Expression of microRNAs (miRNAs) is under stringent regulation at both transcriptional and post-transcriptional levels. Disturbance at either level could cause dysregulation of miRNAs. Here we show that MLL fusion proteins negatively regulate production of miR-150, an miRNA widely repressed in acute leukemia, by blocking miR-150 precursors from being processed to mature miRNAs through MYC/LIN28 functional axis. Forced expression of miR-150 dramatically inhibited leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis, likely through targeting FLT3 and MYB and thereby interfering with the HOXA9/MEIS1/FLT3/MYB signaling network, which in turn caused downregulation of MYC/LIN28. Collectively, we revealed a MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1 signaling circuit underlying the pathogenesis of leukemia, where miR-150 functions as a pivotal gatekeeper and its repression is required for leukemogenesis.
miR-150; MLL-associated leukemia; MYC; LIN28; FLT3; MYB; HOXA9; MEIS1; microRNA maturation; signaling axis; leukemogenesis
AIM: To evaluate the feasibility and safety of full robot-assisted gastrectomy with intracorporeal robot hand-sewn anastomosis in the treatment of gastric cancer.
METHODS: From September 2011 to March 2013, 110 consecutive patients with gastric cancer at the authors’ institution were enrolled for robotic gastrectomies. According to tumor location, total gastrectomy, distal or proximal subtotal gastrectomy with D2 lymphadenectomy was fully performed by the da Vinci Robotic Surgical System. All construction, including Roux-en-Y jejunal limb, esophagojejunal, gastroduodenal and gastrojejunal anastomoses were fully carried out by the intracorporeal robot-sewn method. At the end of surgery, the specimen was removed through a 3-4 cm incision at the umbilicus trocar point. The details of the surgical technique are well illustrated. The benefits in terms of surgical and oncologic outcomes are well documented, as well as the failure rate and postoperative complications.
RESULTS: From a total of 110 enrolled patients, radical gastrectomy could not be performed in 2 patients due to late stage disease; 1 patient was converted to laparotomy because of uncontrollable hemorrhage, and 1 obese patient was converted due to difficult exposure; 2 patients underwent extra-corporeal anastomosis by minilaparotomy to ensure adequate tumor margin. Robot-sewn anastomoses were successfully performed for 12 proximal, 38 distal and 54 total gastrectomies. The average surgical time was 272.52 ± 53.91 min and the average amount of bleeding was 80.78 ± 32.37 mL. The average number of harvested lymph nodes was 23.1 ± 5.3. All specimens showed adequate surgical margin. With regard to tumor staging, 26, 32 and 46 patients were staged as I, II and III, respectively. The average hospitalization time after surgery was 6.2 d. One patient experienced a duodenal stump anastomotic leak, which was mild and treated conservatively. One patient was readmitted for intra-abdominal infection and was treated conservatively. Jejunal afferent loop obstruction occurred in 1 patient, who underwent re-operation and recovered quickly.
CONCLUSION: This technique is feasible and can produce satisfying postoperative outcomes. It is also convenience and reliable for anastomoses in gastrectomy. Full robotic hand-sewn anastomosis may be a minimally invasive technique for gastrectomy surgery.
Robotic surgery; Gastric cancer; Total gastrectomy; Esophagojejunal anastomosis
A significant increase in mortality was observed during cold winters in many temperate regions. However, there is a lack of evidence from tropical and subtropical regions, and the influence of ambient temperatures on seasonal variation of mortality was not well documented.
This study included 213,737 registered deaths from January 2003 to December 2011 in Guangzhou, a subtropical city in Southern China. Excess winter mortality was calculated by the excess percentage of monthly mortality in winters over that of non-winter months. A generalized linear model with a quasi-Poisson distribution was applied to analyze the association between monthly mean temperature and mortality, after controlling for other meteorological measures and air pollution.
