Parathyroidectomy slows renal function decline in patients with primary hyperparathyroidism.

PURPOSE: Primary hyperparathyroidism has deleterious effects on health and causes nephrolithiasis and osteoporosis. However, it remains unclear whether parathyroidectomy benefits kidney function among patients with primary hyperparathyroidism. METHODS: In this retrospective study, patients with primary hyperparathyroidism receiving parathyroidectomy in a tertiary medical center between 2003 and 2017 were followed up until December 31 2017, death, or requiring renal replacement therapy. Impact of parathyroidectomy on kidney function was examined using longitudinal estimated glomerular filtration rate (eGFR) change scales: single, average, absolute difference, percent change, annual decline rate, and slope. We applied linear mixed-effect model to determine the effect of parathyroidectomy on kidney function. RESULTS: During study period, 167 patients with primary hyperparathyroidism were identified from 498 parathyroidectomized patients, and finally, 27 patients fulfilled our stringent criteria. Median follow-up duration was 1.50 years (interquartile range 1.05-1.81) before surgery and 2.47 years (1.37-6.43) after surgery. Although parathyroidectomy did not affect amount of proteinuria and distribution of eGFR, parathyroidectomy significantly slowed decline rate of eGFR compared with that before surgery (- 1.67 versus - 2.73 mL/min/1.73 m2/year, p < 0.001). More importantly, parathyroidectomy made more beneficial effects on kidney function in patients with age < 65 years and those without chronic kidney disease or hypertension. CONCLUSIONS: Our study showed that parathyroidectomy slows renal function decline irrespective of age or comorbidities, which offers novel insight into the revision of guidelines for surgical indications in primary hyperparathyroidism. Given small sample size, further large-scale controlled studies are warranted to confirm our findings.

Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.

BACKGROUND: RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival. METHODS: Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used. RESULTS: From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients. CONCLUSION: Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.

Subdural hematoma in diabetic patients.

BACKGROUND AND PURPOSE: Subdural hematoma (SDH) is associated with a high mortality rate. However, the risk of SDH in diabetic patients has not been well studied. The aim of the study was to examine the risk of SDH in incident diabetic patients. METHODS: From a universal insurance claims database of Taiwan, a cohort of 28,045 incident diabetic patients from 2000 to 2005 and a control cohort of 56,090 subjects without diabetes were identified. The incidence and hazard ratio of SDH were measured by the end of 2010. RESULTS: The mean follow-up years were 7.24 years in the diabetes cohort and 7.44 years in the non-diabetes cohort. The incidence of SDH was 1.57-fold higher in the diabetes cohort than in the non-diabetes cohort (2.04 vs. 1.30 per 1000 person-years), with an adjusted hazard ratio of 1.63 [95% confidence interval (CI) 1.43-1.85]. The stratified data showed that adjusted hazard ratios were 1.51 (95% CI 1.28-1.77) for traumatic SDH and 1.89 (95% CI 1.52-2.36) for non-traumatic SDH. The 30-day mortality rate for those who developed SDH in the diabetes cohort was 8.94%. CONCLUSIONS: This study demonstrates that incident diabetic patients are at higher risk of SDH than individuals without diabetes. Proper intervention for diabetic patients is necessary for preventing the devastating disorder.

Angiotensin II receptor blocker prevents upper gastrointestinal bleeding in hypertensive patients with chronic kidney disease not on dialysis.

