the properties of CSCs in HCC and discuss novel therapeutic strategies that can be used to target LCSCs.
Multiportal video-assisted thoracic surgery (VATS) for major lung resection causes less immunochemokine production compared to thoracotomy. Whether uniportal VATS is similarly associated with lower ...early postoperative circulating levels of immunochemokines compared to multiportal VATS have not been studied. Selected patients who received uniportal or multiportal VATS major lung resection were recruited. Blood samples were collected preoperatively and on postoperative days 1 and 3 for enzyme linked immunosorbent assay of serum levels of Tissue Inhibitor of Metalloproteinase (TIMP)-1, Insulin Growth Factor Binding Protein (IGFBP)-3, and Matrix Metalloproteinase (MMP)-9. A linear mixed-effects models were used to analyze the effects of uniportal VATS on the postoperative circulating chemokine levels. From March 2014 to April 2017, 68 consecutive patients consented for the prospective study and received major lung resection by either uniportal VATS (N = 29) or multiportal VATS (N = 39) were identified. Uniportal VATS major lung resection was associated with lower post-operative levels of TIMP-1 and MMP-9 compared to multiportal VATS after controlling for the effects of the corresponding baseline level and the time of follow-up measurement. No difference was observed for the level of IGFBP-3. Less immunochemokine disturbances was observed after uniportal VATS major lung resection compared to multiportal VATS.
The higher incidence of thyroid cancer in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogen have strongly suggested that ...estrogen may be involved in the occurrence and development of thyroid cancer. Cadmium (Cd) is a potent metalloestrogen that disrupts the endocrine system by mimicking the effects of 17β-estradiol (E2). In the present study, we demonstrate that similar to E2 and G1, a specific agonist for G protein-coupled estrogen receptor (GPER), Cd induces the proliferation, invasion and migration of human WRO and FRO thyroid cancer cells that have endogenous GPER. Moreover, like E2 and G1, Cd leads to a rapid activation of ERK/AKT, and then nuclear translocation of NF-κB, increased expression of cyclin A and D1, and secretion of IL-8, all of which are significantly attenuated by GPER blockage or knock-down in both WRO and FRO cells. Furthermore, the Cd-induced proliferation, invasion and migration are suppressed either by specific inhibitors for GPER, ERK, AKT and NF-κB, or by knock-down of GPER. These results suggest that GPER/ERK&AKT/NF-κB signaling pathway is involved in the Cd-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells.
•Cadmium (Cd) is a potent metalloestrogen.•Human thyroid cancer cells have endogenous GPER.•Cd induces proliferation, invasion and migration of human thyroid cancer cells.•GPER/ERK&AKT/NF-κB pathway is involved in these induction effects of Cd.
Cisplatin is a chemotherapy drug that has been used to treat a number of cancers for decades, and is still one of the most commonly used anti-cancer agents. However, some patients do not respond to ...cisplatin while other patients who were originally sensitive to cisplatin eventually develop chemoresistance, leading to treatment failure or/and tumor recurrence.
Different mechanisms contribute to cisplatin resistance or sensitivity, involving multiple pathways or/and processes such as DNA repair, DNA damage response, drug transport, and apoptosis. Among the various mechanisms, it appears that microRNAs play an important role in determining the resistance or sensitivity. In this article, we analyzed and summarized recent findings in this area, with the aim that these data can aid further research and understanding, leading to the eventual reduction of cisplatin resistance.
microRNAs can positively or negatively regulate cisplatin resistance by acting on molecules or/and pathways related to apoptosis, autophagy, hypoxia, cancer stem cells, NF-κB, and Notch1. It appears that the modulation of relevant microRNAs can effectively re-sensitize cancer cells to cisplatin regimen in certain types of cancers including breast, colorectal, gastric, liver, lung, ovarian, prostate, testicular, and thyroid cancers.
The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of ...hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.
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