The mortality rate in the winter was 26% higher than the average rate in other seasons. On average, there were 1,848 excess winter deaths annually, with around half (52%) from cardiovascular diseases and a quarter (24%) from respiratory diseases. Excess winter mortality was higher in the elderly, females and those with low education level than the young, males and those with high education level, respectively. A much larger winter increase was observed in out-of-hospital mortality compared to in-hospital mortality (45% vs. 17%). We found a significant negative correlation of annual excess winter mortality with average winter temperature (rs=-0.738, P=0.037), but not with air pollution levels. A 1 °C decrease in monthly mean temperature was associated with an increase of 1.38% (95%CI:0.34%-2.40%) and 0.88% (95%CI:0.11%-1.64%) in monthly mortality at lags of 0-1 month, respectively.
Similar to temperate regions, a subtropical city Guangzhou showed a clear seasonal pattern in mortality, with a sharper spike in winter. Our results highlight the role of cold temperature on the winter mortality even in warm climate. Precautionary measures should be strengthened to mitigate cold-related mortality for people living in warm climate.
It is well known that ligand binding to the high-affinity GM-CSF receptor (GMR) activates JAK2. However, how and where this event occurs in a cellular environment remains unclear. Here, we demonstrate that clathrin- but not lipid raft-mediated endocytosis is crucial for GMR signaling. Knockdown expression of clathrin heavy chain or intersectin 2 (ITSN2) attenuated GMR-mediated activation of JAK2, whereas inhibiting clathrin-coated pits or plagues to bud off the membrane by the dominant-negative mutant of dynamin enhanced such event. Moreover, unlike the wild-type receptor, an ITSN2-non-binding mutant of GMR defective in targeting to clathrin-coated pits or plagues [collectively referred to as clathrin-coated structures (CCSs) here] failed to activate JAK2 at such locations. Additional experiments demonstrate that ligand treatment not only enhanced JAK2/GMR association at CCSs, but also induced a conformational change of JAK2 which is required for JAK2 to be activated by CCS-localized CK2. Interestingly, ligand-independent activation of the oncogenic mutant of JAK2 (JAK2V617F) also requires the targeting of this mutant to CCSs. But JAK2V617F seems to be constitutively in an open conformation for CK2 activation. Together, this study reveals a novel functional role of CCSs in GMR signaling and the oncogenesis of JAK2V617F.
GM-CSF receptor; Jak2; casein kinase 2; clathrin-coated pit; myeloproliferative disorders
Nolz-1, as a murine member of the NET zinc-finger protein family, is expressed in post-mitotic differentiating neurons of striatum during development. To explore the function of Nolz-1 in regulating the neurogenesis of forebrain, we studied the effects of ectopic expression of Nolz-1 in neural progenitors. We generated the Cre-loxP dependent conditional transgenic mice in which Nolz-1 was ectopically expressed in proliferative neural progenitors. Ectopic expression of Nolz-1 in neural progenitors by intercrossing the Nolz-1 conditional transgenic mice with the nestin-Cre mice resulted in hypoplasia of telencephalon in double transgenic mice. Decreased proliferation of neural progenitor cells were found in the telencephalon, as evidenced by the reduction of BrdU−, Ki67− and phospho-histone 3-positive cells in E11.5–12.5 germinal zone of telencephalon. Transgenic Nolz-1 also promoted cell cycle exit and as a consequence might facilitate premature differentiation of progenitors, because TuJ1-positive neurons were ectopically found in the ventricular zone and there was a general increase of TuJ1 immunoreactivity in the telencephalon. Moreover, clusters of strong TuJ1-expressing neurons were present in E12.5 germinal zone. Some of these strong TuJ1-positive clusters, however, contained apoptotic condensed DNA, suggesting that inappropriate premature differentiation may lead to abnormal apoptosis in some progenitor cells. Consistent with the transgenic mouse analysis in vivo, similar effects of Nozl-1 over-expression in induction of apoptosis, inhibition of cell proliferation and promotion of neuronal differentiation were also observed in three different N18, ST14A and N2A neural cell lines in vitro. Taken together, our study indicates that ectopic expression of Nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation and induces abnormal apoptosis in the developing telencephalon.