AIMS: Investigate if angiotensin II receptor blocker (ARB) decreases risk of upper gastrointestinal bleeding (UGIB) in hypertensive patients with chronic kidney disease (CKD) not on dialysis. METHODS: All hypertensive patients with CKD not on dialysis in outpatient department of China Medical University Hospital from 2003 to May 2013 were enrolled. The risk of UGIB was analysed using Cox proportional hazard regression. RESULTS: A total of 2744 hypertensive CKD patients including 1515 male and 1229 female, aged 64.9 ± 13.8 years old in a median of 1.9 (0.9-3.9) years were analysed. The incidence of UGIB was 4.5 per 100 patient-years. ARB was associated with a decreased risk of UGIB (p < 0.001) with an adjusted hazard ratio (HR) of 0.533 [95% confidence interval (CI) 0.404-0.703]. A history of UGIB, Helicobacter pylori infection, diabetes, lower estimated glomerular filtration rate, elevated blood urea nitrogen and decreased serum albumin were independently associated with an increased risk of UGIB. CONCLUSIONS: Angiotensin II receptor blocker is associated with a decreased risk of UGIB in hypertensive CKD patients not on dialysis, independent of their renal function, history of gastrointestinal bleeding and nutrition status.

Three-dimensional power Doppler ultrasound in cervical carcinoma: monitoring treatment response to radiotherapy.

OBJECTIVES: To investigate, using three-dimensional power Doppler ultrasound (3D-PDU), alterations in cervical intratumoral vascularization during and after radiotherapy. METHODS: Between 2004 and 2009 we enrolled into the study 37 patients with FIGO Stages IB1-IIB cervical carcinoma who were undergoing radiotherapy. Serial 3D-PDU scans were performed during treatment, providing ultrasonographic measurement of tumor size, vascularization index, flow index and vascularization flow index, as well as monthly for 3 months post-treatment and tri-monthly thereafter, until vascularity was undetectable on two consecutive occasions. Physical examination, cervical cytology and serum marker evaluation were performed every 3-6 months for the first 5 years following treatment. Patients evaluated after a 2-year tumor-free interval and those with clinically assessed positive findings at follow-up underwent 3D-PDU to detect possible local disease. RESULTS: A total of 329 3D-PDU scans were performed in the 37 women. Cervical tumors and intratumoral vascularization disappeared within 3 months following radiotherapy, except in one patient with persistent disease. Nine patients had disease relapse, in four of whom the recurrence was local. In three of these four, there was recurrence of tumor and vascularization after a complete response. At follow-up, 3D-PDU detected local disease with 75.0% sensitivity and 98.5% specificity, while serum markers detected local disease among 34 patients with squamous cell carcinoma with 20.0% sensitivity and 77.3% specificity. CONCLUSIONS: Compared with serum markers in cervical squamous cell carcinoma, 3D-PDU has higher sensitivity and specificity for detecting local recurrence or persistence in cervical carcinoma. Thus, 3D-PDU combined with clinical assessment may be a new and safe method for monitoring radiotherapy treatment response and detecting local recurrence.

A bacteria injection scheme for in situ bioaugmentation.

This article presents an innovative design for inoculating the desired organisms to stratified geological layers at desired rates during in-situ bioaugmentation. The new delivery system consists of intermittent porous tubes connected in series with impermeable polyethylene tubes that run horizontally in each stratified layer of a contaminated aquifer. A bioaugmentation test using the new delivery system was conducted to inject an enriched culture of Escherichia coli (E. coli). Results of the test indicated that the distribution of E. coli through each porous tube was fairly uniform. A mathematical model previously developed to calculate the distribution of water flow through each porous tube was modified to calculate the distribution of E. coli. Geological layers often have different hydraulic conductivities. By controlling the permeability and the length of porous tubes placed in stratified layers, the new design provides a means to selectively deliver aqueous bacteria to various layers at desired rates according to aquifer heterogeneity.

Comparison of the GlideScope® videolaryngoscope and the Macintosh laryngoscope for double-lumen tube intubation.

