Nitric Oxide-Loaded Bioinspired Lipoprotein Normalizes Tumor Vessels To Improve Intratumor Delivery and Chemotherapy of Albumin-Bound Paclitaxel Nanoparticles.

The disorganized vasculatures in tumors represent a substantial challenge of intratumor nanomedicine delivery to exert the anticancer effects. Herein, we rationally designed a glutathione (GSH)-activated nitric oxide (NO) donor loaded bioinspired lipoprotein system (NO-BLP) to normalize tumor vessels and then promote the delivery efficiency of sequential albumin-bound paclitaxel nanoparticles (PAN) in tumors. NO-BLP exhibited higher tumor accumulation and deeper penetration versus the counterpart liposomal formulation (NO-Lipo) in 4T1 breast cancer tumors, thus producing notable vascular normalization efficacy and causing a 2.33-fold increase of PAN accumulation. The sequential strategy of NO-BLP plus PAN resulted in an 81.03% inhibition of tumor growth in 4T1 tumors, which was better than the NO-BLP monotherapy, PAN monotherapy, and the counterpart NO-Lipo plus PAN treatment. Therefore, the bioinspired lipoprotein of NO-BLP provides an encouraging platform to normalize tumor vessels and promote intratumor delivery of nanomedicines for effective cancer treatment.

Full factorial design, physicochemical characterization, ex vivo investigation, and biological assessment of glutathione-loaded solid lipid nanoparticles for topical application.

l-Glutathione (GSH) has exceptional antioxidant activities against UVA irradiation-induced oxidative stress and is used widely for combatting skin ageing. However, topical administration of GSH is challenging due to its inability to penetrate the stratum corneum (SC). This study aims to evaluate the solid lipid nanoparticles (SLNs) carrier system for improving the skin penetration and stability of GSH. The GSH-loaded SLNs (GSH-SLNs) were prepared by the double emulsion technique and were optimized by a full factorial design. The optimized GSH-SLNs formulation had a mean particle size of 305 ± 0.6 nm and a zeta potential of + 20.1 ± 9.5 mV, suitable for topical delivery. The ex-vivo penetration study using human skin demonstrated a 3.7-fold improvement of GSH penetration across SC with GSH-SLNs when compared with aqueous GSH. GSH-SLNs prolonged antioxidant activity on UVA irradiated fibroblast cells when compared to GSH solution, preventing UVA-induced cell death and promoting cell growth for times over 48 h. This research has illustrated that as a carrier system, SLNs were able to enhance the physicochemical stability, skin penetration, and drug deposition in the viable epidermis and dermis layers of the skin for GSH, while also maintaining the ability to protect human skin fibroblast cells against oxidative stress caused by UVA irradiation. This delivery system shows future promise as a topical delivery platform for the topical delivery of GSH and other chemically similar bioactive compounds for improving skin health.

Effect of cervical spine motion on displacement of posterolateral annulus fibrosus in cervical spondylotic radiculopathy with contained posterolateral disc herniation: a three-dimensional finite element analysis.

BACKGROUND: Previous studies on dynamic impingement of nerve root in cervical spondylotic radiculopathy (CSR) have focused on effect of cervical spine motion (CSM) on dimensional changes of intervertebral foramen. However, there are few studies to investigate effect of CSM on displacement of posterolateral intervertebral disc until now. The present study aimed to investigate effect of CSM on displacement of posterolateral annulus fibrosus (AF) in CSR with contained posterolateral disc herniation. METHODS: A C5-C6 CSR finite element model with unilateral contained posterolateral disc herniation was generated based on validated C5-C6 normal finite element model. Forward and backward displacement distributions of posterolateral AFs in CSR model and normal model were compared. Changes in forward and backward displacement magnitudes of posterolateral AFs of the herniated side and the healthy side in CSR model, with respect to those of the ipsilateral posterolateral AFs in normal model, were compared. The comparisons were performed under flexion, extension, lateral bendings and axial rotations. RESULTS: There was no difference in deformation trend of posterolateral AF between CSR model and normal model. Bilateral posterolateral AFs mainly moved forward during flexion and backward during extension. Left posterolateral AF mainly moved backward and right posterolateral AF forward during left lateral bending and left axial rotation. Left posterolateral AF mainly moved forward and right posterolateral AF backward during right lateral bending and right axial rotation. However, with respect to forward and backward displacement magnitudes of the ipsilateral posterolateral AFs in normal model, those of the herniated side increased relatively significantly compared with those of the healthy side in CSR model. CONCLUSIONS: Flexion, lateral bending to the healthy side and axial rotation to the healthy side make posterolateral AF of the herniated side mainly move forward, whereas extension, lateral bending to the herniated side and axial rotation to the herniated side make it mainly move backward. These data may help select CSM or positions to diagnose and treat CSR with contained posterolateral disc herniation. Increase in deformation amplitude of posterolateral AF of the herniated side may also be the reason for dynamic impingement of nerve root in CSR with contained posterolateral disc herniation.