MiR-499 is a cardiac-abundant miRNA. However, the biological functions of miR-499 in differentiated cardiomyocytes or in the cardiomyocyte differentiation process is not very clear. Sox6 is believed to be one of its targets, and is also believed to play a role in cardiac differentiation. Therefore, our aim was to investigate the association between Sox6 and miR-499 during cardiac differentiation.
Using a well-established in
vitro cardiomyocyte differentiation system, mouse P19CL6 cells, we found that miR-499 was highly expressed in the late stage of cardiac differentiation. In cells stably transfected with miR-499 (P-499 cells), it was found that miR-499 could promote the differentiation into cardiomyocytes at the early stage of cardiac differentiation. Notably, cell viability assay, EdU incorporation assay, and cell cycle profile analysis all showed that the P-499 cells displayed the distinctive feature of hyperplastic growth. Further investigation confirmed that miR-499 could promote neonatal rat cardiomyocyte proliferation. MiR-499 knock-down enhanced apoptosis in the late differentiation stage in P19CL6 cells, but overexpression of miR-499 resulted in a decrease in the apoptosis rate. Sox6 was identified as a direct target of miR-499 and its expression was detected from day 8 or day 10 of cardiac differentiation of P19CL6 cells. Sox6 played a role in cell viability, inhibited cell proliferation and promoted cell apoptosis in P19CL6 cells and cardiomyocytes. The overexpression of Sox6 could reverse the proliferation and anti-apoptosis effects of miR-499. It was also found that miR-499 might exert its function by regulating cyclin D1 via its influence on Sox6.
miR-499 probably regulates the proliferation and apoptosis of P19CL6 cells in the late stage of cardiac differentiation via its effects on Sox6 and cyclin D1.
The findings on the association between fish intake and the risk of heart failure (HF) have been inconsistent. The purpose of this study was to clarify this potential association. We searched for relevant studies in the PubMed database through January 2012 and manually reviewed references. Five independent prospective cohort studies involving 5,273 cases and 144,917 participants were included. The summary relative risk estimates (SRRE) based on the highest compared with the lowest category of fish consumption were estimated by variance-based meta-analysis. In addition, we performed sensitivity and dose-response analyses to examine the association. Overall, an absence of an association between fish intake and HF was observed (SRRE=1.00; 95% CI, 0.81–1.24). However, fried fish intake positively associated with HF (SRRE=1.40; 95% CI, 1.22–1.61). In addition, dose-response analysis of fried fish suggested that each increment of six fried fish per month corresponded to a 37% increase of HF rate (RR=1.37; 95% CI, 1.20–1.56). In conclusion, our findings suggest that there is no significant association between fish intake and risk of HF, with the exception of a possible positive correlation with individuals comsuming fried fish, based on a limited number of studies. Future studies are required to confirm these findings.
fish; nutrition; heart failure; meta-analysis
Cancer is the result of a complex multistep process that involves the accumulation of sequential alterations of several genes, including those encoding microRNAs (miRNAs) that have critical roles in the regulation of gene expression.
In this study, we aimed to predict potential mechanisms of bladder cancer related miRNAs and target genes by bioinformatics analyses.
Here we used the method of text mining to identify nine miRNAs in bladder cancer and adopted protein-protein interaction analysis to identify interaction sites between these miRNAs and related-target genes.
There are two relationship types between bladder cancer and its related miRNAs: causal and unspecified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment test showed that there were three pathways related to four miRNA targeted genes. The remaining five miRNAs annotated to disease are not enriched in the KEGG pathways. Of these, PIK3R1 is the overlapping gene among 38 genes in the cancer and bladder cancer pathways.
These findings provide new insights into the role of miRNAs in the pathway of cancer and give us a hypothesis that miR-127 might play a similar role in regulation and control of PIK3R1.