Intubation with a double-lumen tube is important for achieving one-lung ventilation and facilitating thoracic surgery. The GlideScope(®) videolaryngoscope (Verathon Inc., Bothell, WA, USA) is designed to assist tracheal intubation for patients with a difficult airway. We wished to compare the GlideScope and direct laryngoscopy for double-lumen tube intubation. Sixty adult patients requiring a double-lumen tube for thoracic surgery and predicted uncomplicated laryngoscopy were randomly assigned to a direct Macintosh laryngoscopy group (n = 30) or a GlideScope group (n = 30). The mean (SD) duration of intubation was longer in the Macintosh group (62.5 (29.7) s) than in the GlideScope group (45.6 (10.7) s; p = 0.007). There was no difference in the success of the first attempt at intubation (26/30 (87%) and 30/30 (100%) for Macintosh and GlideScope groups, respectively; p = 0.112). The incidence of sore throat and hoarseness was higher in the Macintosh group (18 (60%) and 14 (47%), respectively) than in the GlideScope group (6 (20%) and 4 (13%), respectively; p = 0.003 and 0.004). We conclude that double-lumen tube intubation in patients with predicted normal laryngoscopy is easier using the GlideScope videolaryngoscope than the Macintosh laryngoscope.

Design, evaluation and initial imaging results of a PET insert based on strip-line readout for simultaneous PET/MRI.

We present the development of a PET insert system for potential simultaneous PET/MR imaging using a 9.4 T small animal MRI scanner to test our system. The detectors of the system adopt a strip-line based multiplexing readout method for SiPM signals. In this readout, multiple SiPM outputs in a row share a common strip-line. The position information about a hit SiPM is encoded in the propagation time difference of the signals arriving at the two ends of the strip-line. The use of strip-lines allows us to place the data acquisition electronics remotely from the detector module to greatly simplify the design of the detector module and minimize the mutual electromagnetic interference. The prototype is comprised of 14 detector modules, each of which consists of an 8x4 LYSO scintillator array (each LYSO crystal is 3x3x10 mm3) coupled to two units of Hamamatsu MPPC arrays (4x4, 3.2 mm pitch) that are mounted on a strip-line board. On the strip-line board, outputs of the 32 SiPMs are routed to 2 strip-lines so that 16 SiPM signals share a strip-line. The detector modules are installed inside a plastic cylindrical supporting structure with an inner and outer diameter of 60 mm and 115 mm, respectively, to fit inside a Bruker BioSpec 9.4 Tesla MR scanner. The axial field of view of the prototype is 25.4 mm. The strip-lines were extended by using 5-meter cables to a sampling data acquisition (DAQ) board placed outside the magnet. The detectors were not shielded in the interest of investigating how they may affect and be affected by the MRI. Experimental tests were conducted to evaluate detection performance, and phantom and animal imaging were carried out to assess the spatial resolution and the MR compatibility of the PET insert. Initial results are encouraging and demonstrate that the prototype insert PET can potentially be used for PET/MR imaging if appropriate shielding will be implemented for minimizing the mutual interference between the PET and MRI systems.

The relationship between chronic hepatitis B infection and bone mineral, metabolism in peritoneal dialysis patients.

OBJECTIVE: Abnormality of bone mineral metabolism is a common complication in chronic liver disease and/or chronic renal disease patients. We designed this study to evaluate the relationship between chronic hepatitis B infection and bone mineral metabolism in peritoneal dialysis patients. PATIENTS AND METHODS: Serum calcium[adj], phosphorus, calcium and phosphorus product (Ca x P), along with intact parathyroid hormone (iPTH) levels were compared in peritoneal dialysis patients with and without chronic hepatitis B infection. RESULTS: A total of 220 patients (142 female, 78 male) with a mean age of 56.30 +/- 14.28 (range 19 - 86) years old were recruited, 23 showed chronic hepatitis B infection and 197 showed none. No statistically significant difference in serum calcium[adj] levels (9.90 +/- 0.85 mg/dl vs. 10.08 +/- 0.80 mg/dl, p = 0.354), phosphorus levels (5.26 +/- 1.58 mg/dl vs. 5.21 +/- 1.35 mg/dl, p = 0.879) and calcium and phosphorus product (Ca x P) (52.23 +/- 17.54 mg(2)/dl(2) vs. 52.42 +/- 14.16 mg(2)/dl(2), p = 0.960) between groups with and without chronic hepatitis B infection was observed. Serum iPTH levels were significantly lower in chronic hepatitis B patients (median 143 pg/ml, range 3.42 - 889) than in the control group (median 235 pg/ml, range 3 - 2381) (p = 0.035). As analyzed by multi-variable linear regression, chronic hepatitis B was a predictor of lower serum iPTH levels (beta = -0.271; p = 0.030) after adjustments for age, gender, serum calcium and phosphorus levels and diabetes. CONCLUSION: No significant difference in serum calcium[adj]), phosphorus and calcium and phosphorus product (Ca x P) levels appeared between peritoneal dialysis patients with and without chronic hepatitis B infection. Serum iPTH levels proved to be definitely lower in chronic hepatitis B infection patients.