Multimodal echocardiography in the diagnosis of masses localized to the proximal portions of pulmonary arteries.

Proximal pulmonary artery masses are exceedingly rare, and their diagnosis and therapy are important and challenging for clinicians. This study reviews our experience exploring the value of a combination of transthoracic echocardiography and contrast echocardiography for the differential diagnosis of proximal pulmonary artery masses. Between January 2018 and June 2021, 44 patients diagnosed with a mass attached to the major pulmonary artery and straddling the bilateral pulmonary arteries or pulmonary valve on transthoracic echocardiography were referred to this study. Contrast echocardiography was performed in 17 patients. Masses were diagnosed based on their site of attachment, shape, size, mobility, hemodynamic consequences on transthoracic echocardiography, and tissue perfusion on contrast echocardiographic perfusion imaging. Pathological data were collected from medical records and analyzed. The most frequent location of proximal pulmonary artery masses was the major pulmonary artery trunk. Twelve patients underwent complete mass resection, whereas nine patients underwent percutaneous pulmonary artery biopsy puncture and had a pathological diagnosis. Another 24 patients were confirmed with the validation methods. Contrast echocardiography has good sensitivity and specificity for differentiating thrombi from pulmonary artery sarcomas (PAS). The mass types were distributed as follows: thrombi (19, 43%), PAS (15, 34%), metastatic tumors (6, 14%), vegetations (3, 7%), and primary benign lesions (1, 2%). The majority of proximal pulmonary artery masses were thrombi or PAS. A combination of transthoracic echocardiography and contrast echocardiography offers advantages in the early identification of proximal pulmonary masses and provides clinically important information about the characteristics of masses, especially for differentiating thrombi from PAS.

Comparison of mini-percutaneous nephrolithotomy and retroperitoneal laparoscopic ureterolithotomy for treatment of impacted proximal ureteral stones greater than 15 mm.

BACKGROUND: The optimal treatment for large impacted proximal ureteral stones remains controversial. The aim of this study was to evaluate the efficacy, safety, and potential complications of mini-percutaneous nephrolithotomy (MPCNL) and retroperitoneal laparoscopic ureterolithotomy (RPLU) in the treatment of impacted proximal ureteral stones with size greater than 15 mm. METHODS: A total of 268 patients with impacted proximal ureteral stones greater than 15 mm who received MPCNL or RPLU procedures were enrolled consecutively between January 2014 and January 2019. Data on surgical outcomes and complications were collected and analyzed. RESULTS: Demographic and ureteral stone characteristics found between these two groups were not significantly different. The surgical success rate (139/142, 97.9% vs. 121/126, 96.0%, P = 0.595) and stone-free rate after 1 month (139/142, 97.9% vs. 119/126, 94.4%, P = 0.245) of RPLU group were marginally higher than that of the MPCNL group, but there was no significant difference. There was no significant difference in the drop of hemoglobin between the two groups (0.8 ±â€Š0.6 vs. 0.4 ±â€Š0. 2 g/dL, P = 0.621). The mean operative time (68.2 ±â€Š12.5 vs. 87.2 ±â€Š16.8 min, P = 0.041), post-operative analgesics usage (2/121, 1.7% vs. 13/139, 9.4%, P = 0.017), length of hospital stay after surgery (2.2 ±â€Š0.6 vs. 4.8 ±â€Š0.9 days, P < 0.001), double J stent time (3.2 ±â€Š0.5 vs. 3.9 ±â€Š0.8 days, P = 0.027), time of catheterization (1.1 ±â€Š0.3 vs. 3.5 ±â€Š0.5 days, P < 0.001), and time of drainage tube (2.3 ±â€Š0.3 vs. 4.6 ±â€Š0.6 days, P < 0.001) of MPCNL group were significantly shorter than that of the RPLU group. The complication rate was similar between the two groups (20/121, 16.5% vs. 31/139, 22.3%, P = 0.242). CONCLUSIONS: MPCNL and RPLU have similar surgical success and stone clearance in treating impacted proximal ureteral stones greater than 15 mm, while patients undergoing MPCNL had a lower post-operative pain rate and a faster recovery.