Bladder cancer; miRNA; phosphoinositide 3-kinase
The N-(E)-fluorobutenyl-3β-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as 18F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [18F]9-[18F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [18F]9. PET imaging with [18F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min post-injection of [18F]9 the ratio of uptake in the putamen and caudate vs. cerebellum uptake was ≥ 4.
Pigmentation during insect development is a primal adaptive requirement. In the silkworm, melanin is the primary component of larval pigments. The rate limiting substrate in melanin synthesis is tyrosine, which is converted from phenylalanine by the rate-limiting enzyme phenylalanine hydroxylase (PAH). While the role of tyrosine, derived from phenylalanine, in the synthesis of fiber proteins has long been known, the role of PAH in melanin synthesis is still unknown in silkworm. To define the importance of PAH, we cloned the cDNA sequence of BmPAH and expressed its complete coding sequence using the Bac-to-Bac baculovirus expression system. Purified recombinant protein had high PAH activity, some tryptophan hydroxylase activity, but no tyrosine hydroxylase activity, which are typical properties of PAH in invertebrates. Because melanin synthesis is most robust during the embryonic stage and larval integument recoloring stage, we injected BmPAH dsRNA into silkworm eggs and observed that decreasing BmPAH mRNA reduced neonatal larval tyrosine and caused insect coloration to fail. In vitro cultures and injection of 4th instar larval integuments with PAH inhibitor revealed that PAH activity was essential for larval marking coloration. These data show that BmPAH is necessary for melanin synthesis and we propose that conversion of phenylalanine to tyrosine by PAH is the first step in the melanin biosynthetic pathway in the silkworm.
Although many studies have attempted to clarify the association between hepatitis B virus (HBV) infection and fatty liver disease, no prior studies have emphasized the relationship of HBV and fatty liver regarding different demographics of age and body mass index (BMI).
To investigate the correlation of HBV and fatty liver in the different demographics of age and BMI.
We enrolled consecutive subjects who had received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009 and ultrasonography was used to diagnose fatty liver according to the practice guidelines of the American Gastroenterological Association.
Among the 33,439 subjects enrolled in this study, fatty liver was diagnosed in 43.9% of the population and 38.9% of patients with chronic HBV infection. Multivariate analysis showed that BMI, age, waist circumference, systolic blood pressure, fasting glucose, cholesterol, alanine aminotransferase (ALT) levels, and platelet counts were positively associated, while hepatitis B surface antigen (HBsAg) positivity was inversely associated with fatty liver, especially for subjects with BMI>22.4 kg/m2 and age>50 years. On the contrary, HBV infection was positively correlated with the presence of elevated serum ALT levels in subjects with fatty liver disease regardless of their age and BMI.
Metabolic factors are important determinants for the prevalence of fatty liver. Patients with HBV infection were inversely associated with fatty liver disease than the general population, especially in older and obese patients. Furthermore, metabolic factors and HBV infection were associated with elevated serum ALT levels in fatty liver disease.
Replication of hepatitis B virus (HBV) via protein-primed reverse transcription is initiated by binding of the viral P protein to the conserved ε stem-loop on the pregenomic (pg) RNA. This triggers encapsidation of the complex and the ε-templated synthesis of a short P protein-linked DNA oligonucleotide (priming) for subsequent minus-strand DNA extension. ε consists of a lower and upper stem, a bulge containing the priming template, and an apical loop. The nonhelical subelements are considered important for DNA synthesis and pgRNA packaging whereas the role of the upper stem is not well characterized. Priming itself could until recently not be addressed because in vitro generated HBV P - ε complexes showed no activity. Focussing on the four A residues at the base and tip of the upper ε stem and the two U residues in the loop we first investigated the impact of 24 mutations on viral DNA accumulation in transfected cells. While surprisingly many mutations were tolerated, further analyzing the negatively acting mutations, including in a new cell-free priming system, revealed divergent position-related impacts on pgRNA packaging, priming activity and possibly initiation site selection. This genetic separability implies that the ε RNA undergoes multiple distinct interactions with P protein as pgRNA encapsidation and replication initiation progress, and that the strict conservation of ε in nature may reflect its optimal adaptation to comply with all of them. The data further define the most attractive mutants for future studies, including as decoys for interference with HBV replication.
