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Unusual radiological presentation of sirolimus-associated pneumonitis.

Wed, 07/24/2013 - 10:00

Unusual radiological presentation of sirolimus-associated pneumonitis.

J Chin Med Assoc. 2013 Jul 19;

Authors: Huang LK, Tsai MJ, Chang SC

Abstract
Sirolimus-associated pneumonitis, a rare but serious drug-induced lung injury, has become a great concern clinically, because of the increasing use of sirolimus (rapamycin) in patients who have been subjected to solid organ transplantation. We report sirolimus-associated pneumonitis in two women who underwent renal transplantation. At variance with previous reports, the radiological findings shown on chest radiographs and computed tomography scans of the chest in these two cases were consolidation lesions mainly with minimal interstitial abnormalities. Our reported cases highlight that awareness of various radiological findings of sirolimus-associated pneumonitis is pivotal for physicians to make early diagnosis of the disorder in patients who have undergone solid organ transplantation.

PMID: 23876831 [PubMed - as supplied by publisher]

Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection.

Wed, 07/24/2013 - 10:00

Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection.

Hum Immunol. 2013 Jul 19;

Authors: Angaswamy N, Tiriveedhi V, Sarma NJ, Subramanian V, Klein C, Wellen J, Shenoy S, Chapman WC, Mohanakumar T

Abstract
Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

PMID: 23876679 [PubMed - as supplied by publisher]

An oversized allograft is associated with improved survival after lung transplantation for idiopathic pulmonary arterial hypertension.

Wed, 07/24/2013 - 10:00

An oversized allograft is associated with improved survival after lung transplantation for idiopathic pulmonary arterial hypertension.

J Heart Lung Transplant. 2013 Jul 19;

Authors: Eberlein M, Diehl E, Bolukbas S, Merlo CA, Reed RM

Abstract
BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is associated with high short-term mortality after bilateral lung transplantation (BLT). Previous studies have suggested that oversized allografts are associated with improved outcomes and that this association was strongest within the first year after transplant. We hypothesized that oversizing the allograft is associated with improved survival after BLT for IPAH.
METHODS: All adults in the United Network of Organ Sharing lung transplant registry who underwent first-time BLT for IPAH between October 1989 and April 2010 were studied. Lung size mismatch was assessed by calculating the predicted total lung capacity (pTLC) ratio of the donor to the recipient. The cohort was divided evenly into "undersized" (pTLC ratio less than the median pTLC ratio) and "oversized" (pTLC ratio exceeding the median pTLC ratio). Risk of death after BLT was analyzed using Kaplan-Meier survival and Cox proportional hazards models.
RESULTS: The mean pTLC ratio was 0.93 ± 0.10 in the 302 undersized patients compared with 1.24 ± 0.14 in the 302 oversized patients. Cohorts had comparable baseline characteristics. Median survival was 831 days longer in the oversized cohort (2,166 vs 1,335 days, p = 0.006). In a multivariate model controlling for sex mismatch, recipient factors, acuity, donor factors, and transplant factors, oversizing was associated with decreased hazard for death at 5 years (hazard ratio, 0.73; 95% CI 0.56-0.96, p = 0.02).
CONCLUSION: Oversizing the allograft is associated with improved survival after BLT for IPAH. In the setting of donor organ shortages and waiting list mortality, it is not practical to intentionally oversize the allograft. However, the pTLC ratio could provide further refinement in the peri-transplant risk assessment.

PMID: 23876630 [PubMed - as supplied by publisher]

Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy.

Wed, 07/24/2013 - 10:00
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Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy.

J Orthop Res. 2013 Jul;31(7):1096-102

Authors: Becerra P, Valdés Vázquez MA, Dudhia J, Fiske-Jackson AR, Neves F, Hartman NG, Smith RK

Abstract
This study aimed to investigate immediate cell survival and distribution following different administration routes of mesenchymal stem cells (MSCs) into naturally occurring tendon injuries. Ten million MSCs, labeled with technetium-99m hexamethylpropyleneamine oxime, were implanted into 13 horses with naturally occurring tendon or ligament injuries intra-lesionally, intravenously and by regional perfusion, and traced for up to 48 h using planar gamma scintigraphy. Labeling efficiencies varied between 1.8% and 18.5% (mean 9.3%). Cells were retained in the damaged area after intra-lesional administration but only 24% of cells were still present within the tendon after 24 h. After intravenous injection, cells largely distributed to the lung fields, with no detectable cells in the tendon lesions. Significant labeling of the tendon lesions was observed in 11/12 horses following regional perfusion but at a lower level to intra-lesional injection. The highest cell numbers were retained after intra-lesional injection, although with considerable cell loss, while regional perfusion may be a viable alternative for MSC delivery. Cells did not "home" to damaged tendon in large numbers after intravenous administration. Cells were detected in the lungs most frequently after intravascular administration, although with no adverse effects. Low cell retention has important implications for designing effective clinical therapies for human clinical use.

