TA allele of rs2070673 in the CYP2E1 gene is associated with lobular inflammation and nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E1 is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2E1-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). METHODS: We studied 438 patients with biopsy-proven NAFLD. NASH was defined as NAFLD Activity Score ≥ 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1-333A>T (rs2070673) was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio-plex 200 system to investigate possible mediating factors involved in the process. RESULTS: The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASH (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41-3.78, P < 0.01) or NASH (adjusted odds ratio: 1.82, 95% confidence interval 1.22-2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no-NASH, NASH patients had significantly higher levels of serum interleukin-1 receptor antagonist, interleukin-18, and interferon-inducible protein-10 (IP-10), whereas only IP-10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP-10 was responsible for ~60% of the association between the rs2070672 and NASH. CONCLUSIONS: The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.

catena-Poly[[diaqua-bis-[2-(4-tolyl-sulfanyl)acetato-κO]manganese(II)]-µ-4,4'-bipyridine-κN:N'].

In the polymeric title complex, [Mn(C(9)H(9)O(2)S)(2)(C(10)H(8)N(2))(H(2)O)(2)](n), the Mn(2+) cation and the 4,4'-bipyridine ligand lie on a twofold rotation axis. The cation has an MnN(2)O(4) octa-hedral environment, being coordinated by the O atoms of two water mol-ecules and two monodentate (4-tolyl-sulfan-yl)acetate anions, and by two N atoms of two 4,4'-bipyridine ligands. The latter bridge adjacent cations into linear chains parallel to [010]. The chains are further linked with each other into a two-dimensional network parallel to (100) via inter-molecular O-H⋯O hydrogen bonds.

[Transplantation of large anterior latissimus dorsi muscular flap combination with musculus rectus abdominis flap].

OBJECTIVE: To study the value and surgical techniques of transplantation of large anterior latissimus dorsi muscular flap combination with musculus rectus abdominis flap. METHODS: Three cases (2 male and 1 female) with skin defect and bone exposed were reviewed from May 2005 to January 2007. Two patients suffered from trauma, and 1 suffered from tumor resection. Flaps size were: 60 cm x 32 cm, 55 cm x 30 cm and 50 cm x 25 cm, flaps pattern including: 1 free flap with 2 ends of vascular, 1 flap with pedicle and free vascular end, 1 flap with 2 ends of pedicle. RESULTS: Two flaps survived completely, 1 flap with necrosis edge eventually healed after change of dressing. The infection had been effectively controlled and ready for function recovered. One case caused by trauma recovered with fracture healing, full weight-bearing and restore the original work. CONCLUSIONS: Large anterior latissimus dorsi muscular flap combination with musculus rectus abdominis flap can be used for repair of large skin defect. For the difficulty and technical requirements, surgical indications should be strictly controlled.

[The application of external fixator for complex tissue defect in the forearm].

OBJECTIVE: To discuss the curative effect of the external fixator for complex tissue defect in the forearm. METHODS: From May, 2005 through December, 2008, the external fixators were used in 17 patients to treat the complex tissue defect in the forearm caused by trauma. There were 11 male and 6 female, with a mean age of 25.6. All patients were accompanied with the exposure of tendon, muscle or screw. The skin defect ranged from 7 cm x4 cm to 19 cm x9 cm. All patients underwent pedicle flap repair. The flap ranged from 10 cm x 6 cm to 20 cm x 15 cm. The proximal pedicle of the flap was sutured into a tubular. The position of the pedicle was fixed by the external fixator. The pin was at the ulnar and the iliac (n=5), and the radius and the iliac (n=12). The immobilization lasted 3 to 8 weeks, 5.1 weeks in average. RESULTS: All patients were followed up for 3 to 20 months, 11.3 in average. All pedicle flaps survived with no pressure ulcer, or no erosion in the axilla. No compartment syndrome or osteomyelitis occurred. Four to six week after surgery, the pedicle was cut. Infection occurred at the cutting end in 1 patient. The wound healed after addressing. The wound in the other 16 patients healed successfully. The fracture of the ulnar and the radius healed 8.5 or 15 weeks after surgery, 13.5 weeks in average. Eleven patients underwent second stage reshape and function restoration. The function of the hands and forearms recovered satisfactorily. Eleven patients returned to their work. Six patients can live with basic function for living. CONCLUSIONS: The external fixator used for complex tissue defect in the forearm can keep the position of the pedicle, replacing plaster fixation. It can reduce the incidence of flap and vessel spasm, and get good outcomes.