HOXA9 plays a critical role in both normal hematopoiesis and leukemogenesis, particularly in the development and maintenance of mixed lineage leukemia (MLL)-rearranged leukemia. Through reverse transcription polymerase chain reaction (RT-PCR) analysis of HOXA9 transcripts in human leukemia and normal bone marrow samples, we identified a truncated isoform of HOXA9, namely HOXA9T, and found that both HOXA9T and canonical HOXA9 were highly expressed in leukemia cell lines bearing MLL rearrangements, relative to human normal bone marrow cells or other subtypes of leukemia cells. A frameshift in HOXA9T in exon I causes a premature stop codon upstream of the PBX binding domain and the homeodomain, which leads to the generation of a non-homeodomain-containing protein. Unlike the canonical HOXA9, HOXA9T alone cannot transform normal bone marrow progenitor cells. Moreover, HOXA9T cannot cooperate with MEIS1 to transform cells, despite the presence of a MEIS1-binding domain. Remarkably, although the truncated isoforms of many proteins function as dominant-negative competitors or inhibitors of their full-length counterparts, this is not the case for HOXA9T; instead, HOXA9T synergized with HOXA9 in transforming mouse normal bone marrow progenitor cells through promoting self-renewal and proliferation of the cells. Collectively, our data indicate that both truncated and full-length forms of HOXA9 are highly expressed in human MLL-rearranged leukemia, and the truncated isoform of HOXA9 might also play an oncogenic role by cooperating with canonical HOXA9 in cell transformation and leukemogenesis.
HOXA9; HOXA9T; isoforms; leukemia
The transcription factor 7-like 2 (TCF7L2) gene has been suggested to play an important role in the pathogenesis of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between TCF7L2 polymorphism and cancer risk.
Published literature from PubMed and EMBASE were retrieved. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were calculated using fixed- or random-effects model.
A total of 19 studies (14,814 cases and 33,856 controls) were identified for the analysis of the association between TCF7L2 polymorphism and cancer risk. The results showed that TCF7L2 polymorphism was associated with breast cancer (Homogeneous model: OR = 1.17, 95%CI = 1.02–1.35, I2 = 21.8%, p for heterogeneity = 0.276; Heterogeneous model: OR = 1.11, 95%CI = 1.03–1.20, I2 = 0.0%, p for heterogeneity = 0.543), prostate cancer (Homogeneous model: OR = 0.89, 95%CI = 0.84–0.96, I2 = 0.0%, p for heterogeneity = 0.640; Heterogeneous model: OR = 0.89, 95%CI = 0.84–0.95, I2 = 0.0%, p for heterogeneity = 0.871), and colon cancer (Heterogeneous model: OR = 1.15, 95%CI = 1.01–1.31, I2 = 0.0%, p for heterogeneity = 0.658), but not with colorectal cancer, lung cancer, and ovarian cancer.
The present meta-analysis indicated that there were significantly associations between the TCF7L2 rs7903146 polymorphism and risk of breast, prostate and colon cancers, rather than colorectal cancer, lung cancer, and ovarian cancer.
