[Clinical repair strategy for ischial tuberosity pressure ulcers based on the sinus tract condition and range of skin and soft tissue defects].

Objective: To investigate the clinical repair strategy for ischial tuberosity pressure ulcers based on the sinus tract condition and range of skin and soft tissue defects. Methods: The study was a retrospective observational study. From July 2017 to March 2023, 21 patients with stage Ⅲ or Ⅳ ischial tuberosity pressure ulcers who met the inclusion criteria were admitted to the First Affiliated Hospital of Nanchang University, including 13 males and 8 females, aged 14-84 years. There were 31 ischial tuberosity pressure ulcers, with an area of 1.5 cm×1.0 cm-8.0 cm×6.0 cm. After en bloc resection and debridement, the range of skin and soft tissue defect was 6.0 cm×3.0 cm-15.0 cm×8.0 cm. According to the depth and size of sinus tract and range of skin and soft tissue defects on the wound after debridement, the wounds were repaired according to the following three conditions. (1) When there was no sinus tract or the sinus tract was superficial, with a skin and soft tissue defect range of 6.0 cm×3.0 cm-8.5 cm×6.5 cm, the wound was repaired by direct suture, Z-plasty, transfer of buttock local flap, or V-Y advancement of the posterior femoral cutaneous nerve nutrient vessel flap. (2) When the sinus tract was deep and small, with a skin and soft tissue defect range of 8.5 cm×4.5 cm-11.0 cm×6.5 cm, the wound was repaired by the transfer and filling of gracilis muscle flap followed by direct suture, or Z-plasty, or combined with transfer of inferior gluteal artery perforator flap. (3) When the sinus tract was deep and large, with a skin and soft tissue defect range of 7.5 cm×5.5 cm-15.0 cm×8.0 cm, the wound was repaired by the transfer and filling of gracilis muscle flap and gluteus maximus muscle flap transfer, followed by direct suture, Z-plasty, or combined with transfer of buttock local flap; and transfer and filling of biceps femoris long head muscle flap combined with rotary transfer of the posterior femoral cutaneous nerve nutrient vessel flap; and filling of the inferior gluteal artery perforator adipofascial flap transfer combined with V-Y advancement of the posterior femoral cutaneous nerve nutrient vessel flap. A total of 7 buttock local flaps with incision area of 8.0 cm×6.0 cm-19.0 cm×16.0 cm, 21 gracilis muscle flaps with incision area of 18.0 cm×3.0 cm-24.0 cm×5.0 cm, 9 inferior gluteal artery perforator flaps or inferior gluteal artery perforator adipofascial flaps with incision area of 8.5 cm×6.0 cm-13.0 cm×7.5 cm, 10 gluteal maximus muscle flaps with incision area of 8.0 cm×5.0 cm-13.0 cm×7.0 cm, 2 biceps femoris long head muscle flaps with incision area of 17.0 cm×3.0 cm and 20.0 cm×5.0 cm, and 5 posterior femoral cutaneous nerve nutrient vessel flaps with incision area of 12.0 cm×6.5 cm-21.0 cm×10.0 cm were used. The donor area wounds were directly sutured. The survival of muscle flap, adipofascial flap, and flap, and wound healing in the donor area were observed after operation. The recovery of pressure ulcer and recurrence of patients were followed up. Results: After surgery, all the buttock local flaps, gracilis muscle flaps, gluteus maximus muscle flaps, inferior gluteal artery perforator adipofascial flaps, and biceps femoris long head muscle flaps survived well. In one case, the distal part of one posterior femoral cutaneous nerve nutrient vessel flap was partially necrotic, and the wound was healed after dressing changes. In another patient, bruises developed in the distal end of inferior gluteal artery perforator flap. It was somewhat relieved after removal of some sutures, but a small part of the necrosis was still present, and the wound was healed after bedside debridement and suture. The other posterior femoral cutaneous nerve nutrient vessel flaps and inferior gluteal artery perforator flaps survived well. In one patient, the wound at the donor site caused incision dehiscence due to postoperative bleeding in the donor area. The wound was healed after debridement+Z-plasty+dressing change. The wounds in the rest donor areas of patients were healed well. After 3 to 15 months of follow-up, all the pressure ulcers of patients were repaired well without recurrence. Conclusions: After debridement of ischial tuberosity pressure ulcer, if there is no sinus tract formation or sinus surface is superficial, direct suture, Z-plasty, buttock local flap, or V-Y advancement repair of posterior femoral cutaneous nerve nutrient vessel flap can be selected according to the range of skin and soft tissue defects. If the sinus tract of the wound is deep, the proper tissue flap can be selected to fill the sinus tract according to the size of sinus tract and range of the skin and soft tissue defects, and then the wound can be closed with individualized flap to obtain good repair effect.

Visfatin facilitates gastric cancer malignancy by targeting snai1 via the NF-κB signaling.

BACKGROUND: Visfatin acts as an oncogenic factor in numerous tumors through a variety of cellular processes. Visfatin has been revealed to promote cell migration and invasion in gastric cancer (GC). Snai1 is a well-known regulator of EMT process in cancers. However, the relationship between visfatin and snai1 in GC remains unclear. The current study aimed to explore the role of visfatin in GC. METHODS: The RT-qPCR and western blot analysis were used to measure RNA and protein levels, respectively. The cell migration and invasion were tested by Trans-well assays and western blot analysis. RESULTS: Visfatin showed upregulation in GC cells. Additionally, Visfatin with increasing concentration facilitated epithelial-mesenchymal transition (EMT) process by increasing E-cadherin and reducing N-cadherin and Vimentin protein levels in GC cells. Moreover, endogenous overexpression and knockdown of visfatin promoted and inhibited migratory and invasive abilities of GC cells, respectively. Then, we found that snai1 protein level was positively regulated by visfatin in GC cells. In addition, visfatin activated the NF-κB signaling to modulate snai1 protein expression. Furthermore, the silencing of snai1 counteracted the promotive impact of visfatin on cell migration, invasion and EMT process in GC. CONCLUSION: Visfatin facilitates cell migration, invasion and EMT process by targeting snai1 via the NF-κB signaling, which provides a potential insight for the treatment of GC.

[Therapeutic effect of tonsillectomy on IgA nephropathy after kidney transplantation].

Objective: To observe the clinical effect of tonsillectomy on IgA nephropathy (IgAN) after renal transplantation. Methods: From March 2011 to July 2018, 201 kidney transplantation recipients who were diagnosed of IgAN by transplant renal biopsy in the Department of Organ Transplantation of the First Affiliated Hospital of Sun Yat-sen University were retrospectively reviewed, of which 18 patients underwent tonsillectomy after renal biopsy. The clinical data of the 18 patients were collected, patient and kidney survival time and function of the transplanted kidney were analyzed. Results: Of the 18 recipients, 13 were male and 5 were female, with an average age of (36.0±10.9) years. All 18 patients survived during follow-up. Two patients returned to dialysis treatment 10 months and 14 months after tonsillectomy, respectively. The creatinine was 94 (78, 133) µmol/L, 95 (74, 139) µmol/L, 106 (87, 158) µmol/L and 95(81, 147) µmol/L before tonsillectomy, 3 months, 1 year and 2 years after tonsillectomy, respectively (P=0.206). Urinary protein quantification was 0.31 (0.16, 1.38) g/24 h, 0.34 (0.10, 1.42) g/24 h, 0.33 (0.11, 0.56) g/24 h and 0.25 (0.10, 0.50) g/24 h at the same time points, respectively (P=0.104). The two patients who returned to dialysis were diagnosed of IgAN by transplant renal biopsy because of elevated creatinine, proteinuria and hematuria, 9 years and 4 years after kidney transplant respectively. Renal biopsy suggested that glomerular and segmental sclerosis were 7/24, 5/24 and 1/6, 2/6, respectively. Additionally, interstitial fibrosis and tubular atrophy (IF/TA) were both occupied 30% in the biopsies, and tonsillectomy was performed 461 days and 1 077 days after diagnosis of IgAN, respectively. Conclusions: Tonsillectomy can maintain the stability of renal function and prevent the aggravation of proteinuria in IgAN patients after renal transplantation. However, if pathology suggests obvious glomerulosclerosis or IF/TA, tonsillectomy may not be effective.

Maintenance treatment in advanced HER2-negative gastric cancer.

Survival for patients with advanced gastric cancer (GC) remains poor. Systemic chemotherapy which has reached a plateau stays the standard first-line (1L) treatment for advanced human epidermal growth-factor receptor 2 (HER2)-negative GC. To maximize the benefit of 1L treatment, the concept of maintenance treatment is constantly being explored. In advanced HER2-negative GC, current clinical guidelines do not recommend a standard maintenance therapy strategy. In addition to the monotherapy maintenance with fluorouracil after 4-6 cycles of 1L chemotherapy, some agents that are active against novel targets have been evaluated in clinical trials for maintenance treatment. Whereas most of these trials do not reach their primary endpoints, they open new horizons for the 1L treatment of advanced HER2-negative GC. Therefore, we reviewed the clinical trials in the field of maintenance treatment in advanced HER2-negative GC and discussed some of the problems in clinical trials.

Development of a blocking immunoperoxidase monolayer assay for differentiation between pseudorabies virus-infected and vaccinated animalss.

Pseudorabies (PR) outbreaks have devastated many swine farms in several parts of China since late 2011. The outbreak-associated pseudorabies virus (PRV) variant strains exhibited some typical amino acid changes in glycoprotein E (gE), a diagnostic antigen used for discriminating between PRV-infected and vaccinated animals (DIVA). To counteract the potential impact of epitope variations on current serological diagnostics of PRV, we produced monoclonal antibodies (mAbs) against gE protein of one representative PRV variant strain and developed a blocking immunoperoxidase monolayer assay (b-IPMA) for DIVA. The b-IPMA was based on the inhibition of binding between PRV-infected cells and mAb by PRV-specific antibodies present in clinical swine sera and was validated by comparison with a commercial PRV gpI Antibody Test Kit (IDEXX Laboratories, USA). The diagnostic sensitivity, diagnostic specificity and agreement were determined to be 99.25%, 98.18% and 99.02% respectively upon testing 509 serum samples. b-IPMA detected only PRV-specific antibodies and showed no cross- -reactivity with antibodies elicited by gE-deleted vaccine or other common swine pathogens. Thus, b-IPMA has the potential to be used for high-throughput screening of PRV-infected animals in veterinary clinics.

Association of CYP3A5, CYP2C8, and ABCB1 Polymorphisms With Early Renal Injury in Chinese Liver Transplant Recipients Receiving Tacrolimus.

BACKGROUND: The purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus. METHODS: CYP3A5, ABCB1, and CYP2C8 polymorphisms were genotyped in the Chinese liver transplant recipients in the study receiving tacrolimus for at least 2 years by polymerase chain reaction and high-resolution melting method. Serum cystatin C and urine microprotein (α1-microglobulin, microalbumin, transferrin, and immunoglobulin) of liver transplant recipients were used to determine both the status of early renal injury and the lesion part. RESULTS: We documented 3 genotypes of CYP3A5 and ABCB1 and only 2 genotypes of CYP2C8 in our cohort. The levels of cystatin C and all 4 indicators of the urine microprotein in the recipient group were significantly higher than those in the control group (P < .05). The concentrations of transferrin differed significantly in each CYP3A5 genotype group (P < .05). Based on diverse CYP2C8 genotypes, we divided all the recipients into 2 groups: CYP2C8*1*1 group and CYP2C8*3*1 group. The concentrations of α1-microglobulin and cystatin C differed significantly between the 2 groups (P < .05). For CYP2C8*3, the positive predictive value is 68.5% and negative predictive value is 70.2%. For CYP3A5*3, the positive predictive value is 55.3% and negative predictive value is 60.4%. CONCLUSIONS: CYP2C8*3 and CYP3A5*3 appear to be predictive of risk of tacrolimus-induced early renal impairment. CYP3A5*3 was associated with the risk of early renal glomerular lesion, while CYP2C8*3 was associated with the risk of the tubulointerstitial injury. ABCB1 polymorphisms (both C3435T and C1236T) were not associated with the early renal injury in liver transplant recipients.

Effect of Early Immunosuppression Therapy on De Novo Anti-Human-Leukocyte-Antigen Antibody After Kidney Transplantation.

The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production. METHODS: A single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and February 2016. RESULTS: A total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242). CONCLUSION: The risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects.

Higher Incidence of Renal Allograft Glomerulonephritis in Living-Related Donor Kidney Transplantation.

Glomerulonephritis recurrence has emerged as one of the leading causes of allograft loss. We aimed to investigate the effect of living-related and deceased donation on the incidence of renal allograft glomerulonephritis and its effect on renal allograft survival. METHODS: Adult renal allograft recipients with primary glomerulonephritis were enrolled. Transplantation date was from Feb 2004 to Dec 2015. Exclusion criteria included combined organ transplantation, structural abnormality, diabetic nephropathy, hypertension nephropathy, obstructive nephropathy, and primary uric acid nephropathy. The incidence of biopsy-proven allograft glomerulonephritis was compared between the living-related donor group and the deceased donor group. Graft survival was assessed with Kaplan-Meier method, and Cox proportional hazard model was used to evaluate the effect of posttransplant glomerulonephritis on graft outcome. RESULTS: There were 525 living-related donor kidney transplant recipients (LRKTx) and 456 deceased donor kidney transplant recipients (DDKTx) enrolled. The incidence of IgA nephropathy was 8.8% in the LRKTx group and 1.3% in the DDKTx group (P < .001); the incidence of focal segmental glomerulosclerosis (FSGS) was 3.8% in the LRKTx group and 1.5% in the DDKTx group (P = .03). FSGS increased the risk of graft failure compared with non-FSGS (hazard ratio [HR], 3.703 [1.459-9.397]; P = .006). IgA nephropathy increased the risk of graft failure by over 5 times 5 years after kidney transplantation compared with non-IgA nephropathy, but it did not affect early allograft survival (HR for ≥5 years, 6.139; 95% CI, 1.766-21.345; P = .004; HR for <5 years, 0.385 [0.053-2.814]; P = .35). CONCLUSIONS: Higher incidence of IgA nephropathy and FSGS in renal allograft was observed in living-related donor kidney transplantation compared with deceased donor kidney transplantation. De novo or recurrent IgA nephropathy and FSGS impaired long-term renal allograft survival.

Risk Factors for Acute Rejection After Deceased Donor Kidney Transplantation in China.

OBJECTIVES: This study aimed to identify the potential risk factors of acute rejection after deceased donor kidney transplantation in China. METHODS: Adult kidney transplantations from deceased donors in our center from February 2004 to December 2015 were enrolled for retrospective analysis. All deceased donations complied with China's Organ Donation Program. No organs from executed prisoners were used. The incidence of clinical and biopsy-proved acute rejection was assessed with the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis. RESULTS: One-year, 2-year, 3-year and 5-year incidences of acute rejection were 12.4%, 14.2%, 14.8%, and 17.1%, respectively. Multivariate analysis demonstrated that longer pre-transplant dialysis duration (hazard ratio [HR] 1.009 per month; 95% confidence interval, 1.003-1.015; P = .003), positive pre-transplant panel reactive antibody (PRA) (positive vs negative HR 3.266; 1.570-6.793; P = .023), and increasing HLA mismatches (≥4 vs < 4 HR 2.136; 1.022-4.465; P = .044) increased the risk of acute rejection, while tacrolimus decreased acute rejection risk compared to cyclosporine (HR 0.317; 0.111-0.906; P = .032). CONCLUSION: Longer pre-transplant dialysis duration, HLA mismatch, and positive pre-transplant PRA increase the risk of acute rejection, while tacrolimus helps prevent acute rejection compared to cyclosporine in deceased donor kidney transplantation.

Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression.

Increasing evidences suggest that inflammatory microenvironment has a crucial role in prostate cancer (PCa) progression; however, the underlying mechanisms are unclear. Here, we used the inflammation-associated prostate cellular transformation model to screen out a crucial microRNA, miR186, which was significantly downregulated in the transformed cells and effectively rescued the transformed phenotype. On stimulation of inflammatory cytokines, the activated nuclear factor kappa B (NF-κB)/p65 was able to induce miR186 expression through binding to its promoter in non-transformed cells, whereas this pathway was lost in transformed cells. Interestingly, Twist1, which is a reported downstream target of miR186, was responsible for the loss of NF-κB/p65-miR186 pathway. Twist1 downregulated miR186 expression in a novel negative feedback loop binding to the E-box and simultaneously recruiting Dnmt3a, which facilitated the site-specific CpG methylation of the miR186 promoter, thereby blocked the transcriptional activity of NF-κB/p65 and the responsiveness of miR186 to inflammatory signals. The high level of Twist1 triggered this feedback loop that underlies the epigenetic switch, which was essential for maintaining transformed and advanced PCa state. Finally, our clinical data confirmed that the CpG methylation and miR186 expression levels were closely related with inflammation-associated human PCa progression.

Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus is a widely used immunosuppressive drug with marked pharmacokinetic variability partly due to CYP3A5 polymorphism. Our study aimed to investigate the dynamic effects of CYP3A5 genotypes on dose requirement and trough concentration (C0 ) of tacrolimus in renal transplant recipients. METHODS: A total of 194 Chinese renal transplant recipients received oral tacrolimus twice daily. Whole-blood C0 of tacrolimus were measured on the 3rd day, 7th day, 14th day, 1st month, 3rd month and 6th month post-transplantation. CYP3A5 genotypes were determined and the recipients were categorized as CYP3A5 expressers (CYP3A5*1 allele carriers) and non-expressers (homozygous CYP3A5*3). The correlated serum creatinine, haematocrit and albumin were also detected. RESULTS: The allele frequencies for CYP3A5*1/*1, *1/*3 and *3/*3 were 7·7%, 44·8% and 47·4%, respectively. There were no significant variability in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. Larger doses were administered to CYP3A5 expressers than to non-expressers after surgery except the initial dose. C0 were much lower in CYP3A5 expressers than in non-expressers on the 3rd day, 7th day, 14th day and 1st month post-transplantation (P < 0·01); however, no significant differences were found on the 3rd and 6th months post-transplantation. All of the dose-adjusted C0 in CYP3A5 expressers were significantly lower than non-expressers (P < 0·01). Less of the recipients achieving target C0 (4-8 ng/mL) were found in CYP3A5 expressers than in non-expressers after initial dose (35·7% vs. 50%). Meanwhile, CYP3A5 non-expressers were detected having higher C0 (>8 ng/mL) during 3 months post-transplantation. Besides, the proportions in the two groups both increased gradually over time and up to 91·8% and 94% on the 6th month, respectively. WHAT IS NEW AND CONCLUSION: There are no significant differences in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. CYP3A5 expressers have decreased dose-adjusted tacrolimus C0 when compared to non-expressers. Dose-adjusted C0 of tacrolimus increases in a time-dependent manner in both groups.

Cytokine Profile in Calcineurin Inhibitor-Induced Chronic Nephrotoxicity in Chinese Liver Transplant Recipients.

