We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc).
Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc.
Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05).
Our research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C.
HLA-DRB1 alleles; polymorphisms; hepatocellular carcinoma; familial aggregation; pcr-ssp
A noninvasive test for the detection of Helicobacter pylori infection that uses [15N]urea as a tracer has been established. The principle the test is based on is the strong urease activity of H. pylori. After oral ingestion, [15N]urea is broken down into ammonia and carbon dioxide by H. pylori urease in the stomach. The ammonia is absorbed into the blood and excreted in the urine. The amount of [15N]urea, reflecting the magnitude of H. pylori infection, is evaluated by measuring the abundance and excretion rate of 15N in ammonia in the urine. Thirty-six patients were examined in our study. The 15N excretion rates in urine ammonia of patients who were H. pylori positive were significantly higher than those of H. pylori-negative patients (P less than 0.05). Twenty-three patients were H. pylori positive by Gram stain and culture. The sensitivity of the 15NH4 excretion test compared with these techniques was 96%, and no false positives were obtained. The 15NH4+ excretion rates of 13 H. pylori-negative subjects were all in the normal range (less than 0.3%). This method is a simple, precise, highly sensitive, noninvasive, nonradioactive test. It could be used for diagnosis as well as for the followup of patients receiving H. pylori eradication therapy, especially children and pregnant women. It could also be used in epidemiological investigation of H. pylori infection in a general population.
Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1+/Blbp+ progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.
The objective of the study was to compare fatty acid composition of longissimus dorsi (LD) and kidney fat (KF) in Holstein steers (HS), Simmental steers (SS) and Chinese LongDong Yellow Cattle steers (CLD). All steers received the same nutrition and management but in different locations. Cattle were harvested at approximately 550 kg and fatty acid composition of longissimus dorsi and kidney fat was analyzed in samples taken after 3 days of aging. There was evidence (P < 0.05) that C18:3n6 was greater in KF than LD in CLD cattle but not in HS or SS cattle. Percentage C18:1n9, C18:2n6, C18:3n3, and n6 fatty acids were greater in LD than KF for all breeds (P < 0.05), but the difference between fat sources for n6 in CLD cattle was smaller than the other two breeds. The LD had greater percentage of polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), and a greater ratio of n6:n3 PUFAs compared to the KF in each breed (P < 0.05). The △9-desaturase catalytic activity index was greater in LD than in KF in each breed group (P < 0.05). Percentage cis-9, trans-11 CLA was greater in KF than LD in HS (P < 0.05) but not SS or CLD cattle. These results indicate fatty acid percentages generally differed between longissimus dorsi fat and kidney fat. Further, there was some indication that some of these differences between fatty acid deposition sites were not consistent across breed group.
Breed; Longissimus dorsi; Kidney fat; FAME composition
Anal intraepithelial neoplasia precedes the development of anal squamous cell carcinoma. Detection of the lesion is essential to management. This paper describes a prospective study to detect and ablate anal squamous intraepithelial lesions (SILs) using white light narrow band imaging (NBI) and NBI with acetic acid (NBIA).
Sixty patients with abnormal anal cytology and risk factors for anal dysplasia underwent examination of the anoderm with a high definition gastroscope and NBIA. Targeted biopsies were taken and the lesions were ablated and characterized histopathologically. Visualization of the anal transitional zone was facilitated by retroflexion and examination through a disposable anoscope.
Targeted biopsies were taken from lesions in 58 patients. No lesion was seen in two patients. Histopathology showed SIL in 48 (80.0%) of 60 biopsies. One biopsy showed lymphoid aggregates. Biopsies in nine (15%) of the 60 patients showed normal mucosa. Lesions were seen in white light in 27 (45%) of the 60 cases, NBI in 39 (65%) and NBIA in 57 (95%). There was no major morbidity. Sensitivity analysis showed that all methods were significantly different from each other.