Contrast-induced nephropathy (CIN) is a complex syndrome of acute kidney injury that follows exposure to intravascular contrast media. Although a series of preventive measures have been developed, CIN remains a major challenge encountered in elderly patients by interventional cardiologists. No data are currently available concerning the potential effects of the combined use of hydration and alprostadil in the prevention of CIN following percutaneous coronary intervention (PCI) in elderly patients. Therefore, the aim of the present study was to investigate the ability of a combination of hydration and alprostadil to prevent CIN following PCI in elderly patients. From June 1, 2010 to January 31, 2012, 85 elderly patients undergoing PCI were included in the present study. The included patients were randomly allocated into three groups: the control (22 cases), hydration (28 cases) and hydration + alprostadil (35 cases) group. Serum creatinine (SCr) levels were measured prior to PCI and then daily for 3 days following PCI. Creatinine clearance (Ccr) was also calculated. Following investigation of the incidence of CIN, a significant decline in Ccr was observed in the control group but not in the hydration + alprostadil group after PCI. The reduction in the level of Ccr from baseline in the hydration + alprostadil group was the smallest among the three groups. Moreover, the highest incidence of CIN was in the control group (6 cases, 27.27%), followed by the hydration group (3 cases, 10.71%) and the hydration + alprostadil group (1 case, 2.86%). Therefore, the combined use of hydration and alprostadil significantly reduces the incidence of CIN in elderly patients undergoing PCI. Hydration and alprostadil are suggested to act synergistically to protect renal function. In conclusion, the combined use of hydration and alprostadil is more effective in the prevention of CIN in elderly patients undergoing PCI compared with hydration alone.
alprostadil; percutaneous coronary intervention; contrast-induced nephropathy; elderly patient
Slc26 anion transporters play crucial roles in transepithelial Cl− absorption and HCO3− secretion; Slc26 protein mutations lead to several diseases. Slc26a9 functions as a Cl− channel and electrogenic Cl−-HCO3− exchanger, and can interact with CFTR. Slc26a9(−/−) mice have reduced gastric acid secretion, yet no human disease is currently associated with SLC26A9 coding mutations. Therefore, we tested the function of non-synonymous, coding, single nucleotide polymorphisms (cSNPs) of SLC26A9. Presently, eight cSNPs are NCBI-documented: Y70N, T127N, I384T, R575W, P606L, V622L, V744M and H748R. Using two-electrode voltage-clamp and anion selective electrodes, we measured the biophysical consequences of these cSNPs. Y70N (cytoplasmic N-terminus) displays higher channel activity and enhanced Cl−-HCO3− exchange. T127N (transmembrane) results in smaller halide currents but not for SCN−. V622L (STAS domain) and V744M (STAS adjacent) decreased plasma membrane expression which partially accounts for decreased whole cell currents. Nevertheless, V622L transport is reduced to ~50%. SLC26A9 polymorphisms lead to several function modifications (increased activity, decreased activity, altered protein expression) which could lead to a spectrum of pathophysiologies. Thus, knowing an individual’s SLC26A9 genetics becomes important for understanding disease potentially caused by SLC26A9 mutations or modifying diseases, e.g., cystic fibrosis. Our results also provide a framework to understand SLC26A9 transport modalities and structure-function relationships.
SLC26A9; single nucleotide polymorphisms; voltage clamp; Cl− channel; intracellular pH; Xenopus oocytes
Hepatocellular carcinoma (HCC) is a serious public health issue, the incidence of which is considered to be closely related to tobacco smoking, alcohol consumption, hepatitis B virus (HBV) infection and family history. The DNA repair system is an important protective mechanism against the development of malignant cells induced by internal and external environmental factors. The aim of this study was to investigate the association of polymorphisms of XRCC1-194, XRCC1-280 and XPD-312 DNA repair genes and the risk of development of HCC in Han Chinese patients. A case-control design was used including 252 HCC inpatients and 250 healthy controls recruited and matched by age, gender, tobacco smoking, alcohol consumption, HBV infection and family history. XPD Asp312Asn, XRCC1 Arg194Trp and XRCC1 Arg280His genes were examined using a sequencing assay method. Distributions of the genotype frequency and odds ratio (OR) between the two groups were analyzed. The results demonstrated that there was no significant difference in the frequencies of XPD Asp312Asn, XRCC1 Arg194Trp and XRCC1 Arg280His in the HCC cases and the control group. In the stratified analysis of different allele genotypes, the frequency of the XRCC1-194 site genotype was not significantly different between the case and control group. The presence of the XRCC1 280His genotype was associated with a significantly increased risk of HCC under conditions of HBV infection and family history [OR (95% CI): 1.68 (1.08–2.60), 4.20 (1.34–13.20), respectively]. Similarly, the XPD 312Asn significantly increased the risk of HCC under conditions of alcohol consumption, tobacco smoking, HBV infection and family history [OR (95% CI): 1.67 (1.10–2.60), 1.87 (1.18–2.96), 1.96 (1.24–3.10), 3.40 (1.32–8.76), respectively]. In conclusion, tobacco smoking and alcohol consumption are high risk factors of HCC for the XPD 312Asn genotype; HBV infection and family history increase the risk of HCC for the genotypes XRCC1 280His and XPD 312Asn.