Complete plastid genome of Holcoglossum tsii (Orchidaceae, Aeridinae) and phylogenetic analysis.

The complete plastid genome of Holcoglossum tsii was determined and analyzed in this work. The plastome was 146,897 bp in length with 83,366 bp of the large single-copy (LSC) region, 11,957 bp of the small single-copy (SSC) region, and 25,787 bp of the invert repeats (IR) regions. The genome contained 127 genes, 74 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Phylogenetic analysis suggested H. tsii is sister to H. rupestre.

Protective Effects and Mechanisms of Shenhua Tablet () on Toll-Like Receptors in Rat Model of Renal Ischemia-Reperfusion Injury.

OBJECTIVES: To investigate the protective effects and potential mechanisms of Shenhua Tablet (, SHT) on the toll-like receptors (TLRs)-mediated signaling pathways in a rat model of kidney ischemia-reperfusion injury (IRI). METHODS: Sixty male Wistar rats were randomly divided into 5 groups: sham surgery, model control, astragaloside (150 mg•kg-1•d-1), low- and high-dose SHT (1.5 and 3.0 g•kg-1•d-1, repectively) groups. One week after drug treatment, rats underwent surgery to establish the IRI models. At 24 h and 72 h after the modeling, serum creatinine (Scr) and blood urea nitrogen (BUN) were analyzed; pathological damage were scored after periodic acid-Schiffstaining. TLR2, TLR4 and myeloid differentiation factor 88 (MyD88) protein and mRNA expressions were detected by inmmunohistochemistry, Western blot and qPCR. Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) protein expressions were detected by enzyme linked immunosorbent assay. RESULTS: Compared with the sham group, the model group exhibited severe change in renal function (Scr: 189.42±21.50, P<0.05), pathological damage (damage score: 4.50±0.55, P<0.05), and the expression levels of TLR2, TLR4, MyD88, TNF-α, IL-6 were significantly higher than other groups. Meanwhile, the levels of TLRs in model group showed upward tendency from 24 to 72 h, unparalleled with pathological and functional changes. The aforementioned parameters were alleviated to a certain extent, and, in addition to TLRs, presented the obvious downward trending from the 24 to 72 h after the intervention in the SHT and astragaloside groups relative to the model (P<0.05); in particular, the most significant mitigation of these changes was observed in the SHT-H group (P<0.05). CONCLUSION: TLRs may be an important spot to treat and research in acute kidney injury. SHT could effectively mitigate renal injuries and promote recovery of IRI injuries through suppression of degeneration induced by up-regulation of TLR2 and TLR4 expression levels in the MyD88-dependent signaling pathway and exhibit some dose dependence.

catena-Poly[[diaqua-[(4-tolyl-sulfan-yl)acetato-κO]cadmium(II)]-µ-4,4'-bipyridine-κN:N'].

The title complex, [Cd(C(9)H(9)O(2)S)(2)(C(10)H(8)N(2))(H(2)O)(2)](n), has a linear chain structure. The central Cd(II) ion is in a slightly disorted octa-hedral environment, coordinated by two aqua ligands, two (4-tolyl-sulfan-yl)acetate ligands and two bridging 4,4'-bipyridine ligands. The Cd(II) ion lies on a twofold rotation axis. Inter-molecular O-H⋯O hydrogen bonds connect adjacent chains, forming a layer structure. An intramolecular O-H⋯O hydrogen bond is also present.

[Endothelial dysfunction and target organ damage in hypertensive patients complicating with or without metabolic syndrome].

OBJECTIVE: To investigate the impacts of metabolic syndrome (MS) on endothelial function and target organ damage in hypertensive patients. METHODS: Patients with essential hypertension (EH) were divided into two groups: hypertension and metabolic syndrome (EH + MS, n = 61), hypertension without metabolic syndrome (EH + nonMS, n = 95) and 31 healthy subjects served as normal control (NC). The change of brachial artery vascular diameter, blood flow volume and vascular resistance after reactive hyperemia were measured by color Doppler ultrasonography. RESULTS: (1) Triglyceride (TG), fasting blood glucose (FBG), body mass index (BMI) were higher in EH + MS group than that in EH + nonMS group (P < 0.05). (2) Endothelium-dependent Dilatation (FMD%) and rate of flow volume of reactive hyperemia were significantly lower in EH + MS group than that in EH + nonMS and NC group [(7.08 +/- 3.21)% vs. (8.18 +/- 1.74)% and (10.41 +/- 4.52)%, P < 0.05 and 0.01 respectively; (154.19 +/- 78.94)% vs. (196.44 +/- 64.22)% and (221.81 +/- 89.64)%, P < 0.05 and 0.01 respectively], while these parameters were similar between EH + nonMS and NC groups (P > 0.05). (3) The high sequence of forearm dilatation capability was also significantly reduced in EH + MS group compared to other groups. (4) The incidences of carotid atherosclerotic plaque and left ventricular hypertrophy (LVH) were significantly increased in EH + MS group compared to EH + nonMS group and NC group. (5) FMD was correlated with age, gender, smoking, SBP, DBP, TG, Fib respectively (P < 0.05). Intima-media thickness (IMT) of carotid artery was positively related with age, smoking, SBP, DBP, BMI, TG, Fib respectively. The left ventricular mass index (LVMI) was positively related with age, smoking, SBP, DBP, BMI, TG respectively. FMD was negatively related with IMT and LVMI respectively (P < 0.01). CONCLUSION: Metabolic syndrome further aggravated endothelial dysfunction and target organ damage in patients with essential hypertension.

[Vascularized pedicle iliac crest for the repair of bone and soft tissue defect of lower extremity].

OBJECTIVE: To study the role of transplantation of the vascularized pedicle iliac crest for the repair of bone and soft tissue defect of lower extremity. METHODS: The vascularized pedicle iliac crest was designed for the repair of bone and soft tissue defect of lower extremity according to anatomic feature of leg and foot. Skin graft was used for coverage of the iliac flap. RESULTS: Skin survival could demonstrate the survival of the vascularized pedicle iliac crest indirectly one week postoperatively. Skin survived completely in 4 cases and partly in 3 cases. Callus was seen at the transplantation site one month postoperatively, and K-wires were removed 4 months later in the cases of metatarsal defect. The external fixators were removed in the cases of tibia defect 6 to 8 months postoperatively. The functions of lower extremities were restored in 2 to 4 months. The bone and soft tissue defects were repaired, and ultimate function and cosmetic effects were satisfied after the mean follow up of 10 months (ranged from 6 to 15 months). CONCLUSION: Transplantation of the vascularized pedicle iliac crest is an ideal method for the repair of bone and soft tissue defect of lower extremity. The operation can be performed in one stage. The functions and cosmetic effects are better than the traditional methods.

Protective effect of salidroside on contrast-induced nephropathy in comparison with N-acetylcysteine and its underlying mechanism.

OBJECTIVE: To study the prevention effect of salidroside on contrast-induced-nephropathy (CIN) and its underlying mechanism. METHODS: A total of 24 Wistar rats were randomly divided into 4 groups with 6 in each group. Rats were firstly administrated with normal saline (control and model groups), N-acetylcysteine (NAC, NAC group) and salidroside (salidroside group) for 7 days before model establishment in each group, respectively. Histopathological analysis was performed by periodic acid-Schiff (PAS) staining. Oxidative stress related parameters including superoxide dismutase (SOD) and methane dicarboxylic aldehyde (MDA), nitric oxide (NO), angiotensin II (Ang II), 8-hydroxy-2'-deoxyguanosine (8-OHdG), mRNA and protein levels of endothelial nitric oxide synthase (eNOS), and nitric oxide synthase (NOS) activity were measured. RESULTS: Compared with the control group, the levels of MDA, Ang II and 8-OHdG were all significantly increased and levels of SOD, NO, and eNOS mRNA and protein were decreased significantly in the model group (P<0.05). Meanwhile, the NOS activity was also significantly decreased in the model group (P<0.05). In addition, the levels of these parameters were all improved in the NAC (P<0.05) and salidroside groups and no significant different was found between these two groups (P>0.05). CONCLUSION: Salidroside can be the potential substitute of NAC to prevent CIN. The underlying mechanism may be associated with oxidative stress damage caused by contrast agents.

A network pharmacology approach to understanding the mechanisms of action of traditional medicine: Bushenhuoxue formula for treatment of chronic kidney disease.