Anal SIL in the anal transitional zone and anal canal can be identified by NBIA. Patient selection influences findings. Limitations include small sample size and non‐randomization.
Anal dysplasia; anal transitional zone; human immunodeficiency virus; human papillomavirus; narrow band imaging; squamous intraepithelial lesion
MicroRNAs (miRNAs) have been demonstrated to have critical roles in regulating cancer cell proliferation, survival and sensitivity to chemotherapy. The potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms have not been completely understood. Here, we show a strong correlation between miR-621 expression and chemosensitivity to paclitaxel plus carboplatin (PTX/CBP) regimen, an effective neoadjuvant chemotherapy for breast cancer patients. High level of miR-621 predicts better response to PTX/CBP regimen neoadjuvant chemotherapy in breast cancer patients, who also tend to achieve pathological complete response. Ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to PTX and CBP both in cultured breast cancer cells and in xenograft tumor model. We further show that FBXO11 is a direct functional target of miR-621 and miR-621 level is negatively correlated with FBXO11 expression in breast cancer patients. Ectopic expression of FBXO11 attenuated increased apoptosis in breast cancer cells overexpressing miR-621 upon PTX or CBP treatment. Consistently, high FBXO11 expression significantly correlated with poor survival in breast cancer patients. Mechanistically, we found in breast cancer cells FBXO11 interacts with p53 and promotes its neddylation, which suppressed the p53 transactivity. Accordingly, miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics. Taken together, our data suggest that miR-621 enhances chemosensitivity of breast cancer cells to PTX/CBP chemotherapy by suppressing FBXO11-depedent inhibition of p53. miR-621 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.
The present study screened potential genes related to lung adenocarcinoma, with the
aim of further understanding disease pathogenesis. The GSE2514 dataset including 20
lung adenocarcinoma and 19 adjacent normal tissue samples from 10 patients with lung
adenocarcinoma aged 45-73 years was downloaded from Gene Expression Omnibus.
Differentially expressed genes (DEGs) between the two groups were screened using the
t-test. Potential gene functions were predicted using functional
and pathway enrichment analysis, and protein-protein interaction (PPI) networks
obtained from the STRING database were constructed with Cytoscape. Module analysis of
PPI networks was performed through MCODE in Cytoscape. In total, 535 upregulated and
465 downregulated DEGs were identified. These included ATP5D,
UQCRC2, UQCR11 and genes encoding nicotinamide
adenine dinucleotide (NADH), which are mainly associated with mitochondrial ATP
synthesis coupled electron transport, and which were enriched in the oxidative
phosphorylation pathway. Other DEGs were associated with DNA replication
(PRIM1, MCM3, and RNASEH2A),
cell surface receptor-linked signal transduction and the enzyme-linked receptor
protein signaling pathway (MAPK1, STAT3,
RAF1, and JAK1), and regulation of the
cytoskeleton and phosphatidylinositol signaling system (PIP5K1B,
PIP5K1C, and PIP4K2B). Our findings suggest that
DEGs encoding subunits of NADH, PRIM1, MCM3, MAPK1, STAT3, RAF1, and JAK1 might be
associated with the development of lung adenocarcinoma.
Lung adenocarcinoma; Pathogenesis; Differentially expressed genes; Protein-protein interaction; Network module
Although the heart is one of the body’s vital organs, with an abundant blood supply, metastasis to the heart is considered rare. In a previous study, we found that the myocardial microenvironment might contain a low molecular weight natural tumour suppressor. The present study was designed to investigate the inhibitory effect of cardiac myocyte–conditioned medium (cmcm) on the growth of A549 human lung adenocarcinoma cells in vitro and in vivo.
An mtt assay was used to detect the inhibition ratio with respect to A549 proliferation. Human lung adenocarcinoma cells (A549 cell strain) were transplanted subcutaneously into nude mice to produce tumours. The xenograft tumour growth in mice was observed after selected drug administration.