hepatocellular carcinoma; genotype; polymorphisms; susceptibility
Betel quid (BQ) products, with or without tobacco, have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx. There are estimated 600 million BQ users worldwide. In Taiwan alone there are 2 million habitual users (approximately 10% of the population). Oral and pharyngeal cancers result from interactions between genes and environmental factors (BQ exposure). Cytochrome p450 (CYP) families are implicated in the metabolic activation of BQ- and areca nut-specific nitrosamines. In this review, we summarize the current knowledge base regarding CYP genetic variants and related oral disorders. In clinical applications, we focus on cancers of the oral cavity and pharynx and OPMDs associated with CYP gene polymorphisms, including CYP1A1, CYP2A6, CYP2E1, and CYP26B1. Our discussion of CYP polymorphisms provides insight into the importance of screening tests in OPMDs patients for the prevention of oral and pharyngeal cancers. Future studies will establish a strong foundation for the development of chemoprevention strategies, polymorphism-based clinical diagnostic tools (e.g., specific single-nucleotide polymorphism (SNP) “barcodes”), and effective treatments for BQ-related oral disorders.
Urachal carcinoma is a rare tumor that is usually associated with a poor prognosis, especially the pathological type, urachal mucinous adenocarcinoma. Surgery remains the primary treatment in prolonging the overall survival time of patients.
We report on a 41-year-old woman with urachal mucinous adenocarcinoma who underwent three surgeries and several courses of chemotherapy over a 42-month period. The first surgery, involving en-bloc excision of the urachal mass, partial urinary bladder, urachal ligament, and umbilicus was performed in May 2007. It is well known that the correct surgical scheme plays a key role in preventing recurrence or metastasis. However, a second debulking surgery with only a single salpingo-oophorectomy may have contributed directly to the patient’s subsequent left ovarian metastasis. Therefore, we strongly recommend performing a bilateral salpingo-oophorectomy once ovarian metastasis has been detected, even if the metastasis is only present on one side. Although postoperative adjuvant chemotherapy regimens, first with Taxol, carboplatin, gemcitabine, and cisplatin, and then with IFO, EPI, and mesna were consecutively administered after the first and second surgeries, they seemed less effective, since recurrence and metastasis occurred shortly after each surgical treatment. After a third debulking surgery in June 2009, docetaxel, oxaliplatin, and capecitabine were administered. This chemotherapy regimen was chosen based on an immunohistochemical test that involved the multidrug resistance gene; this test indicated that the urachal mucinous adenocarcinoma was resistant to the two chemotherapy regimens used previously. Surprisingly, the patient exhibited a marker response to the new regimen and the metastatic foci entered into a stable disease stage. However, the patient still died of diffuse metastatic disease 1.5 years later. During the whole period of treatment, we found that serum tumor markers including CA724, CA125, CA19-9, and CEA were elevated in a linear pattern, with parallel increases in line with peritoneal carcinomatosis and parallel reductions in line with response to personalized chemotherapy.