C-reactive protein predicts ischaemic stroke in haemodialysis patients.

Dialysis patients have a higher incidence of cerebrovascular events compared with the general population. However, the value of C-reactive protein (CRP) in predicting stroke in chronic haemodialysis patients is unknown. The aim of this study was to determine the association between serum CRP levels and ischaemic stoke in chronic haemodialysis patients. We retrospectively reviewed 391 chronic haemodialysis patients between November 2001 and November 2004. Patients who developed acute ischaemic stroke within 36-month were recorded. Patients who had lacunar infarction discovered accidentally during brain computed tomography or magnetic resonance imaging scans were recorded for subgroup analysis. The relation of predialysis serum CRP levels, measured via the nephelometric method, to the development of acute ischaemic stroke was analysed using Kaplan-Meier analysis. Factors related to lacunar infarctions were analysed by multivariate logistic regression. Of the 391 patients, 21 developed acute stroke and 24 had lacunar infarction. Kaplan-Meier analysis showed that patients with a serum CRP > 0.8 mg/dl were at risk of developing acute infarction (p = 0.002). In the Cox regression model adjusted for age, cardiovascular disease, hypertension and diabetes, patients with serum CRP > 0.8 mg/dl are at risk of developing acute ischaemic stroke (p = 0.03). In multivariate logistic regression with adjusted for age, hypertension and diabetes, serum CRP levels significantly associated with lacunar infarction (p = 0.05). Serum CRP levels, independent of cardiovascular disease, age, hypertension and diabetes, are associated with the development of acute ischaemic stroke and lacunar infarct in chronic haemodialysis patients.

Hyponatraemia in patients with normal pressure hydrocephalus.

BACKGROUND: In clinical practice, hyponatraemia was frequently found in patients with hydrocephalus. We conducted this study to determine the prevalence and risk factors for hyponatraemia in patients with normal pressure hydrocephalus (NPH). METHODS: We retrospectively reviewed all patients with NPH who were admitted to China Medical University Hospital between 1998 and 2006. Hyponatraemia was defined as a plasma sodium concentration < 135 mEq/l on admission. Possible risk factors between patients with and without hyponatraemia were analysed using Student's t-test or chi2 test. The association between hyponatraemia and possible factors was analysed using multivariate logistic regression. The odds ratio was calculated to determine the effect of possible risk factors. RESULTS: A total of 146 patients (84 men and 62 women) who had NPH with a mean age of 66.1 +/- 15.9 years old were reviewed and 33 (22.6%) patients were found having hyponatraemia. Patients who developed hyponatraemia had a significantly higher prevalence of hypertension, use of nasogastric tube (NG), bed-ridden status and fever. In multivariate logistic regression, the presence of hypertension and the use of NG were two important risk factors for hyponatraemia. The odds ratio (95% CI) for hypertension and NG were 2.604 (95% CI: 1.136-5.967, p = 0.024) and 7.179 (95% CI: 2.3-22.409, p = 0.001) respectively. CONCLUSION: Hyponatraemia is not uncommon in patients with NPH. Physicians should be aware of this complication and obtain necessary laboratory examination for early detection of hyponatraemia.