PMID: 23508674 [PubMed - indexed for MEDLINE]

Recombinant human endostatin endostar suppresses angiogenesis and lymphangiogenesis of malignant pleural effusion in mice.

Wed, 07/24/2013 - 10:00
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Recombinant human endostatin endostar suppresses angiogenesis and lymphangiogenesis of malignant pleural effusion in mice.

PLoS One. 2012;7(12):e53449

Authors: Ma X, Yao Y, Yuan D, Liu H, Wang S, Zhou C, Song Y

Abstract
BACKGROUND: Malignant pleural effusion (MPE) is a common complication of lung cancer. One widely used treatment for MPE is Endostar, a recombined humanized endostatin based treatment. However, the mechanism of this treatment is still unclear. The aim of this study was to investigate the effects of Endostar in mice with MPE.
METHODS AND MATERIALS: Lewis lung carcinoma (LLC) cell line expressing enhanced green fluorescent protein (EGFP) was injected into pleural cavity to establish MPE mice model. Mice were randomly divided into four groups. High dose of Endostar (30 mg/kg), low dose of Endostar (8 mg/kg), normal saline, or Bevacizumab (5 mg/kg) was respectively injected into pleural cavity three times with 3-day interval in each group. Transverse computed tomography (CT) was performed to observe pleural fluid formation 14 days after LLC cells injection. Mice were anesthetized and sacrificed 3 days after final administration. The volume of pleural effusion n was measured using 1 ml syringe. Micro blood vessel density (MVD), Lymphatic micro vessel density (LMVD), the expression level of vascular endothelial growth factor A (VEGF-A) and VEGF-C were observed by immunohistochemistry (IHC) staining.
RESULTS: The volume of pleural effusion as well as the number of pleural tumor foci, MVD and the expression of VEGF-A were significantly reduced in high dose of Endostar treat group. More importantly, LMVD and the expression of VEGF-C were markedly lower in treat group than those in the other three control groups.
CONCLUSION: Our work demonstrated that Endostar played an efficient anti-cancer role in MPE through its suppressive effect on angiogenesis and lymphangiogenesis, which provided a certain theoretical basis for the effectiveness of Endostar on the MPE treatment.

PMID: 23285296 [PubMed - indexed for MEDLINE]

Lung transplantation triggered "jackhammer esophagus": a case report and review of literature.

Tue, 07/23/2013 - 10:18

Lung transplantation triggered "jackhammer esophagus": a case report and review of literature.

J Neurogastroenterol Motil. 2013 Jul;19(3):390-4

Authors: Khan MQ, Nizami IY, Khan BJ, Al-Ashgar HI

Abstract
A 19-years-old girl was referred for lung transplant due to end stage lung disease secondary to idiopathic bilateral bronchiectasis. Her routine pre lung transplant evaluation showed normal esophageal high-resolution manometry (HRM) and 24-hours impedance pH monitoring. Four weeks after the bilateral sequential lung transplantation (LTx), she developed dysphagia, chest pain and regurgitation, complicated by aspiration pneumonia. Repeated HRM showed Jackhammer esophagus, delayed gastric emptying and abnormal 24-hour pH impedance monitoring consistent with the diagnosis of gastroesophageal reflux disease. Twelve weeks after LTx, she was symptom free, HRM and 24-hour impedance pH monitoring returned to normal. To the best of our knowledge, this rare transient esophageal hypercontractility episode occurred after LTx and recovered without any specific treatment was never reported in literature. The etiopathogenesis of Jackhammer esophagus in general and LTx induced dysmotility in particular is discussed and reviewed.

PMID: 23875107 [PubMed]

The lung in liver disease: old problem, new concepts.

Tue, 07/23/2013 - 10:18

The lung in liver disease: old problem, new concepts.

Trans Am Clin Climatol Assoc. 2013;124:250-62

Authors: Fallon MB, Zhang J

Abstract
Liver dysfunction has been recognized to influence the lung in many different clinical situations, although the mechanisms for these effects are not well understood. One increasingly recognized interaction, the hepatopulmonary syndrome (HPS) occurs in the context of cirrhosis and results when alveolar microvascular dilation causes arterial gas exchange abnormalities and hypoxemia. HPS occurs in up to 30% of patients with cirrhosis and significantly increases mortality in affected patients. Currently, liver transplantation is the only curative therapy. Experimental biliary cirrhosis induced by common bile duct ligation (CBDL) in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and has been contrasted with other experimental models of cirrhosis in which HPS does not develop. Microvascular dilation, intravascular monocyte infiltration, and angiogenesis in the lung have been identified as pathologic features that drive gas exchange abnormalities in experimental HPS. Our recent studies have identified biliary epithelium and activation and interaction between the endothelin-1 (ET-1)/endothelial endothelin B (ETB) receptor and CX3CL1/CX3CR1 pathways as important mechanisms for the observed pathologic events. These studies define novel interactions between the lung and liver in cirrhosis and may lead to effective medical therapies.

PMID: 23874031 [PubMed - in process]

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma.

Tue, 07/23/2013 - 10:18

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma.

Genes Dev. 2013 Jul 15;27(14):1557-67

Authors: Li CM, Chen G, Dayton TL, Kim-Kiselak C, Hoersch S, Whittaker CA, Bronson RT, Beer DG, Winslow MM, Jacks T

Abstract
Metastasis accounts for the vast majority of cancer-related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to the formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically engineered mouse model of lung adenocarcinoma. Nonmetastatic primary tumor-derived cells predominantly expressed a short isoform, Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long to Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared with nonmetastatic cells. Further characterization of these isoforms by knockdown and overexpression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long to Tks5short ratio promotes invadopodia-mediated invasion and metastasis.

PMID: 23873940 [PubMed - in process]

Paracorporeal lung assist device: An innovative surgical strategy for bridging to lung transplant in an infant with severe pulmonary hypertension caused by alveolar capillary dysplasia.

Tue, 07/23/2013 - 10:18

Paracorporeal lung assist device: An innovative surgical strategy for bridging to lung transplant in an infant with severe pulmonary hypertension caused by alveolar capillary dysplasia.

J Thorac Cardiovasc Surg. 2013 Jul 18;

Authors: Boston US, Fehr J, Gazit AZ, Eghtesady P

PMID: 23871141 [PubMed - as supplied by publisher]

A Comparative Analysis of Bronchial Stricture After Lung Transplantation in Recipients With and Without Early Acute Rejection.

Tue, 07/23/2013 - 10:18

A Comparative Analysis of Bronchial Stricture After Lung Transplantation in Recipients With and Without Early Acute Rejection.

Ann Thorac Surg. 2013 Jul 18;

Authors: Castleberry AW, Worni M, Kuchibhatla M, Lin SS, Snyder LD, Shofer SL, Palmer SM, Pietrobon R, Davis RD, Hartwig MG

Abstract
BACKGROUND: Risk factors and outcomes of bronchial stricture after lung transplantation are not well defined. An association between acute rejection and development of stricture has been suggested in small case series. We evaluated this relationship using a large national registry.
METHODS: All lung transplantations between April 1994 and December 2008 per the United Network for Organ Sharing (UNOS) database were analyzed. Generalized linear models were used to determine the association between early rejection and development of stricture after adjusting for potential confounders. The association of stricture with postoperative lung function and overall survival was also evaluated.
RESULTS: Nine thousand three hundred thirty-five patients were included for analysis. The incidence of stricture was 11.5% (1,077/9,335), with no significant change in incidence during the study period (P = 0.13). Early rejection was associated with a significantly greater incidence of stricture (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.22-1.61; p < 0.0001). Male sex, restrictive lung disease, and pretransplantation requirement for hospitalization were also associated with stricture. Those who experienced stricture had a lower postoperative peak percent predicted forced expiratory volume at 1 second (FEV1) (median 74% versus 86% for bilateral transplants only; p < 0.0001), shorter unadjusted survival (median 6.09 versus 6.82 years; p < 0.001) and increased risk of death after adjusting for potential confounders (adjusted hazard ratio 1.13; 95% CI, 1.03-1.23; p = 0.007).
CONCLUSIONS: Early rejection is associated with an increased incidence of stricture. Recipients with stricture demonstrate worse postoperative lung function and survival. Prospective studies may be warranted to further assess causality and the potential for coordinated rejection and stricture surveillance strategies to improve postoperative outcomes.

PMID: 23870829 [PubMed - as supplied by publisher]

Decellularization of Human and Porcine Lung Tissues for Pulmonary Tissue Engineering.

Tue, 07/23/2013 - 10:18

Decellularization of Human and Porcine Lung Tissues for Pulmonary Tissue Engineering.

Ann Thorac Surg. 2013 Jul 18;

Authors: O'Neill JD, Anfang R, Anandappa A, Costa J, Javidfar J, Wobma HM, Singh G, Freytes DO, Bacchetta MD, Sonett JR, Vunjak-Novakovic G

Abstract
BACKGROUND: The only definitive treatment for end-stage organ failure is orthotopic transplantation. Lung extracellular matrix (LECM) holds great potential as a scaffold for lung tissue engineering because it retains the complex architecture, biomechanics, and topologic specificity of the lung. Decellularization of human lungs rejected from transplantation could provide "ideal" biologic scaffolds for lung tissue engineering, but the availability of such lungs remains limited. The present study was designed to determine whether porcine lung could serve as a suitable substitute for human lung to study tissue engineering therapies.
METHODS: Human and porcine lungs were procured, sliced into sheets, and decellularized by three different methods. Compositional, ultrastructural, and biomechanical changes to the LECM were characterized. The suitability of LECM for cellular repopulation was evaluated by assessing the viability, growth, and metabolic activity of human lung fibroblasts, human small airway epithelial cells, and human adipose-derived mesenchymal stem cells over a period of 7 days.
RESULTS: Decellularization with 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) showed the best maintenance of both human and porcine LECM, with similar retention of LECM proteins except for elastin. Human and porcine LECM supported the cultivation of pulmonary cells in a similar way, except that the human LECM was stiffer and resulted in higher metabolic activity of the cells than porcine LECM.
CONCLUSIONS: Porcine lungs can be decellularized with CHAPS to produce LECM scaffolds with properties resembling those of human lungs, for pulmonary tissue engineering. We propose that porcine LECM can be an excellent screening platform for the envisioned human tissue engineering applications of decellularized lungs.

PMID: 23870827 [PubMed - as supplied by publisher]

Energy Expenditure and Nutritional Status in Pediatric Patients before and after Lung Transplantation.

Tue, 07/23/2013 - 10:18

Energy Expenditure and Nutritional Status in Pediatric Patients before and after Lung Transplantation.

J Pediatr. 2013 Jul 16;

Authors: Kalnins D, Pencharz PB, Grasemann H, Solomon M

Abstract
Resting energy expenditure and nutritional status in pediatric patients was determined before and then 1 and 2 years after lung transplantation. Mean resting energy expenditure was increased (132%) before transplantation and declined (112%) after transplantation. Body mass index and weight z-scores improved posttransplantation, but nutritional measurements remained below normal population values.

PMID: 23870785 [PubMed - as supplied by publisher]

Automatic Event Detection in Lung Transplant Recipients Based on Home Monitoring of Spirometry and Symptoms.

Tue, 07/23/2013 - 10:18

Automatic Event Detection in Lung Transplant Recipients Based on Home Monitoring of Spirometry and Symptoms.

Telemed J E Health. 2013 Jul 20;

Authors: Wang W, Finkelstein SM, Hertz MI

Abstract
Abstract Objective: The goal of this study was to develop, implement, and test an automated decision system to provide early detection of clinically important bronchopulmonary events in a population of lung transplant recipients following a home monitoring protocol. Subjects and Methods: Spirometry and other clinical data were collected daily at home by lung transplant recipients and transmitted weekly to the study data center. Decision rules were developed using wavelet analysis of declines in spirometry and increases in respiratory symptoms from a learning set of patient home data and validated with an independent patient set. Results: Using forced expiratory volume in 1 s or symptoms, the detection captured the majority of events (sensitivity, 80-90%) at an acceptable level of false alarms. On average, detections occurred 6.6-10.8 days earlier than the known event records. Conclusions: This approach is useful for early discovery of pulmonary events and has the potential to decrease the time required for humans to review large amount of home monitoring data to discover relatively infrequent but clinically important events.

PMID: 23869394 [PubMed - as supplied by publisher]

Total artificial heart in the pediatric patient with biventricular heart failure.

Tue, 07/23/2013 - 10:18

Total artificial heart in the pediatric patient with biventricular heart failure.