After treatment with cmcm and cisplatin (Cis), A549 cell viability significantly declined (p < 0.001). The cell viability in the cmcm and Cis groups were 53.42% ± 3.45% and 58.45% ± 6.39% respectively. Growth of implanted tumour cells in vivo was significantly inhibited in the cmcm group, the group treated with recombinant human adenovirus–p53, and the Cis-treated group compared with a control group. The inhibition rates were 41.44% in the cmcm group, 41.34% in the p53 group, and 64.50% in the Cis group. Lung metastasis capacity was significantly reduced in the presence of cmcm (p < 0.05). Lung metastasis inhibition rates in mice were 56.52% in the cmcm group, 47.83% in the p53 group, and 82.61% in the Cis group. With cmcm, the lives of A549-tumour-bearing mice could be significantly prolonged without any effect on weight loss.
Use of cmcm has the effect of reducing A549 cell viability, tumour volume, and lung metastasis rate, while prolonging survival duration without severe toxicity.
Cardiac myocyte–conditioned medium; lung adenocarcinoma; nude mice; tumour inhibition; metastasis
Here, we present the basic concept and theoretical framework of a scientific hypothesis called Cancer Evolution–Development (“Cancer Evo-Dev”), based on our recent studies of the molecular mechanisms by which chronic infection with the hepatitis B virus induces hepatocarcinogenesis, together with related advances in that field. Several aspects central to our hypothesis are presented:
■ Immune imbalance—caused by the interaction of genetic predispositions and environmental exposures such as viral infection—is responsible for the maintenance of chronic non-resolving inflammation. Non-resolving inflammation promotes the occurrence and progression of cancers, characterized by an evolutionary process of “mutation–selection–adaptation” for both viruses and host cells.■ Under a microenvironment of non-resolving inflammation, proinflammatory factors promote mutations in viral or host genomes by transactivation of the expression of cytidine deaminases and their analogues. Most cells with genomic mutations and mutated viruses are eliminated in the competition for survival in the inflammatory microenvironment. Only a small percentage of the mutated cells that alter their survival signal pathways and exhibit the characteristics of “stem-ness” can survive and function as cancer-initiating cells.■ Cancers generally develop with properties of “backward evolution” and “retro-differentiation,” indicating the indispensability of stem-like signal pathways in the evolution and development of cancers.
The hypothesis of Cancer Evo–Dev not only lays the theoretical foundation for understanding the mechanisms by which inflammation promotes the development of cancers, but also plays an important role in specific prophylaxis, prediction, early diagnosis, and targeted treatment of cancers.
Hepatocarcinogenesis; evolution; inflammation; hepatitis B virus; mutations
In this paper, symmetric and asymmetric tapering on the arms of the gammadion nanostructure is proposed to enhance both local field distribution and extinction difference (ED). The asymmetric tapered gammadion with tapering fraction (TF) of 0.67 is seen to have the largest ED and spatial local field distribution, producing a large wavelength shift of more than 50 percent as compared to the untapered gammadion nanostructures when immersed in a solution of actin molecules and filaments. The optical chirality, ζ shows that the larger local field amplitudes produced by the asymmetric designs increases the rate of chiral molecules excitation. This enhanced field is strongly rotating and highly sensitive to single molecules and larger filaments. Here, we show that the ED, optical chirality, sensitivity and rate of chiral molecules excitation can be improved by incorporating asymmetric designs into chiral gammadion nanostructures through tapering.
BACKGROUND AND PURPOSE
Buprenorphine is a potent analgesic with high affinity at μ, δ and κ and moderate affinity at nociceptin opioid (NOP) receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogues with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays.
Compounds were tested for binding affinity and functional activity using [35S]GTPγS binding at each receptor and a whole-cell fluorescent assay at μ receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice.
BU08073 bound with high affinity to all opioid receptors. It had virtually no efficacy at δ, κ and NOP receptors, whereas at μ receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade was not evident at 1 h post-treatment, but is present at 6 h and remains for up to 3–6 days.