BACKGROUND: Calcineurin inhibitor-associated chronic nephrotoxicity threatens the prognosis of liver transplant recipients. This study aimed to study the mechanisms involved by identifying the cytokine profiles in tacrolimus (Tac)-induced nephrotoxicity. METHODS: We enrolled 125 living-donor liver transplant recipients. All of the recipients had normal serum cystatin (Cys) C and urine microalbumin before transplantation. They received a Tac-based immunosuppressive regimen (Tac + mycophenolate mofetil + prednisone) thereafter. Patients were grouped according to Cys-C results (measured a mean 3.55 ± 1.89 years after transplantation) as a measure of renal injury: the early renal damage group was Cys-C >1 mg/L, and normal renal function was Cys-C ≤1 mg/L. Serum levels of 10 cytokines and chemokines, as well as urine proteins including α1 microglobulin, microalbumin, transferrin, and immunoglobulin G, were compared between groups. RESULTS: In the early renal damage group, the concentration of interferon-γ-induced protein (IP) 10 was higher and monocyte chemotactic protein (MCP) 1 was lower compared with the group with normal renal function (P = .027 and .048, respectively). Multivariate logarithmic regression analysis showed that IP-10 and MCP-1 were independently correlated with renal damage. CONCLUSIONS: High level of IP-10 and low level of MCP-1 may be involved in renal injury and therefore may indicate poor prognosis. IP-10 could be a target for renal injury treatment after liver transplantation. Further studies with larger sample sizes are recommended to validate the study results.

Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy.

Acute promyelocytic leukemia (APL) cells exhibit disrupted regulation of cell death and differentiation, and therefore the fate of these leukemic cells is unclear. Here, we provide the first evidence that a small percentage of APL cells undergo a novel cell death pathway by releasing extracellular DNA traps (ETs) in untreated patients. Both APL and NB4 cells stimulated with APL serum had nuclear budding of vesicles filled with chromatin that leaked to the extracellular space when nuclear and cell membranes ruptured. Using immunofluorescence, we found that NB4 cells undergoing ETosis extruded lattice-like structures with a DNA-histone backbone. During all-trans retinoic acid (ATRA)-induced cell differentiation, a subset of NB4 cells underwent ETosis at days 1 and 3 of treatment. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly elevated at 3 days, and combined treatment with TNF-α and IL-6 stimulated NB4 cells to release ETs. Furthermore, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against Atg7 attenuated LC3 autophagy formation and significantly decreased ET generation. Our results identify a previously unrecognized mechanism for death in promyelocytes and suggest that ATRA may accelerate ET release through increased cytokines and autophagosome formation. Targeting this cellular death pathway in addition to conventional chemotherapy may provide new therapeutic modalities for APL.

The efficacy and safety of intensified enteric-coated mycophenolate sodium with low exposure of calcineurin inhibitors in Chinese de novo kidney transplant recipients: a prospective study.

AIMS: The aim of this study was to investigate the efficacy and safety of a transient intensified enteric-coated mycophenolate sodium (EC-MPS) dosing regimen with low exposure of calcineurin inhibitors (CNIs) in Chinese de novo kidney transplantation. METHODS: In a 6-month prospective study, a total of 97 recipients were enrolled and assigned to either an intensified EC-MPS dosing (IS) regimen or a standard EC-MPS dosing (SD) regimen. The area under the curve (AUC) of MPA was assessed at week 1 post transplant. The incidences of acute rejection, patient and graft survival, renal allograft function and adverse events were analysed. RESULTS: The IS regimen displayed a trend of acute rejection risk reduction (IS 2.7% vs. SD 13.3%, p = 0.061) and allograft function improvement (IS 62.8 ± 14.0 ml/min per 1.73 m(2) vs. SD 56.6 ± 18.3 ml/min per 1.73 m(2) , p = 0.084) after 6-month follow-up. MPA-AUC0-12 h was substantially higher in the intensified EC-MPS group than the standard EC-MPS group, though without a significant difference (71.4 ± 41.7 vs. 53.0 ± 27.0 mg·h/l, p = 0.107). The IS regimen did not increase the incidence of adverse effects (IS 54.1% vs. 45.0%, p = 0.39), including diarrhoea or leucopenia. CONCLUSIONS: The intensified EC-MPS dosing regimen maintaining low-dose CNIs in this study may be beneficial for Chinese adult de novo kidney transplant recipients in terms of acute rejection and allograft function and is safe within 6 months post transplant.

[Salvage surgical treatment for local recurrent nasopharyngeal cancer].

