Publisher Correction: Translating genomic data into healthcare practice with the Singapore National Precision Medicine program.
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Published Erratum↗
Biomedical subjects
Xiaoyan Wang
Publications and source records attributed to Xiaoyan Wang.
Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma.
Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) cases are diagnosed at advanced stages, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients requiring aggressive treatment is crucial. We present mutational, transcriptomic, and proteomic studies of 103 Chinese HPSCC patients and observe a higher prevalence and poorer prognosis in males. Estrogen response pathways are up-regulated, and proteins phosphorylated by protein kinase C (PKC) and cyclin-dependent kinases (CDKs) are aberrantly regulated in HPSCC. We identify aberrant copy number regions including SOX2(3q26.33), FGFR(8p11.23), CCND1(11q13.3), CDKN2A/2B(9p21.3), and MYC(8q24.21). Human papillomavirus (HPV) status combined with highly mutated genes, such as SYNE1 in HPV(-) and MUC4 in HPV(+) patients, were assessed as prognosis markers. A predictive model involving clinical factors and expression of six genes was established and cross-site validated. These findings open new opportunities for stratifying high-risk patients and molecular targets for personalized therapeutic strategies.
Humans↗
Reactive oxygen species-dependent hypertension in dopamine D2 receptor-deficient mice.
Dysfunction of D2-like receptors has been reported in essential hypertension. Disruption of D2R in mice (D2-/-) results in high blood pressure, and several D2R polymorphisms are associated with decreased D2R expression. Because D2R agonists have antioxidant activity, we hypothesized that increased blood pressure in D2-/- is related to increased oxidative stress. D2-/- mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D2R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D2-/- mice. Because D2Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D2-/- mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D2-/- mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D2R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D2R function may result in ROS-dependent hypertension.
Aldosterone↗
Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate.
Phyllodes tumor of the prostate is a rare neoplasm with an unpredictable clinical behavior. It may undergo early recurrence with sarcomatous transformation or may even metastasize. Because targeted therapies have shown great success against several malignancies, there is hope that these same therapies may show similar promise in the treatment of other neoplasms. This study was undertaken to investigate both amplification of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridization and the overexpression of EGFR, Her-2/neu, CD117 (c-kit), and androgen receptor by immunohistochemical staining in a series of 11 phyllodes tumors of the prostate. In the stromal elements, EGFR gene amplification was present in four of 11 tumors and polysomy chromosome 7 was present in two of 11 tumors. No amplification was present in the epithelial components. Only one of 11 tumors had polysomy of chromosome 7 in the epithelial components. Immunohistochemically, in the stromal components, EGFR expression was demonstrable in four of 11 tumors and androgen receptor was demonstrated in six of 10 tumors. Neither Her-2/neu nor c-kit expression was seen in the stromal components of any of the 11 tumors. In the epithelial components, EGFR expression was present in all 11 tumors with strong staining in the basal cell layers and weak or no staining in luminal epithelium; androgen receptor expression was seen in seven of 10 tumors; Her-2/neu was weakly positive in four of 11 tumors; and c-kit expression was present focally and weakly in two of 11 cases with only 2-5% of cells staining. The highest staining intensity and the highest percentage of positively staining cells were seen with EGFR immunostaining in both the stromal and epithelial (mainly basal cells) components. Androgen receptor staining showed the next highest staining intensity and percentage of positive cells in both components. Her-2/neu and c-kit were only weakly or infrequently expressed in the epithelial components of prostatic phyllodes tumors. Our data indicate that EGFR and androgen receptor are frequently and strongly expressed in both epithelial and stromal components of prostatic phyllodes tumors. EGFR gene amplification is frequently present in prostatic phyllodes tumors and may account for one of the mechanisms leading to protein overexpression in some but not all cases. Anti-EGFR and/or antiandrogen agents may be potentially useful for management of patients with tumors expressing EGFR and/or androgen receptor.
Adult↗
Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer.
BACKGROUND: An important advance in medical oncology has been the use of adjuvant chemotherapy for lymph node-positive colon cancer. However, to the authors' knowledge, the effect of the interval between surgery and the initiation of chemotherapy on survival has not been investigated. METHODS: The authors analyzed predictors and outcomes of time intervals to treatment after surgery among patients older than 65 years who were diagnosed with stage III colon cancer between 1992 and 1999 using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear and logistic regression analyses were used to model predictors of delay, and Cox proportional hazards models were used to analyze the impact of treatment timing on survival. RESULTS: Among 4382 patients with colon cancer, 1122 patients (26%) began adjuvant chemotherapy within 1 month, 2391 patients (55%) began adjuvant chemotherapy in 1 to 2 months, 454 patients (10%) began adjuvant chemotherapy in 2 to 3 months, and 415 patients (9%) began adjuvant chemotherapy >/=3 months after surgery. Intervals of >/=3 months (delay) were associated with older age, increased comorbid conditions, well/moderately differentiated grade, and being unmarried. Colon cancer-specific mortality was associated with a delay in the initiation of chemotherapy (hazards ratio [HR], 1.48; 95% confidence interval [95% CI], 1.15-1.92), advanced age, increased comorbidity, poorly differentiated tumor grade, the presence of >/=4 positive lymph nodes, and undergoing surgery in a nonteaching hospital. All-cause mortality was associated with intervals >2 months between surgery and chemotherapy (2 to 3 months: HR, 1.41; 95% CI, 1.15-1.74; >/=3 months: HR, 1.62; 95% CI, 1.31-1.99) compared with <1 month. CONCLUSIONS: In the older population that was studied, only 9% of patients initiated adjuvant chemotherapy >3 months after the date of curative surgery. However, delay in initiation was associated with both cancer-specific and all-cause mortality. Determining whether these results were because of chemotherapy timing or other associated factors will require further study.
Age Factors↗
Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response.
Low rates of angiotensin II (Ang II) infusion raise blood pressure, renal vascular resistance (RVR), NADPH oxidase activity, and superoxide. We tested the hypothesis that these effects are ameliorated by extracellular superoxide dismutase (EC-SOD). EC-SOD knockout (-/-) and wild type (+/+) mice were equipped with blood pressure telemeters and infused subcutaneously with Ang II (400 ng/kg per minute) or vehicle for 2 weeks. During vehicle infusion, EC-SOD -/- mice had significantly (P<0.05) higher MAP (+/+: 107+/-3 mm Hg versus -/-: 114+/-2 mm Hg; n=11 to 14), RVR, lipid peroxidation, renal cortical p22(phox) expression, and NADPH oxidase activity. Ang II infusion in EC-SOD +/+ mice significantly (P<0.05) increased MAP, RVR, p22(phox), NADPH oxidase activity, and lipid peroxidation. Ang II reduced SOD activity in plasma, aorta, and kidney accompanied by reduced renal EC-SOD expression. During Ang II infusion, both groups had similar values for MAP (+/+ Ang II: 125+/-3 versus -/- Ang II: 124+/-3 mmHg; P value not significant), RVR, NADPH oxidase activity, and lipid peroxidation. SOD activity in the kidneys of Ang II-infused mice was paradoxically higher in EC-SOD -/- mice (+/+: 8.8+/-1.2 U/mg protein(-1) versus -/-: 13.7+/-1.6 U/mg protein(-1); P<0.05) accompanied by a significant upregulation of mRNA and protein for Cu/Zn-SOD. In conclusion, EC-SOD protects normal mice against oxidative stress by attenuating renal p22(phox) expression, NADPH oxidase activation, and the accompanying renal vasoconstriction and hypertension. However, during an Ang II slow pressor response, renal EC-SOD expression is reduced and, in its absence, renal Cu/Zn-SOD is upregulated and may prevent excessive Ang II-induced renal oxidative stress, renal vasoconstriction, and hypertension.
Angiotensin II↗
Delay in initiating adjuvant radiotherapy following breast conservation surgery and its impact on survival.
PURPOSE: Delays in the diagnosis of breast cancer are associated with advanced stage and poor survival, but the importance of the time interval between lumpectomy and initiation of radiation therapy (RT) has not been well studied. We investigated factors that influence the time interval between lumpectomy and RT, and the association between that interval and survival. PATIENTS AND METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database on women aged 65 years and older, diagnosed with Stages I-II breast cancer, between 1991 and 1999. Among patients who did not receive chemotherapy, we studied factors associated with the time interval between lumpectomy and the initiation of RT, and the association of delay with survival, using linear regression and Cox proportional hazards modeling. RESULTS: Among 24,833 women with who underwent lumpectomy, 13,907 (56%) underwent RT. Among those receiving RT, 97% started treatment within 3 months; older age, black race, advanced stage, more comorbidities, and being unmarried were associated with longer time intervals between surgery and RT. There was no benefit to earlier initiation of RT; however, delays >3 months were associated with higher overall mortality (hazard ratio, 1.92; 95% confidence interval, 1.64-2.24) and cancer-specific mortality (hazard ratio, 3.84; 95% confidence interval 3.01-4.91). CONCLUSIONS: Reassuringly, early initiation of RT was not associated with survival. Although delays of >3 months are uncommon, they are associated with poor survival. Whether this association is causal or due to confounding factors, such as poor health behaviors, is unknown; until it is better understood, efforts should be made to initiate RT in a timely fashion.
Aged↗
Protective effect of flavonoids from Scutellaria baicalensis Georgi on cerebral ischemia injury.
The protective effect of flavonoids extracted from Scutellaria baicalensis Georgi on cerebral ischemia injury has been explored in experimental animals. Scutellaria flavonoid (SF) could significantly prolong gasping time (prolonged ratio, 23.79%) and survival time after carotid artery occlusion, and decrease attenuate malondialdehyde (MDA) content in damaged brain tissues from 118.56+/-47.95 nmol/g in untreated to 199.29+/-24.24 nmol/g. SF could also increase the content of superoxide dismutase (SOD) in brain tissues after ischemic mice from 1486+/-94 NU/g in untreated to 1168+/-76 NU/g, and showed significant protective effect on cerebral hypoxia and reperfusion brain tissues in middle cerebral artery occlusion (MCAO) procedure. Additionally, SF has inhibitory effect on platelet aggregation, with the average inhibition rate of 45.52%, while the aspirin group was 54.96%. These results suggest that SF has a significant protective effect on cerebral ischemia and ischemia-reperfusion induced brain injury.
Animals↗
Enhancing micro-scale membrane extraction by implementing a barrier film.
Hollow fiber based microextraction techniques have shown much promise in the extraction and preconcentration of analytes. Typically, a solvent held in the membrane is used as an extractant (or an acceptor). However, the acceptor also permeates out during long extractions and vigorous agitation. The stabilization of the acceptor is important for high enrichment and good reproducibility. Coating the membrane with a low permeability barrier film can provide diffusional resistance to reduce the outflow of the acceptor. Several compounds were evaluated as potential barrier films. They were found to protect the organic acceptor and significantly enhance extraction performance. In a study with six polycyclic aromatic hydrocarbons (PAHs), enrichment factors ranged between 494 and 4555 were obtained and the detection limits were at low ppb to ppt levels. Good reproducibility with RSDs between 1.60 and 7.65%, and large linear dynamic ranges with good linearity (R2 between 0.9870 and 0.9997) were also achieved.
Chemical Fractionation↗
ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency.
BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1(delta11/delta11)) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca1(delta11/delta11)p53+/- mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca1(delta11/delta11) mice to escape from embryonic lethality. Compared to Brca1(delta11/delta11)p53+/- mice, lifespan of Brca1(delta11/delta11)Chk2-/- mice was remarkably extended. Analysis of Brca1(delta11/delta11)Chk2-/- mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(delta11/delta11)Chk2-/- female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer.
Aging, Premature↗
Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression.
Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.
Animals↗
Duration of adjuvant chemotherapy for colon cancer and survival among the elderly.