CONCLUSIONS AND IMPLICATIONS
These studies provide structural requirements for synthesis of ‘universal’ opioid ligands. BU08073 had high affinity for all the opioid receptors, with moderate efficacy at μ receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. However, in vivo, BU08073 had long-lasting antagonist activity, indicating that its pharmacokinetics determined both the time course of its effects and what receptor-mediated effects were observed.
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Dysregulated cell cycle progression has a critical role in tumorigenesis. Cell division cycle 27 (CDC27) is a core subunit of the anaphase-promoting complex/cyclosome, although the specific role of CDC27 in cancer remains unknown. In our study, we explored the biological and clinical significance of CDC27 in colorectal cancer (CRC) growth and progression and investigated the underlying molecular mechanisms. Results showed that CDC27 expression is significantly correlated with tumor progression and poor patient survival. Functional assays demonstrated that overexpression of CDC27 promoted proliferation in DLD1 cells, whereas knockdown of CDC27 in HCT116 cells inhibited proliferation both in vitro and in vivo. Further mechanistic investigation showed that CDC27 downregulation resulted in G1/S phase transition arrest via the significant accumulation of p21 in HCT116 cells, and the upregulation of CDC27 promoted G1/S phase transition via the attenuation of p21 in DLD1 cells. Furthermore, we also demonstrated that CDC27 regulated inhibitor of DNA binding 1 (ID1) protein expression in DLD1 and HCT116 cells, and rescue assays revealed that CDC27 regulated p21 expression through modulating ID1 expression. Taken together, our results indicate that CDC27 contributes to CRC cell proliferation via the modulation of ID1-mediated p21 regulation, which offers a novel approach to the inhibition of tumor growth. Indeed, these findings provide new perspectives for the future study of CDC27 as a target for CRC treatment.
MRI-guided radiotherapy is particularly attractive for abdominal targets with low CT contrast. To fully utilize this modality for pancreas tracking, automated segmentation tools are needed. A hybrid gradient, region growth and shape constraint (hGReS) method to segment two-dimensional (2D) upper abdominal dynamic MRI (dMRI) is developed for this purpose.
2D coronal dynamic MR images of two healthy volunteers were acquired with a frame rate of 5 frames per second. The regions of interest (ROIs) included the liver, pancreas and stomach. The first frame was used as the source where the centres of the ROIs were manually annotated. These centre locations were propagated to the next dMRI frame. Four-neighborhood region transfer growth was performed from these initial seeds before refinement using shape constraints. Results from hGReS and two other automated segmentation methods using integrated edge detection and region growth (IER) and level set, respectively, were compared with manual contours using Dice's index (DI).
For the first patient, the hGReS resulted in the organ segmentation accuracy as a measure by the DI (0.77) for the pancreas, superior to the level set method (0.72) and IER (0.71). The hGReS was shown to be reproducible on the second subject, achieving a DI of 0.82, 0.92 and 0.93 for the pancreas, stomach and liver, respectively. Motion trajectories derived from the hGReS were highly correlated to respiratory motion.
We have shown the feasibility of automated segmentation of the pancreas anatomy on dMRI.
Advances in knowledge:
Using the hybrid method improves segmentation robustness of low-contrast images.
This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.
Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day).
Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses.
The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.