Clinical implications of insulin-like growth factor 1 system in early-stage cervical cancer.

This study was aimed to identify the expression and the correlation of insulin-like growth factor-1 (IGF-1) system and their prognostic impacts in cervical cancer. Seventy-two patients with early-stage cervical cancer were eligible. We obtained the serum levels of total IGF-1 and IGF binding protein-3 (IGFBP-3) by enzyme-linked immunosorbent assay and the expression of IGF-1 receptor (IGF-1R) in cancerous tissue by immuno-fluorescent (IF) stains. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.003 and P=0.01, respectively) among patients with high-grade expression of tissue IGF-1R, compared with those with low-grade expression. After adjustment for other factors, preoperative serum total IGF-1 or IGFBP-3 levels failed to predict cancer death and recurrence. High-grade expression of IGF-1R and elevated preoperative squamous cell carcinoma antigen level were independent predictors of both death and recurrence, and combination of both factors could further help identify the subgroup of patients at higher death risk. The IF staining indicates the colocalisation of IGF-1 and IGF-1R in the cancerous tissues, whereas the IGF-1R expression is not correlated with circulating levels of IGF-1 or IGFBP-3. In early-stage cervical cancer, IGF-1 system may have a paracrine or autocrine function and the adverse impacts on prognosis by IGF-1R overexpression are implicated.

Anti-inflammatory effects of dimemorfan on inflammatory cells and LPS-induced endotoxin shock in mice.

BACKGROUND AND PURPOSE: Dimemorfan (a sigma1 receptor agonist) showed neuroprotective properties in animal models of inflammation-mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear. EXPERIMENTAL APPROACH: The effects of dimemorfan on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)- induced neutrophils and lipopolysaccharide (LPS)-activated microglial cells, as well as LPS-induced endotoxin shock in mice were elucidated. KEY RESULTS: Dimemorfan decreased PMA- and fMLP-induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of sigma1 receptors, possibly by blocking ROS production and G-protein-mediated intracellular calcium increase. Dimemorfan also inhibited LPS-induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha (TNF-alpha), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up-regulation through interfering with nuclear factor kappa-B (NF-kappaB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg(-1), i.p., at three successive times after LPS) decreased plasma TNF-alpha, and neutrophil infiltration and oxidative stress in the lung and liver. CONCLUSIONS AND IMPLICATIONS: Our results suggest that dimemorfan acts via sigma1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kappaB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro-inflammatory cytokines. These effects may contribute its anti-inflammatory action and protective effects against endotoxin shock in mice.

Association between waist-to-hip ratio and chronic kidney disease in the elderly.

BACKGROUND: To compare the anthropometric indices of obesity and identify which index serves as a better discriminator in the chronic kidney disease (CKD) for the elderly. METHODS: Participants of a 1-day health check, older than 60 years, in our hospital from 2003 to 2005 were enrolled. CKD was defined as estimated glomerular filtration rate by modification of diet in renal disease formula less than 60 mL/min per 1.73 m(2). Indices of obesity include body mass index, waist circumference, waist-to-hip ratio (WHR) and waist-to-height ratio. Traditional risk factors including diabetes, hypertension and metabolic syndrome were also taken into consideration. The accuracy of indices of obesity in predicting CKD was measured by area under the receiver operating characteristic curve (AUC). Association between risk factors was estimated by multivariate logistic regression. RESULTS: We studied 984 participants (537 men and 447 women) with a mean age of 66.7 +/- 5.3 years. A total of 161 (16.4%) participants was found having CKD. In the indices of obesity, WHR showed best diagnostic accuracy in predicting CKD (AUC: 0.58). A WHR cut-off value of 0.88 had a sensitivity of 68.9% and a specificity of 45.4%. The odds ratios were significant for WHR, hypertension and diabetes (P = 0.025, P < 0.001 and P = 0.033). CONCLUSION: In indices of obesity, WHR is better than body mass index, bodyweight and waist circumferences in predicting CKD in elder Taiwanese. Furthermore, the association of WHR and CKD is independent of hypertension and diabetes.