Needle Adjustment Free (NAF) running suture technique (PAN suture) in laparoscopic partial nephrectomy.

BACKGROUND: It is proposed a new running suture technique called Needle Adjustment Free (NAF) technique, or PAN suture. The efficiency and the safety were evaluated in laparoscopic partial nephrectomy. METHODS: This new running suture technique avoids the Needle Adjustment method used in traditional techniques. The new continuous suture technique (11 patients) was compared with the traditional continuous suture method (33 patients) used in both transperitoneal and retroperitoneal laparoscopic partial nephrectomy (LPN) in terms of suture time (ST), warm ischemia time (WIT), blood loss (BL), open conversion rate and post-op discharge time, post-op bleeding, post-op DVT, ΔGFR (affected side, 3 months post-op). Differences were considered significant when P < 0.05. RESULTS: ST in the PAN suture group was 30.37 ± 16.39 min, which was significant shorter (P = 0.0011) than in the traditional technique group which was 13.68 ± 3.33 min. WIT in the traditional technique group was 28.73 ± 7.89 min, while in the PAN suture group was 20.64 ± 5.04 min, P = 0.0028. The BL in entirety in the traditional technique group was 141.56 ± 155.23 mL, and in the PAN suture group was 43.18 ± 31.17 mL (P = 0.0017). BL in patients without massive bleeding in the traditional technique group was significantly greater than in the PAN suture group at 101.03 ± 68.73 mL versus 43.18 ± 31.17 mL (P = 0.0008). The open conversion rate was 0 % in both groups. There was no significant difference between the two groups in postoperative discharge time, post-op bleeding, post-op DVT, ΔGFR (affected side, 3 months post-op). CONCLUSIONS: The NAF running suture technique, or PAN suture, leading to less ST, WIT and BL, which was shown to be more effective and safer than the traditional technique used for LPN. A further expanded research with larger sample size is needed.

Simultaneous transthoracic intervention for multiple cardiac defects in children.

BACKGROUND: Transthoracic intervention for isolated congenital heart disease (CHD) has been well tested for its technological feasibility and is increasingly used in clinical practice. We aimed to present our experience in simultaneous transthoracic intervention for multiple cardiac lesions in a series of pediatric patients. METHODS: Between March 2015 and December 2019, 20 patients with multiple CHD were referred to this study; mean age was 18.8±8.6 (range, 4-36) months. The transthoracic echocardiography (TTE) diagnosis was atrial septal defect (ASD) and perimembranous ventricular septal defect (pmVSD) in 7 patients, patent ductus arteriosus (PDA) and ASD in 6, pmVSD and PDA in 2, pmVSD and valvular pulmonary stenosis (PS) in 2, ASD and PS in 2, and doubly committed subarterial VSD (dcsVSD) and PS in 1 patient. These patients underwent simultaneous transthoracic interventions with transesophageal echocardiography guidance. The procedure sequence was PS→VSD→PDA→ASD. Electrocardiography and TTE were scheduled at discharge and follow-ups. RESULTS: All patients were occluded successfully without any thoracotomy conversion. Operation time was 56-120 (mean, 75±13) minutes. A 1.5-2.0-cm median sternum incision was performed in 6 ASD&PDAs, 2 ASD&PSs, and 1 dcsVSD&PS. In 11 other patients, a 1.5-2.0-cm incision in the inferior sternum was made and the chest closed with a drain. There were no serious complications before discharge and at follow-up. CONCLUSIONS: Simultaneous transthoracic intervention for multiple cardiac defects in children is feasible with good short-term outcomes. For different lesions, the appropriate surgical incision and operational sequence can render the intervention minimally invasive and safer.