Personalized treatment can be given to those patients who experience a poor response to initial therapy. Moreover, an immunohistochemical test for the multidrug resistance gene and serum tumor markers may supply key information in the choice of reasonable chemotherapeutics.
Chemotherapy; Surgery; Urachal carcinoma
Alteration to blood flow in the maternal-fetal compartment has been proposed as a mechanism underlying maternal psychological effects on pregnancy outcomes. This study characterized the progression of umbilical and uterine blood flow resistance in healthy pregnancies and evaluated concurrent and longitudinal associations with maternal anxiety and other psychological factors.
The study assessed participants (n = 107) at five visits spanning 24 to 38 weeks gestation. The resistance index (RI) in the uterine and umbilical arteries was measured with Doppler ultrasound. Maternal psychological function was assessed using validated, self-report instruments.
Hierarchical linear modeling revealed that uterine and umbilical RI decreased during the second half of gestation, and that uterine RI was lower in nulliparous women. Few concurrent associations emerged between psychological factors and RI. Longitudinal analyses determined that psychological well-being was associated with decreased left uterine artery RI, and psychological distress was associated with lower right artery RI.
While uterine artery resistance was modestly associated with the maternal psychological milieu during gestation, our findings do not indicate an association between increased maternal distress and decreased RI. Thus, this study fails to affirm a key component of the hypothesized relation of maternal stress to fetal outcomes via vasoconstriction.
Doppler; maternal anxiety; resistance index; umbilical artery; uterine artery
The nanomechanical properties of BiFeO3 (BFO) thin films are subjected to nanoindentation evaluation. BFO thin films are grown on the Pt/Ti/SiO2/Si substrates by using radio frequency magnetron sputtering with various deposition temperatures. The structure was analyzed by X-ray diffraction, and the results confirmed the presence of BFO phases. Atomic force microscopy revealed that the average film surface roughness increased with increasing of the deposition temperature. A Berkovich nanoindenter operated with the continuous contact stiffness measurement option indicated that the hardness decreases from 10.6 to 6.8 GPa for films deposited at 350°C and 450°C, respectively. In contrast, Young's modulus for the former is 170.8 GPa as compared to a value of 131.4 GPa for the latter. The relationship between the hardness and film grain size appears to follow closely with the Hall–Petch equation.
BiFeO3 thin films; XRD; AFM; Nanoindentation; Hardness
The aim of this study was to assess complex cases of multiple pulmonary nodules (PNs) with high metabolic activity that may have benefited from being managed in a manner outside the formal guidelines. The study describes the case of a patient with multiple highly metabolically-active PNs, where an original diagnosis of lung cancer metastasis was proposed. Following a failed transbronchial lung biopsy (TBLB), multiple nodule biopsies by video-assisted thoracic surgery (VATS) were performed, and a diagnosis of lymphoepithelioma-like carcinoma (LELC; stage IA) and tuberculosis was reached. This case report demonstrated that multiple nodule biopsies by VATS were effective and were able to improve the prognosis without delay.
pulmonary nodules; video-assisted thoracic surgery; lymphoepithelioma-like carcinoma; tuberculosis
Most mammalian genes produce multiple distinct mRNAs through alternative splicing, but the extent of splicing conservation is not clear. To assess tissue-specific transcriptome variation across mammals, we sequenced cDNA from 9 tissues from 4 mammals and one bird in biological triplicate, at unprecedented depth. We find that while tissue-specific gene expression programs are largely conserved, alternative splicing is well conserved in only a subset of tissues and is frequently lineage-specific. Thousands of novel, lineage-specific and conserved alternative exons were identified; widely conserved alternative exons had signatures of binding by MBNL, PTB, RBFOX, STAR and TIA family splicing factors, implicating them as ancestral mammalian splicing regulators. Our data also indicate that alternative splicing often alters protein phosphorylatability, delimiting the scope of kinase signaling.
Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer′s disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention.