Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.

Active Targeting of P-Selectin by Fucoidan Modulates the Molecular Profiling of Metastasis in Docetaxel-Resistant Prostate Cancer.

The standard of care for prostate cancer (PCa) is androgen deprivation therapy (ADT). Although hormone-sensitive PCa is curable by ADT, most conditions progress to castration-resistant prostate cancer (CRPCa) and metastatic CRPCa (mCRPCa). Front-line docetaxel has been administered to patients with CRPCa and mCRPCa. Nevertheless, docetaxel resistance after half a year of therapy has emerged as an urgent clinical concern in patients with CRPCa and mCRPCa. We verified the mechanism by which docetaxel-resistant PCa cells (DU/DX50) exhibited significant cell migration and expression of malignant tumor-related proteins. Our study shows that the biological activity of fucoidan has an important application for docetaxel-resistant PCa cells, inhibiting IL-1R by binding to P-selectin and reducing the expression levels of NF-κB p50 and Cox2 in this metastasis-inhibiting signaling pathway. Furthermore, the combined treatment of fucoidan and docetaxel showed significant anticancer and synergistic effects on the viability of DU/DX50 cells, which is relevant for overcoming the current limitations and improving treatment outcomes. Overall, fucoidan-based combination chemotherapy may exert beneficial effects and facilitate the treatment of docetaxel-resistant PCa.

Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation.

In previously published studies, intra-arterial (i.a.), but not intravenous (i.v.) delivery of recombinant tissue-type plasminogen activator (rtPA) immobilized on the surface of magnetic nanoparticles induces thrombolysis by magnetic targeting. We asked whether i.v. delivery of protected rtPA in a thermosensitive magnetoliposome (TML@rtPA) may achieve target thrombolysis. PEGylated TML@rtPA was optimized and characterized; controlled release of rtPA was achieved by thermodynamic and magnetic manipulation in vitro. The lysis index of TML@rtPA incubated with blood at 43 °C vs. 37 °C was 53 ±â€¯11% vs. 81 ±â€¯3% in thromboelastograms, suggesting thermosensitive thrombolysis of TML@rtPA. In a rat embolic model with superfusion of 43 °C saline on a focal spot on the iliac artery with clot lodging, release of rtPA equivalent to 20% regular dose from TML@rtPA administered i.a. vs. i.v. significantly restored iliac blood flow 15 vs. 55 min after clot lodging, respectively. TML@rtPA with magnetic guiding and focal hyperthermia may be potentially amendable to target thrombolysis.

Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation.

In thrombolytic therapy, plasminogen activators (PAs) are still the only group of drug approved to induce thrombolysis, and therefore, critical for treatment of arterial thromboembolism, such as stroke, in the acute phase. Functionalized nanocomposites have attracted great attention in achieving target thrombolysis due to favorable characteristics associated with the size, surface properties and targeting effects. Many PA-conjugated nanocomposites have been prepared and characterized, and some of them has been demonstrated with therapeutic efficacy in animal models. To facilitate future translation, this paper reviews recent progress of this area, especially focus on how to achieve reproducible thrombolysis efficacy in vivo.

Effect of intense pulsed light on the expression of aquaporin 3 in rat skin.

Intense pulsed light (IPL) technology has been popularly employed in clinical treatments for dermatological and cosmetic purposes in recent years; yet, the underlying mechanisms of its functions are not fully elucidated. On the other hand, aquaporin (AQP) 3, a member of a subgroup of the aquaporin family that transports both water and small solutes, such as glycerol, has been documented to play an important role in the skin homeostasis. We thus examined the possible involvement of AQP3 in the functional mechanisms of IPL irradiation. Rat dorsal skin areas were irradiated one to three times with IPL at doses of 15, 25, and 35 J/cm2. Skin specimens were collected 7 days after the final irradiation and analyzed for changes in histology, skin hydration, mRNA, and protein expressions of AQP3. IPL induced no significant variations in the mRNA expression levels. Twice or thrice irradiation at the dose of 25 or 35 J/cm2 significantly enhanced AQP3 protein expression. Immunofluorescence study revealed that AQP3 was mainly localized to keratinocyte membranes in the basal layer of epidermis, and the localization was unaltered by IPL. In addition, the pattern of IPL-induced changes in skin hydration was generally coincided with the expression profile of AQP3. These results suggest the possibility that one of the functional mechanisms of IPL might be related to the regulation of AQP3 protein expression.

Mixed epithelial and stromal tumor of the kidney with elevated serum level of cancer antigen 125.

Mixed epithelial and stromal tumor of the kidney is a newly categorized lesion, with few reported cases. We report a rare case of a 45-year-old woman with a palpable abdominal mass and elevated serum level of serum cancer antigen 125, who was not receiving hormones or contraceptive agents. Abdominal magnetic resonance imaging revealed a large multilocular cystic tumor that arose in the left central kidney. Nephrectomy was performed under the initial impression of cystic renal cell carcinoma; however, a diagnosis of mixed epithelial and stromal tumor was confirmed according to pathological and immunohistochemical findings. Serum level of cancer antigen 125 returned to normal after 1 month postoperatively and no recurrence was found in the following 18 months.

Large pedunculated lipoma of the esophagus.

Pedunculated lipoma of the esophagus is rare and easily misdiagnosed in clinical practice. The presenting symptoms of esophageal lipoma are dysphagia, regurgitated mass and persistent sensation of a lump in the throat. The most frequent location of the tumor pedicle is the upper esophageal sphincter. Although the lipoma is pathologically benign, if it is large enough, it may cause airway obstruction secondary to the mechanical pressure to the larynx when the tumor is regurgitated. We present the case of a 67-year-old man who had the symptoms of dysphagia, nausea and vomiting. Esophagography and chest computed tomography revealed that he might have an esophageal submucosal or intraluminal tumor mass. Panendoscopy showed a pedunculated tumor mass within the esophageal lumen with its peduncle arising from the cervical esophagus. The tumor mass measured 9.0 x 4.7 x 2.5 cm in size. Thoracic approach via the right chest wall was performed for confirmation. After removal of the intraluminal mass, the patients symptoms dramatically improved. Pathology showed a lipoma arising from the submucosa of the esophagus.

Magnetically controlled release of recombinant tissue plasminogen activator from chitosan nanocomposites for targeted thrombolysis.

Ionic cross-linking of water-soluble chitosan with sodium tripolyphosphate in the presence of recombinant tissue plasminogen activator (rtPA) and magnetite (Fe3O4) nanoparticles could produce rtPA-encapsulated magnetic chitosan nanoparticles (MCNPs-rtPA). MCNPs do not elicit cytotoxicity and hemolysis in vitro. MCNPs-rtPA showed a negligible release of the rtPA protein when stored in phosphate buffer for 28 days. In contrast, the burst release of rtPA from MCNPs-rtPA was found in the serum with 60% of the original activity released in 30 min. The drug release into the serum is also magnet-sensitive; the release could be turned down with a magnetic field when MCNPs-rtPA was pelleted and reversibly turned on after removing the magnetic field when MCNPs-rtPA was dispersed. An in vitro thrombolytic study by thromboelastometry indicated a controlled release of rtPA from MCNPs-rtPA. In a rat embolic model where a preformed blood clot lodged in the left iliac artery upstream of the pudic epigastric branch, MCNPs-rtPA (0.2 mg kg-1 rtPA) was administered and guided magnetically to the clot, followed by mobile magnetic guidance for 60 min. Iliac blood flow increased immediately in response to the treatment, and reached a stable level ∼50 min after drug administration and the hind limb perfusion rate was restored from 53% to 75% of the basal level. Effective thrombolysis was therefore successfully demonstrated at an rtPA dose equivalent to 20% of the regular dose when the MCNPs-rtPA pellet was magnet-guided to the blood clot, followed by a triggered release of rtPA when switched to mobile magnetic guidance.

Medical device surveillance: gender differences in pulmonary artery rupture after pulmonary artery catheterization.

BACKGROUND: Pulmonary artery (PA) rupture is a rare but often fatal complication of PA catheterization. METHODS: An analysis was performed of all the case reports of PA rupture after PA catheterization that were submitted to the Food and Drug Administration's Medical Device Reporting (MDR) system between the years 1991 and 2001. The MDR system is a national passive surveillance system that includes adverse event reports from such sources as manufacturers and healthcare professionals. The Nationwide Inpatient Sample (NIS), a massive, nationally representative database maintained by the Agency for Healthcare Research and Quality, was examined to study patterns of PA catheter use. RESULTS: A total of 71 PA rupture cases were identified from the MDR data. The most likely outcome following PA rupture was death. These PA ruptures were associated with 47 deaths and 24 injuries. The range of reported ages of the cases was between 40 and 91 years, with a mean age of 74 years. Of the 71 PA rupture cases, 52 were in women and 10 were in men, with gender not reported in 9 of the cases. There were significantly more cases in women than expected (Mantel-Haenszel common odds ratio estimate = 5.84, 95% confidence interval = 2.97 - 11.46, p < 0.001). CONCLUSIONS: These data suggest that women may be at significantly greater risk of PA rupture after PA catheterization than men. Clinicians must be aware of the potential for this complication of PA catheterization.

Aneurysm-related mortality rates in the US AneuRx clinical trial.

BACKGROUND: The AneuRx (Medtronic) stent graft was approved by the FDA in September 1999. The purpose of this study was to ascertain the aneurysm-related mortality rate of a subgroup of the patient cohort from Medtronic's investigational premarket study. STUDY DESIGN: There were 931 study subjects, from 19 medical centers, who were followed for an average of 3.48 years. Abdominal aortic aneurysm (AAA)-related mortality rates were examined, using death certificates and medical records. RESULTS: The 1-month postimplant death rate was 1.61%. Not counting deaths related to the initial implant, there was an increase in the rate of AAA-related mortality after 3 years, from an average of 0.18% in the first 3 years to an average of 1.39% in years 4 and 5. CONCLUSIONS: Mortality in patients implanted with an AneuRx graft (as determined in this study) probably exceeds that of open procedure patients (based on medical literature) at some point in time, likely within 4 years after implant.

Tuberculous myofasciitis in dermatomyositis.

Extraspinal musculoskeletal tuberculosis (TB) was an uncommon manifestation with a frequency about 1 to 2% in all TB patients. According to the report, tuberculous arthritis and osteomyelitis remained the two leading etiologies, while others constituted less than 2% of all extraspinal musculoskeletal tuberculous infections; less than 0.04% of those who suffered from TB were represented as extraspinal musculoskeletal tuberculous infections, neither tuberculous arthritis- nor osteomyelitis-associated. We presented one extremely rare case of primary tuberculous myofasciitis manifesting painful swelling on the left thigh without previous history of tuberculous infection in a patient with dermatomyositis. We also lodged several predisposing symptoms, such as gradually enlarging swelling of extremity within months and proximal muscle painful weakness with prompt response to steroid, which may help early diagnosing of analogous extraspinal musculoskeletal tuberculosis in dermatomyositis patients; and seasonable administrating of anti-TB agents could prevent deterioration in advance.