PURPOSE: In randomized trials, patients with stage III colon cancer who received 6 months of fluorouracil (FU)-based adjuvant chemotherapy had better survival than patients who did not. However, little is known about the predictors of, or the survival associated with, duration of chemotherapy in the community. PATIENTS AND METHODS: The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify individuals > or = 65 years of age diagnosed with stage III colon cancer between 1995 and 1999. We used logistic and Cox proportional hazards regression models to analyze factors associated with early discontinuation of FU-based chemotherapy among these elderly colon cancer patients. RESULTS: Among 1,722 patients who received 1 to 7 months of FU-based chemotherapy, older age, being unmarried, and having comorbid conditions were associated with receiving less than 5 months of treatment. Among the 1,579 patients who survived > or = 8 months, the 1,091 (69.1%) who received 5 to 7 months of treatment had lower overall (hazard ratio [HR], 0.59; 95%, CI 0.49 to 0.71) and colon cancer-specific (HR, 0.53; 95% CI, 0.43 to 0.66) mortality than the 488 (30.9%) who received 1 to 4 months of treatment. CONCLUSION: More than 30% of elderly patients who initiated FU-based chemotherapy for stage III colon cancer and survived for at least 8 months discontinued treatment early. Mortality rates among such patients were nearly twice as high as among patients who completed 5 to 7 months of treatment. If the association we observed between duration of treatment and survival is confirmed, additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment are responsible.
Age Factors↗
Delay of adjuvant chemotherapy initiation following breast cancer surgery among elderly women.
BACKGROUND: Delay in the diagnosis of breast cancer is associated with worse stage distribution at diagnosis and decreased survival. However, the occurrence of delay in the delivery of adjuvant therapy and its impact on prognosis is not well understood. METHODS: To investigate the timeliness of initiation of adjuvant chemotherapy following surgery for breast cancer, we used data from the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. Among women > or = 65 years diagnosed between 1992 and 1999 with stages I-II breast cancer, we used linear regression and Cox proportional hazards models to investigate the time intervals between surgery and initiation of adjuvant chemotherapy, factors associated with delay, and the effect of delay on survival. RESULTS: Our sample consisted of 5003 women who received adjuvant chemotherapy. Of these, 47% initiated chemotherapy within 1 month, 37% between 1 and 2 months, 6% between 2 and 3 months and 10% >3 months (delay) following surgery. Delay was associated with increasing age, residing in a rural location, being unmarried, earlier tumor stage, hormone receptor positivity, mastectomy, and non-receipt of radiation therapy. Survival did not differ among patients who initiated chemotherapy within 1, 2, or 3 months after surgery. Delay beyond 3 months was, however, associated with increased disease-specific mortality (HR 1.69; 95% CI 1.31-2.19) and overall mortality (HR 1.46; 95% CI 1.21-1.75). CONCLUSIONS: Among older patients, moderate delays in the receipt of adjuvant chemotherapy occur frequently, but long delays (>3 months) are uncommon. While early initiation of therapy is no benefit, significant delays are associated with increased mortality. Whether this reflects the medical impact of the delay of chemotherapy or factors associated with delay is unclear, but until this is clarified, patients should be encouraged to initiate treatment without significant delay.
Age Factors↗
A two-stage linkage analysis of Chinese schizophrenia pedigrees in 10 target chromosomes.
We performed a two-stage linkage scan involving 25 Chinese schizophrenia families, focusing on 10 target chromosomes which have already been the subject of considerable research. We initially genotyped 237 individuals with 186 markers, five candidate regions were then chosen for fine mapping and 49 additional markers were genotyped. In region 1q21-23, a maximum multipoint HLOD (HLOD=2.38) was observed between D1S484 and D1S2705, under the dominant model. In region 5q35, dominant HOLD of 2.36, 2.04, and 2.31 were found at marker D5S2030, D5S408, and D5S2006, respectively. Consistent multipoint results also supported linkage to this region under the same dominant model, with a highest HOLD of 2.47. Furthermore, single-point HLODs (HLOD=1.95 at D22S274, and HLOD=1.91 at D22S1157) were found in region 22q13, under the dominant model. Evidence from these three regions satisfied the criteria for suggestive linkage and should help in identifying schizophrenia susceptibility genes.
China↗
Anti-influenza agents from plants and traditional Chinese medicine.
Influenza is a serious threat to health in all parts of the world. The control and treatment of influenza depends mainly on chemical or biochemical agents and, to date, some anti-influenza agents have been isolated from plants as a result of chemical and pharmacological studies. These agents include a variety of polyphenols, flavonoids, saponins, glucosides and alkaloids. Traditional medicine focuses on the use of herbs and traditional Chinese medicine has performed well in clinical practice and shows a potential in the therapy of influenza and its symptoms. The present paper reviews some constituents and extracts from plants and traditional Chinese medicine with anti-influenza activity.
Antiviral Agents↗
D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure.
Activation of D1-like receptors (D1 and/or D5) induces antioxidant responses; however, the mechanism(s) involved in their antioxidant actions are not known. We hypothesized that stimulation of the D5 receptor inhibits NADPH oxidase activity, and thus the production of reactive oxygen species (ROS). We investigated this issue in D5 receptor-deficient (D5-/-) and wild-type (D5+/+) mice. NADPH oxidase protein expression (gp91(phox), p47(phox), and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARS) were higher in D5-/- than in D5+/+ mice. Furthermore, apocynin, an NADPH oxidase inhibitor, normalized blood pressure, renal NADPH oxidase activity, and plasma TBARS in D5-/- mice. In HEK-293 cells that heterologously expressed human D5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91(phox)), and ROS production. The inhibitory effect of the D5 receptor activation on NADPH oxidase activity was independent of cAMP/PKA but was partially dependent on phospholipase D2. The ability of D5 receptor stimulation to decrease ROS production may explain, in part, the antihypertensive action of D5 receptor activation.
Animals↗
Management of agricultural nonpoint source pollution in China: current status and challenges.
Water quality in China shows an overall trend of deterioration in recent years. Nonpoint source pollution from agricultural and rural regions is the leading source of water pollution. The agricultural nonpoint source pollutants are mainly from fertilization of cropland, excessive livestock and poultry breeding and undefined disposal of daily living wastes in rural areas. Agricultural nonpoint sources contribute the main source of pollution to most watersheds in China, but they are ignored in management strategy and policy. Due to the lack of full understanding of water pollution control and management and the lack of perfect water quality standard systems and practical legislative regulations, agricultural nonpoint source pollution will become one of the biggest challenges to the sustainable development of rural areas and to society as a whole. The system for agricultural nonpoint source pollution control in China should include an appropriate legislation and policy framework, financing mechanisms, monitoring system, and technical guidelines and standards. The management of agricultural nonpoint source pollution requires multidisciplinary approaches that will involve a range of government departments, institutions and the public.
Agriculture↗
Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice.
Dopamine receptors are important in systemic blood pressure regulation. D4 receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D4 receptor-deficient (D4(-/-)) mice and in tenth-generation D4(-/-) mice compared with D4 wild-type (D4(+/+)) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D4(-/-) mice than in D4 littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330+/-53%, n=5) and brain (272+/-69%, n=5) of D4(-/-) mice relative to D4(+/+) mice (kidney: 100+/-12%, n=5; brain: 100+/-32%, n=5). The expression of the receptor in renal membrane was also increased in D4(-/-) mice (289+/-28%, n=8) relative to D4(+/+) mice (100+/-14%, n=10). In contrast, the expression in the heart was similar in the 2 strains. Bolus intravenous injection of angiotensin II type 1 receptor antagonist losartan initially decreased mean arterial pressures to a similar degree in D4(-/-) and D4(+/+) littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D4(+/+) mice, whereas the effect persisted for >45 minutes in D4(-/-) mice. We conclude that the absence of the D(4) receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.
Angiotensin II Type 1 Receptor Blockers↗