An experimental model of the epithelial to mesenchymal transition and pro-fibrogenesis in urothelial cells related to bladder pain syndrome/interstitial cystitis.

BACKGROUND: Suitable in vitro models are needed to investigate urothelial epithelial to mesenchymal transition (EMT) and pro-fibrogenesis phenotype in bladder pain syndrome/interstitial cystitis (BPS/IC). This study is to establish a novel experimental BPS/IC cell model and explore how different concentrations of tumor necrosis factor (TNF)-α influence the EMT and pro-fibrogenesis phenotype of urothelial cells. METHODS: SV-HUC-1 urothelial cells were cultured with 2, 10, or 50 ng/mL TNF-α to mimic chronic inflammatory stimulation. The EMT and pro-fibrogenesis phenotype, including production of collagen I and pro-fibrosis cytokines, were estimated after 72 h of culture. RESULTS: The bladder urothelial cells of BPS/IC exhibited upregulated vimentin, TNF-α and TNF receptor, downregulated E-cadherin, and increased collagen I. Higher concentrations of TNF-α (10 and 50 ng/mL) produced an obvious mesenchymal morphology, enhanced invasion and migratory capacity, increased expression of vimentin, and decreased expression of E-cadherin. Collagen I was increased in cells treated with 2 and 10 ng/mL TNF-α after 72 h. Secretion of interleukin (IL)-6 and IL-8 was promoted with 10 and 50 ng/mL TNF-α, while that of IL-1ß or transforming growth factor-ß was unaffected. Slug and Smad2 were upregulated by TNF-α after 72 h. The Smad pathway was activated most strongly with 10 ng/mL TNF-α and Slug pathway activation was positively correlated with the concentration of TNF-α. CONCLUSIONS: Sustained 10 ng/mL TNF-α stimulation induced the EMT and pro-fibrogenesis phenotype resembling BPS/IC in SV-HUC-1 cells. Minor inflammatory stimulation induced the pro-fibrogenesis phenotype while severe inflammatory stimulation was more likely to produce significant EMT changes. Different degrees of activation of the Slug and Smad pathways may underlie this phenomenon.

Preformulation studies of l-glutathione: physicochemical properties, degradation kinetics, and in vitro cytotoxicity investigations.

Objectives: l-Glutathione (GSH) is an endogenous tripeptide with super antioxidant properties. In this study, preformulation parameters of GSH and its degradation products were fully investigated.Significance: To date, no experimental preformulation data is available for GSH. Therefore, to the author's knowledge, this is the first study to experimentally determine the preformulation parameters of GSH, which can be considered more reliable for further studies.Methods: An HPLC method for GSH was optimized and validated to accurately quantify the GSH amount in solution, used to investigate GSH's solubility and Log P. Differential Scanning Calorimeter and Thermogravimetric Analyzer were used to evaluate the thermal properties of GSH. Polarized microscope and Fourier-transform Infrared Spectroscopy were used to determine GSH's crystal habits and functional groups, respectively. Forced degradation kinetics and the degradation products were investigated and identified by LC-MS, respectively. GSH's cellular cytotoxicity on fibroblasts was investigated by MTT assay.Results: It was determined that GSH has high aqueous solubility (252.7 mg/mL), low Log P (-3.1), a melting endotherm of 195 °C and decomposition at 210°C, negligible moisture content, and a rectangular/cylindrical-shaped crystalline form. Seven degradation products were identified; one of the major degradation products of GSH under different conditions is first order kinetic oxidation into glutathione disulfide. No cytotoxicity was observed when fibroblasts were treated with GSH (0.005-10.000 mg/mL).Conclusions: Precise preformulation parameters of GSH were obtained, and these are imperative for the development and optimization of advanced GSH formulations.

Beforehand transection and suturing (BTS) of the dorsal vascular complex: a novel technique in laparoscopic radical prostatectomy.