Colloid interaction and pair correlation function of one-dimensional colloid-polymer systems.

The interaction and pair correlation function of weakly charged colloidal particles in quasi-one-dimensional colloid-polymer systems are determined by enhanced video microscopy and digital image analysis. The pair correlation function is found to depend not only on the polymer concentration, but also on the degree of confinement; in particular, it depends on whether the channel width is such that mutual passage of the colloid particles is possible or not. These findings are compared with exact results on short-range order in linear continuous systems.

Volume-sensitive chloride channels associated with human cervical carcinogenesis.

Previous controversy has risen from the purported equivalence of the volume-sensitive chloride channels with P-glycoprotein. The aim of this study was to investigate the association between expression of volume-sensitive Cl- channels and the process of malignant transformation of cervical epithelial cells. We studied the activations of volume-sensitive and cAMP-mediated chloride currents in various human cervical squamous cells that were representative of different stages of cervical carcinogenesis, i.e., normal cervical epithelium, low-grade cervical intraepithelial neoplasia, carcinoma in situ, and invasive carcinoma using the whole-cell patch clamp technique. The volume-sensitive chloride channels, however, were significantly activated only in the four cervical cancer cell lines, primary culture cells of carcinoma in situ, and invasive cancer of the cervix. The expression of volume-sensitive chloride currents was independent of the state of human papillomavirus positivity. When these cells were exposed to hypotonic shock, the cells swelled, and outward rectified chloride currents were observed. These effects were readily reversed by returning the cells to isotonic medium. In addition, 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid, 1,9-dideoxyforskolin, and verapamil reversibly abolished the volume-sensitive Cl- currents. In contrast, none of the cells from normal cervices and human papillomavirus-immortalized cell lines, the in vitro equivalent of low-grade cervical intraepithelial neoplasia, developed substantial chloride currents on exposure to hypotonicity. cAMP-mediated chloride currents were ubiquitously activated in all cervical squamous cells, regardless of the stages of carcinogenesis. This is the first report suggesting an in vivo association between the development of volume-sensitive chloride currents and human carcinogenesis.

Volume-sensitive chloride channels in the primary culture cells of human cervical carcinoma.

Previous study shows volume-sensitive chloride currents are induced by hypotonicity in human cervical cancer cell lines, but not in normal cervical epithelium. To ascertain whether the preferential activation of these channels in cancer cell lines could be similarly and directly detected in cervical cancer tissues, we studied volume-sensitive chloride channels on the primary culture cells of invasive cervical carcinoma using the whole-cell patch-clamp technique. The process of regulatory volume decrease (RVD) was also studied using electronic cell sizing to measure cell volume. Results demonstrate that, in these cultured cells, RVD was mediated in part by chloride loss through the volume-sensitive Cl- channels. A small background current with a slope conductance of 0.32 +/- 0.07 nS/pF at +30 mV (n=60 cells from 10 different samples) was observed. Hypotonicity induced a fast activating and outward rectifying current which was reversed at about 0 mV, and the slope conductance at +30 mV was increased by 10-fold to 3.62 +/- 0.62 nS/pF. These effects were readily reversed by returning the cells to isotonic medium. Moreover, DIDS, NPPB, and 1,9-dideoxyforskolin, reversibly abolished the volume-sensitive Cl- currents. The EC50 required for the inhibitory effect of DIDS, NPPB and 1,9-dideoxyforskolin was 150, 120, and 50 microM, respectively. Volume-sensitive Cl- channels were ubiquitously expressed in cultured cells from 10 samples of different cancer stages, histopathologic types, and state of HPV DNA positivity. Interestingly, similar outward rectifying chloride currents were activated by intracellular 300 microM GTP gamma S. It is proposed that this Cl- conductance may play an important role leading to RVD in human cervical cancer.