Gefitinib; irinotecan; bioavailability; phase I; refractory solid tumors
Sonic hedgehog (Shh) signaling is critical during normal development, and the abnormal activation of the Shh pathway is involved in many human cancers. As a target gene of the Shh pathway and as a transcription activator downstream of Shh signaling, Gli1 autoregulates and increases Shh signaling output. Gli1 is one of the key oncogenic factors in Shh-induced tumors such as medulloblastoma. Gli1 is posttranslationally modified, but the nature of the active form of Gli1 was unclear. Here we identified a Src family kinase Hck as a novel activator of Gli1. In Shh-responsive NIH3T3 cells, Hck interacts with Gli1 and phosphorylates multiple tyrosine residues in Gli1. Gli1-mediated target gene activation was significantly enhanced by Hck with both kinase activity-dependent and -independent mechanisms. We provide evidence showing that Hck disrupts the interaction between Gli1 and its inhibitor Sufu. In both NIH3T3 cells and cerebellum granule neuron precursors, the Hck gene is also a direct target of Gli1. Therefore, Gli1 and Hck form a positive feedback loop that amplifies Shh signaling transcription outcomes. In Shh-induced medulloblastoma, Hck is highly expressed and Gli1 is tyrosine phosphorylated, which may enhance the tumorigenic effects of the Gli1 oncogene. RNAi-mediated inhibition of Hck expression significantly repressed medulloblastoma cell growth. In summary, a novel positive feedback loop contributes to maximal Gli1 oncogenic activities in Shh-induced tumors such as medulloblastoma.
Superconductor is a compelling plasmonic medium at terahertz frequencies owing to its intrinsic low Ohmic loss and good tuning property. However, the microscopic physics of the interaction between terahertz wave and superconducting plasmonic structures is still unknown. In this paper, we conducted experiments of the enhanced terahertz transmission through a series of superconducting NbN subwavelength hole arrays, and employed microscopic hybrid wave model in theoretical analysis of the role of hybrid waves in the enhanced transmission. The theoretical calculation provided a good match of experimental data. In particular, we obtained the following results. When the width of the holes is far below wavelength, the enhanced transmission is mainly caused by localized resonance around individual holes. On the contrary, when the holes are large, hybrid waves scattered by the array of holes dominate the extraordinary transmission. The surface plasmon polaritions are proved to be launched on the surface of superconducting film and the excitation efficiency increases when the temperature approaches critical temperature and the working frequency goes near energy gap frequency. This work will enrich our knowledge on the microscopic physics of extraordinary optical transmission at terahertz frequencies and contribute to developing terahertz plasmonic devices.
The small intestine has been considered inaccessible for a long term. The development of single-balloon endoscopy has greatly improved the diagnosis and treatment possibilities for small intestinal diseases.
In this study, we aimed to explore the demographic characteristics and small intestinal diseases of patients who underwent single-balloon enteroscopy between 2009 and 2014 at our endoscopy center. We determined the enteroscopic findings for each small intestinal disease and the most susceptible age groups.
In total, 186 patients were included in the study. Their mean age was 45.87 ± 15.77 years. Patients who underwent single-balloon enteroscopy were found to have neoplasms (most common age group: 14–45 years, most common lesion location: jejunum), lymphoma (46–59 and 60–74 years, ileum), protuberant lesions (45–59 years, jejunum), inflammation (14–45 and 46–59 years, ileum), benign ulcers (14–45 years, jejunum), diverticulum (14–45 years, ileum), vascular malformations (60–74 years, jejunum), polyps (14–45 years, jejunum), Crohn's disease (14–45 years, jejunum), hookworm infection (14–45 years, jejunum), lipid pigmentation (14–45 and 46–59 years, jejunum), undetermined bleeding (46–59 years, ileum), or undetermined stenosis (31 years, duodenum). Each small intestinal disease had distinct enteroscopic findings.
Optical clocks have been the focus of science and technology research areas due to their capability to provide highest frequency accuracy and stability to date. Their superior frequency performance promises significant advances in the fields of fundamental research as well as practical applications including satellite-based navigation and ranging. In traditional optical clocks, ultrastable optical cavities, laser cooling and particle (atoms or a single ion) trapping techniques are employed to guarantee high stability and accuracy. However, on the other hand, they make optical clocks an entire optical tableful of equipment, and cannot work continuously for a long time; as a result, they restrict optical clocks used as very convenient and compact time-keeping clocks. In this article, we proposed, and experimentally demonstrated, a novel scheme of optical frequency standard based on comb-directly-excited atomic two-photon transitions. By taking advantage of the natural properties of the comb and two-photon transitions, this frequency standard achieves a simplified structure, high robustness as well as decent frequency stability, which promise widespread applications in various scenarios.