BACKGROUND: Beforehand transection and suturing (BTS) of the dorsal vascular complex (DVC), a novel technique in non-neurovascular bundle sparing (NVB-sparing) extraperitoneal laparoscopic radical prostatectomy (eLRP), had been proposed; this study aimed to evaluate this technique in clinical laparoscopic procedures. METHODS: Using this new technique, the DVC was transected and sutured after dissection of the pelvic fascia and before dissection of the prostate, especially before ligation of the bilateral prostatic pedicles. This study retrospectively analyzed the data of 90 non NVB-sparing eLRP patients [traditional technique (n=60) and BTS technique (n=30)]. RESULTS: The surgical time in the BTS technique group was 121.73±24.53 min, which was significantly shorter (P=0.0015) than the traditional technique group (144.12±39.68 min). The calculated blood loss in the traditional technique group was 388.45±232.78 mL, and 264.16±130.70 mL in the BTS technique group (P=0.0016). The estimated blood loss in the traditional technique group was 350.34±311.80 mL, which was significantly greater than the BTS technique group (250.33±145.31 mL, P=0.0422). The transfusion rate in the traditional technique group was significantly greater than the BTS technique group (15.00% vs. 0.00%; P=0.0266). The biochemical recurrence rate in traditional technique group was 48.33%, which was higher than in the BTS group (30.00%) (P=0.0465). There was no significant difference between the 2 groups with respect to the pre-operative hemoglobin (Hb) concentration, pre-operative hematocrit (HCT), post-operative Hb concentration, post-operative HCT, ΔHCT, pre-operative blood volume, rectal perforation, open conversion, apical capsule residue, false suture, post-operative bleeding, urinary leakage, re-operation, surgical site infection, post-operative stay, and emission time of urinary incontinence. CONCLUSIONS: In managing the relationship between the DVC and prostate in patients undergoing non NVB-sparing eLRP, the BTS technique was shown to be more effective and safer than the traditional technique.

Antibody-Drug Conjugates Derived from Cytotoxic seco-CBI-Dimer Payloads Are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo.

This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings.

Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates.

A Pd-catalysed amination method is used to convert seco-CBI, a synthetic analogue of the alkylating subunit of the duocarmycin natural products, from the phenol to amino form. This allows efficient enantioselective access to the more potent S enantiomer of aminoCBI and its incorporation into analogues of DNA minor groove cross-linking agents. Evaluation in a panel of nine human tumour cell lines shows that the bifunctional agents containing aminoCBI are generally less cytotoxic than their phenolCBI analogues and more susceptible to P-glycoprotein-mediated resistance. However, all bifunctional agents are potent cytotoxins, some in the sub-pM IC50 range, with in vitro properties that compare favourably with established microtubule-targeted ADC payloads.

Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients.

OBJECTIVE: Professional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs). METHODS: We searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect. RESULTS: Twelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3(+) T-lymphocytes (MD=-11.65, P<0.05) and CD4(+) T-lymphocytes (MD=-8.18, P<0.01) of the combination group were higher. CONCLUSIONS: Immunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.

Retroperitoneal laparoscopic ureterolithotomy in comparison with ureteroscopic lithotripsy in the management of impacted upper ureteral stones larger than 12 mm.

OBJECTIVE: To compare the results of ureteroscopic lithotripsy (URSL) with retroperitoneal laparoscopic ureterolithotomy (RPLU) as two minimally invasive techniques in the management of proximal ureteral stones larger than 12 mm. PATIENTS AND METHODS: From January 2009 to October 2013, patients with impacted unilateral upper ureteral stones larger than 12 mm were enrolled including 182 males and 93 females with a medium age of 40 years (22-72 years). Patients were randomized to receive URSL (139 cases) with semirigid ureteroscope or RPLU (136 cases). RESULTS: Stone size was similar in RPLU and URSL groups (13.8 ± 1.9 vs 13.6 ± 1.4 mm, P = 0.312). Operating time and hospitalizing days in URSL group were significantly shorter than those in RPLU group (P < 0.001), whereas stone clearance rate was significantly higher in RPLU group (97.1 vs 89.9 %, P = 0.017). Ureteral strictures happened higher in URSL group (5 patients, 3.6 %) than RPLU group (2 patients, 1.5 %) with no statistical significance, while the strictures requiring surgical intervention were significantly higher in URSL group (4 cases) (2.9 vs 0 %, P = 0.046). CONCLUSION: RPLU could provide better stone clearance rate than semirigid URSL for upper ureteral impacted stones larger than 12 mm. It may also reduce the chance of surgical intervention for postoperative ureteral stricture.