The salvage radiation or surgery is the main choice for recurrent nasopharyngeal cancer now. However the recurrent tumor becomes radiation insensitive and meanwhile,morbidity and mortality become higher.Recently the endoscopic salvage surgery has been developed;the collective evidence from a number of such studies suggests that endoscopic nasopharyngectomy is a safe and effective procedure for the treatment of rNPC.This article reviewed related researches about the feasibility,methods, and current situation of endoscopic salvage surgery.

Risk factors for BK virus infection and BK virus-associated nephropathy under the impact of intensive monitoring and pre-emptive immunosuppression reduction.

BACKGROUND: BK virus (BKV) nephropathy (BKVN) is an increasingly recognized cause of kidney allograft loss and is thought to be related to the newer, more potent immunosuppressive agents. However, the risk factors for different types of BKV infection under the impact of intensive monitoring and reduction of maintenance immunosuppression are not well understood. METHODS: Quantitative BKV DNA surveillance in plasma/urine and cytological testing in urine were performed regularly within the first year post-transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN treated with immunosuppression reduction were monitored for BKV every 3-6 months. All the patients were followed up for a minimum of 5 years to exclude later development of BKVAN. Potential variables were compared and analyzed using logistic regression model multivariate analysis to assess and rank the BKV infection-related factors. RESULTS: Seventy-eight (34.1%) patients had decoy cells, 99 (43.2%) BK viruria, 38 (16.6%) BK viremia, and 7 (3.1%) BKVAN. Risk for decoy cells, BK viruria, and viremia, and BKVAN in univariate analyses were higher with tacrolimus (Tac) and deceased kidney donation. Multivariate analysis showed that Tac ([HR, 2.7; P = .008], [HR, 2.3; P = .016], [HR, 2.9; P = .032]) and deceased kidney donation ([HR, 2.5; P = .004], [HR, 2.6; P = .002], [HR, 2.1; P = .071]) were risk factors for BK decoy cells, BK viruria, and viremia, respectively. BKVAN was inclined to the patients with the combination of Tac and mycophenolate mofetil and longer BKV clearance time. CONCLUSIONS: Tac and deceased kidney donation are independent risk factors for BKV infection under the impact of therapeutic drug monitoring.

Feedback loops blockade potentiates apoptosis induction and antitumor activity of a novel AKT inhibitor DC120 in human liver cancer.

The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca(2+) via Ca(2+)/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment.

Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis.

Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.

MiRNA-296-3p-ICAM-1 axis promotes metastasis of prostate cancer by possible enhancing survival of natural killer cell-resistant circulating tumour cells.

Natural killer (NK) cells are important in host to eliminate circulating tumour cells (CTCs) in turn preventing the development of tumour cells into metastasis but the mechanisms are very poorly defined. Here we find that the expression level of miR-296-3p is much lower in the non-metastatic human prostate cancer (PCa) cell line P69 than that in the highly metastatic cell line M12, which is derived from P69. We demonstrate that miR-296-3p directly targets and inhibits the expression of intercellular adhesion molecule 1 (ICAM-1) in the malignant M12. The data from clinical tissue microarrays also show that miR-296-3p is frequently upregulated and ICAM-1 is reversely downregulated in PCa. Interestingly, ectopic expression of miR-296-3p in P69 increases the tolerance to NK cells whereas knockdown of miR-296-3p in M12 reduces the resistance to NK cells, which both phenotypes can be rescued by re-expression or silencing of ICAM-1 in P69 and M12, respectively. These results are also manifested in vivo by the decrease in the incidence of pulmonary tumour metastasis exhibited by knockdown of miR-296-3p in M12 when injected into athymic nude mice via tail vein, and consistently down-expression of ICAM-1 reverses this to increase extravasation of CTCs into lungs. Above results suggest that this newly identified miR-296-3p-ICAM-1 axis has a pivotal role in mediating PCa metastasis by possible enhancing survival of NK cell-resistant CTC. Our findings provide novel potential targets for PCa therapy and prognosis.