Spin Hall effect of light is a spin-dependent transverse shift of optical beam propagating along a curved trajectory, where the refractive index gradient plays a role of the electric field in spin Hall effect of solid-state systems. In order to observe optical spin Hall shift in a refraction taking place at air-glass interface, an amplification technique was necessary such as quantum weak measurement. In phase-discontinuity metasurface (PMS) a rapid phase-change along metasurface takes place over subwavelength distance, which leads to a large refractive index gradient for refraction beam enabling a direct detection of optical spin Hall shift without amplification. Here, we identify that the relative optical spin Hall shift depends on incidence angle at PMS, and demonstrate a control of optical spin Hall shift by constructing weak value measurement with a variable phase retardance in the post-selection. Capability of optical spin Hall shift control permits a tunable precision metrology applicable to nanoscale photonics such as angular momentum transfer and sensing.
Activation of cyclin E1, a key regulator of the G1/S cell-cycle transition, has been implicated in many cancers including hepatocellular carcinoma (HCC). Although much is known about the regulation of cyclin E1 expression and stability, its post-transcriptional regulation mechanism remains incompletely understood. Here, we report that nuclear factor 90 (NF90), a double-stranded RNA (dsRNA) binding protein, regulates cyclin E1 in HCC. We demonstrate that NF90 is upregulated in HCC specimens and that suppression of NF90 decreases HCC cell growth and delays G1/S transition. We identified cyclin E1 as a new target of NF90 and found a significant correlation between NF90 and cyclin E1 expression in HCC. The mRNA and protein levels of cyclin E1 were downregulated upon NF90 knockdown. Suppression of NF90 caused a decrease in the half-life of cyclin E1 mRNA, which was rescued by ectopic expression of NF90. Furthermore, NF90 bound to the 3′ untranslated regions (3′UTRs) of cyclin E1 mRNA in vitro and in vivo. Knockdown of NF90 also inhibited tumor growth of HCC cell lines in mouse xenograft model. Moreover, we showed that inhibition of NF90 sensitized HCC cells to the cyclin-dependent kinase 2 (CDK2) inhibitor, roscovitine. Taken together, downregulation of NF90 in HCC cell lines can delay cell-cycle progression, inhibit cell proliferation, and reduce tumorigenic capacity in vivo. These results suggest that NF90 has an important role in HCC pathogenesis and that it can serve as a novel therapeutic target for HCC.
Accumulating evidence suggests that gender affects the incidence and severity of several pulmonary diseases. Previous studies on mice have shown gender differences in susceptibility to naphthalene-induced lung injury, where Clara cell damage was found to occur earlier and to be more extensive in females than in males. However, very little is known about whether there are any gender differences in subsequent lung repair responses. The aim of this study was to investigate whether gender plays an important role in pulmonary regenerative response to naphthalene-induced Clara cell ablation.
Materials and methods
Adult male and female mice were injected with a low, medium, or high dose of naphthalene, and lung tissue regeneration was examined by immunohistochemical staining for cell proliferation marker (Ki-67) and mitosis marker (phosphohistone-3).
Histopathological analysis showed that naphthalene-induced Clara cell necrosis was more prominent in the lungs of female mice as compared to male mice. Cell proliferation and mitosis in both the distal bronchiolar airway epithelium and peribronchiolar interstitium of female mice was significantly greater than that of male mice after treatment with the low and medium doses. However, after treatment with high dose of naphthalene, lung regeneration was delayed in female mice, while male mice mounted a timely regenerative response.
These findings show that there are clear gender differences in naphthalene-induced lung injury and repair.
PMID: 19614675 CAMSID: cams271
Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hematopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
PU.1; MEIS1; MLL leukemia; transcription regulation
The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.