Cross-bridged cyclen or cyclam Co(III) complexes containing cytotoxic ligands as hypoxia-activated prodrugs.

A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O)2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)](2+) (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.

Reduction of intercellular adhesion molecule 1 may play a role in anti-inflammatory effect of hyaluronic acid in a rat model of severe non-bacterial cystitis.

PURPOSE: To evaluate the impact of intercellular adhesion molecule 1 (ICAM-1) in hyaluronic acid (HA) therapy in rats model of severe non-bacterial cystitis. METHODS: Cystitis models in Sprague-Dawley female rats were produced by combination of intraperitoneal cyclophosphamide (CYP) with intravesical protamine/lipopolysaccharide (PS/LPS). HA or heparin (0.5 ml) was introduced intravesically to rats' bladders followed PS/LPS. Bladder tissue was prepared for histology including mast cell presence and measurement of ICAM-1, tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6). RESULTS: Cystitis model using intraperitoneal CYP and intravesical SP/LPS showed serious inflammation, higher mast cell count with elevated ICAM-1, TNF-α, and IL-6 levels. After intravesical heparin or HA treatment, incidence of grades 3-4 bladder inflammation and tissue ICAM-1 level were only significantly lower in HA group (P = 0.017, P = 0.021, respectively), but not in heparin group (P = 0.12, P = 0.798, respectively). Remarkably lower level of TNF-α (P = 0.003) and ICAM-1 (P = 0.006) was detected in HA-treated rats compared with heparin-treated rats. Inflammation grade and ICAM-1 level had strong correlation (P < 0.001). IL-6 level after HA or heparin instillation had no difference. CONCLUSIONS: Intravesical administration of HA decreased the severity of bladder inflammation, mast cell presence, and levels of ICAM-1 and TNF-α in a rat model of severe non-bacterial cystitis; its effect was more obvious than that of heparin. Reduction of ICAM-1 may play a role in the anti-inflammatory effect of HA.

Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis.

OBJECTIVE: • To compare the efficacy of intravesical hyaluronic acid (HA) instillation and hyperbaric oxygen (HBO) in the treatment of radiation-induced haemorrhagic cystitis (HC). PATIENTS AND METHODS: • In total 36 patients who underwent radiotherapy for their pelvic malignancies and subsequently suffered from HC were randomly divided into an HA group and an HBO group. • Symptoms of haematuria, frequency of voiding and the visual analogue scale of pelvic pain (range 0-10) were evaluated before and after the treatment with follow-up of 18 months. RESULTS: • All patients completed this study and no obvious side effects of intravesical HA were recorded. • The improvement rate showed no statistical difference between the two groups at 6, 12 and 18 months after treatment. • Decrease of frequency was significant in both groups 6 months after treatment, but was only significant in the HA group 12 months after therapy. • The improvement in the visual analogue scale remained significant in both groups for 18 months. CONCLUSIONS: • Intravesical instillation of HA was as effective in treating radiation-induced HC as HBO. • It is well tolerated and resulted in a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12 months.

N-alkylated cyclen cobalt(III) complexes of 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol DNA alkylating agent as hypoxia-activated prodrugs.

A series of cobalt complexes of the potent DNA minor groove alkylator 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol (seco-6-azaCBI-TMI) were prepared from a series of N-substituted cyclen ligands. The final N-substituted complexes carried formal overall charges ranging from +2 to -2 and showed limited improvements in solubility. They showed similar stabilities to that of the complex with the unsubstituted cyclen ligand, and large but variable attenuation of the cytotoxicity of the free alkylator (2-30-fold), compared to 150-fold for the unsubstituted ligand. However, they had oxic/hypoxic ratios (2-22-fold) comparable to that of the unsubstituted cyclen complex (5).

Synthesis of 9,9-dialkyl-4,5-diazafluorene derivatives and their structure-activity relationships toward human carcinoma cell lines.

A homologous set of 9,9-dialkyl-4,5-diazafluorene compounds were prepared by alkylation of 4,5-diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB-231 breast carcinoma, and SKHep-1 hepatoma cells, were investigated; a structure-activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC(50))] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9-dihexyl-4,5-diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in vitro cytotoxicity was not observed at clinically relevant concentrations.