Traditional Chinese medicine (TCM) has unique therapeutic effects for complex chronic diseases. However, for the lack of an effective systematic approach, the research progress on the effective substances and pharmacological mechanism of action has been very slow. In this paper, by incorporating network biology, bioinformatics and chemoinformatics methods, an integrated approach was proposed to systematically investigate and explain the pharmacological mechanism of action and effective substances of TCM. This approach includes the following main steps: First, based on the known drug targets, network biology was used to screen out putative drug targets; Second, the molecular docking method was used to calculate whether the molecules from TCM and drug targets related to chronic kidney diseases (CKD) interact or not; Third, according to the result of molecular docking, natural product-target network, main component-target network and compound-target network were constructed; Finally, through analysis of network characteristics and literature mining, potential effective multi-components and their synergistic mechanism were putatively identified and uncovered. Bu-shen-Huo-xue formula (BSHX) which was frequently used for treating CKD, was used as the case to demonstrate reliability of our proposed approach. The results show that BSHX has the therapeutic effect by using multi-channel network regulation, such as regulating the coagulation and fibrinolytic balance, and the expression of inflammatory factors, inhibiting abnormal ECM accumulation. Tanshinone IIA, rhein, curcumin, calycosin and quercetin may be potential effective ingredients of BSHX. This research shows that the integration approach can be an effective means for discovering active substances and revealing their pharmacological mechanisms of TCM.

Effects of compound Shenhua tablet on renal tubular Na+-K+-ATPase in rats with acute ischemic reperfusion injury.

OBJECTIVE: To observe the effect of Compound Shenhua Tablet (, SHT) on the sodium-potassium- exchanging adenosinetriphosphatase (Na(+)-K(+)-ATPase) in the renal tubular epithelial cells of rats with acute ischemic reperfusion and to investigate the mechanisms underlying the effects of SHT on renal ischemic reperfusion injury (RIRI). METHODS: Fifty male Wistar rats were randomly divided into the sham surgery group, model group, astragaloside group [150 mg/(kg·d)], SHT low-dose group [1.5 g/(kg·d)] and SHT high-dose group [3.0 g/(kg·d)], with 10 rats in each group. After 1 week of continuous intragastric drug administration, surgery was performed to establish the model. At either 24 or 72 h after the surgery, 5 rats in each group were sacrificed, blood biochemistry, renal pathology, immunoblot and immunohistochemical examinations were performed, and double immunofluorescence staining was observed under a laser confocal microscope. RESULTS: Compared with the sham surgery group, the serum creatinine (SCr) and blood urea nitrogen (BUN) levels were significantly increased, Na(+)-K(+)-ATPase protein level was decreased, and kidney injury molecule-1 (KIM-1) protein level was increased in the model group after the surgery (P<0.01 or P<0.05). Compared with the model group, the SCr, BUN, pathological scores, Na(+)-K(+)-ATPase, and the KIM-1 protein level of the three treatment groups were significantly improved at 72 h after the surgery (P<0.05 or P<0.01). And the SCr, BUN of the SHT low- and high-dose groups, and the pathological scores of the SHT high-dose group were significantly lower than those of the astragaloside group (P<0.05). The localizations of Na(+)-K(+)-ATPase and megalin of the model group were disrupted, with the distribution areas overlapping with each other and alternately arranged. The severity of the disruption was slightly milder in three treatment groups compared with that of the model group. The results of immunofluorescence staining showed that the SHT high-dose group had a superior effect as compared with the astragaloside group and the SHT low-dose group. CONCLUSIONS: The SHT effectively alleviated RIRI caused by ischemic reperfusion, promoted the recovery of the polarity of renal tubular epithelial cells, and protected the renal tubules. The therapeutic effects of SHT were superior to those of astragaloside as a single agent.

A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients.

OBJECTIVE: This study compared the efficacy of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in the effect of insulin resistance (IR) as assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) in non-diabetic patients. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched to identify studies published before December 2012 that investigated the use of ARBs and CCBs to determine the effect on the HOMA-IR index in non-diabetics. Parameters on IR and blood pressure were collected. Review Manager 5.2 and Stata 12.0 were used to perform the meta-analysis. Fixed and random effects models were applied to various aspects of the meta-analysis, which assessed the therapeutic effects of the two types of drug using the HOMA-IR index in non-diabetic patients. RESULTS: The meta-analysis included five clinical trials. Patient comparisons before and after treatment with ARBs and CCBs revealed that ARBs reduced the HOMA-IR index (weighted mean difference (WMD) -0.65, 95% confidence interval (CI) -0.93 to -0.38) and fasting plasma insulin (FPI) (WMD -2.01, 95% CI -3.27 to -0.74) significantly more than CCBs. No significant differences in the therapeutic effects of these two types of drug on blood pressure were observed. CONCLUSION: Given that there are no significant differences in the therapeutic effects of ARBs and CCBs on blood pressure, as ARBs are superior to CCBs in their effect on the HOMA-IR index in non-diabetics, they might be a better choice in hypertension patients without diabetes.

Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis.

AIM: To investigate the efficacy and safety of combined antiviral and immunosuppressant therapy in adult hepatitis B virus-associated glomerulonephritis (HBV-GN) patients. METHODS: A computerized literature search was carried out in the PubMed database, Embase, the Cochrane Library, Chinese BioMedical Literature on disc, Chinese Medical Current Contents, Chinese National Knowledge Infrastructure, Wanfang and VIP (Chinese Technological Journal of Database) to collect articles between June 1980 and December 2010 on therapy with immunosuppressants, e.g., glucorticosteroids, mycophenolate mofetil and leflunomide, combined with antivirals, e.g., interferon, lamivudine, entecavir and adefovir dipivoxil, in adult HBV-GN patients. The primary outcomes were remission of proteinuria, clearance of HBV e-antigen, and elevation of serum albumin. The secondary outcomes were blood levels of alanine aminotransferase, serum creatinine, and HBV-DNA titer. Meta-analysis was performed using Review Manager 5.1. Fixed or random effect models were employed to combine the results after a heterogeneity test. The effects of the combined therapy were analyzed for different doses of glucorticosteroid and different types of HBV-GN. RESULTS: Twelve clinical trials with 317 patients were included. A significantly higher incidence of HBV-GN was found in male patients (relative risk = 2.40, 95% CI: 1.98-2.93). Combined therapy reduced the proteinuria significantly with a mean difference of 4.19 (95% CI: 3.86-4.53) and increased the serum albumin concentration significantly with a mean difference of -11.95 (95% CI: -12.97-10.93) without significant alterations of liver function (mean difference: 4.62, 95% CI: -2.55-11.79) and renal function (mean difference: 10.29, 95% CI: 0.14-20.45). No significant activation of HBV-DNA replication occurred (mean difference: 0.12, 95% CI: -0.37-0.62). There was no significant difference between the high dose glucorticosteroid group and the low dose glucorticosteroid group in terms of proteinuria remission (P = 0.76) and between different pathological types of HBV-GN [membranous glomerulonephritis (MN) vs. mesangial proliferative glomerulonephritis, P = 0.68; MN vs membranoproliferative glomerulonephritis, P = 0.27]. CONCLUSION: Combined antiviral and immunosuppressant therapy can improve the proteinuria in HBV-GN patients without altering HBV replication or damaging liver and renal functions.

Effects of Fufang Shenhua Tablet on the expression of toll-like receptors during acute kidney injury induced by ischemia-reperfusion in rats.

OBJECTIVE: To investigate the impact of a traditional Chinese medicinal compound known as Fufang Shenhua Tablet (SHP) on the expression of Toll-like receptors (TLRs) during renal ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) in rats. METHODS: A total of 28 Wistar rats were randomly divided into five groups: (1) pseudo-operation control group, (2) ischemia-reperfusion model group, (3) Astragaloside group, (4) high-dose SHP group, and (5) low-dose SHP group. There were four rats in the pseudo-operation group and six rats in each of the other groups. The accepted ischemia-reperfusion model was established after a 7-day gavage intervention, and pathological changes and renal function were observed, using an enzyme-linked immunosorbent assay (ELISA) to detect interleukin 8 (IL-8) and interferon gamma (IFN-γ) levels, as well as immunohistochemical staining to detect altered levels of TLR2 and TLR4 expression in renal tissue. RESULTS: After 24 h, renal pathological damage and the expression levels of serum creatinine (Scr), IL-8, IFN-γ, TLR2, and TLR4 were significantly higher in the model group as compared with the pseudo-operation group (P<0.05). In addition, at 24 h the above indicators decreased significantly in the Astragaloside group, high-dose SHP group and low-dose SHP group as compared with the ischemia-reperfusion model group (P< 0.05). TLR2 and TLR4 expression levels were significantly reduced in the SHP treatment and Astragaloside group as compared with the pseudo-operation group (P<0.05). Further, the high-dose SHP group showed significantly less renal damage score and decreased levels of TLR expression than those of low-dose SHP group and Astragaloside group (all P<0.05). CONCLUSION: SHP can alleviate the renal structural and functional damage caused by IRI-induced AKI in rats by reducing the damage of renal pathology, which may reduce inflammatory cytokine levels by downregulating the expression of TLRs in renal tissue in a dose-dependent manner.

Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis.

Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.