Perfusion. 2013 Jul 18;

Authors: Park S, Sanders D, Smith B, Ryan J, Plasencia J, Osborn M, Wellnitz C, Southard R, Pierce C, Arabia F, Lane J, Frakes D, Velez D, Pophal S, Nigro J

Abstract
Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m(2), thus, limiting pediatric application of this device.This unique case report shares this pediatric institution's first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m(2)) below the recommendation of 1.7m(2). A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.

PMID: 23868320 [PubMed - as supplied by publisher]

Shedding of c-Met ectodomain correlates with c-Met expression in non-small cell lung cancer.

Tue, 07/23/2013 - 10:18
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Shedding of c-Met ectodomain correlates with c-Met expression in non-small cell lung cancer.

Biomarkers. 2013 Mar;18(2):126-35

Authors: Fu L, Guo W, Liu B, Sun L, Bi Z, Zhu L, Wang X, Liu B, Xie Q, Li K

Abstract
OBJECTIVE: The aim of this study is to reveal the correlation of shedding and expression of c-Met in non-small cell lung cancer (NSCLC) patient.
MATERIALS AND METHODS: We measured soluble c-Met and c-Met level in a panel of pre-clinical models and 197 advanced Chinese NSCLC patients by enzyme-linked immunosorbent assay and immunohistochemistry, respectively.
RESULTS: Shedding of soluble c-Met associates with total c-Met amount in pre-clinical models, and soluble c-Met correlates with both c-Met expression level and tumor size in human, high soluble c-Met predicts poorer outcome.

PMID: 23410046 [PubMed - indexed for MEDLINE]

"Iron-saturated" bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice.

Tue, 07/23/2013 - 10:18
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"Iron-saturated" bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice.

BMC Cancer. 2012;12:591

Authors: Sun X, Jiang R, Przepiorski A, Reddy S, Palmano KP, Krissansen GW

Abstract
BACKGROUND: Tamoxifen is used in hormone therapy for estrogen-receptor (ER)-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf), a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers.
METHODS: In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg) were fed an Fe-Lf supplemented diet (5 g/Kg diet) or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumor cell injection. Tumor growth, metastasis, body weight, and levels of interleukin 18 (IL-18) and interferon γ (IFN-γ) were analyzed.
RESULTS: Tamoxifen weakly (IC(50) ~ 8 μM) inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors.
CONCLUSIONS: The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.

PMID: 23231648 [PubMed - indexed for MEDLINE]

An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans-presentation at the tumor site.

Tue, 07/23/2013 - 10:18
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An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans-presentation at the tumor site.

Mol Cancer Ther. 2012 Jun;11(6):1279-88

Authors: Kermer V, Baum V, Hornig N, Kontermann RE, Müller D

Abstract
Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibody-cytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15Rα chain fragment, mimicking physiologic trans-presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL-15Rαsushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15Rβγ) cells and reduced proliferation response on CTLL-2 (IL-15Rαβγ) cells, while in FAP-targeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15Rαβγ) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target-bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed trans-presentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15.

PMID: 22491823 [PubMed - indexed for MEDLINE]

Receptor for Advanced Glycation End Products (RAGE) on iNKT Cells Mediates Lung Ischemia-Reperfusion Injury.

Sat, 07/20/2013 - 10:12

Receptor for Advanced Glycation End Products (RAGE) on iNKT Cells Mediates Lung Ischemia-Reperfusion Injury.

Am J Transplant. 2013 Jul 19;

Authors: Sharma AK, Lapar DJ, Stone ML, Zhao Y, Kron IL, Laubach VE

Abstract
Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia-reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage-produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE(-/-) mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti-HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE(-/-) mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in Jα18(-/-) mice reconstituted with RAGE(-/-) iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia-reoxygenation, alveolar macrophage-derived HMGB1 augmented IL-17 production from iNKT cells in a RAGE-dependent manner. These results suggest that HMGB1-mediated RAGE activation on iNKT cells is critical for initiation of lung IR injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung IR injury.

PMID: 23865790 [PubMed - as supplied by publisher]

[Research on effects of bone marrow mononuclear cells implantation on model of experimental pulmonary artery hypertension].

Sat, 07/20/2013 - 10:12

[Research on effects of bone marrow mononuclear cells implantation on model of experimental pulmonary artery hypertension].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2013 Jun;30(3):601-6

Authors: Lu Y, Zhang Z, Cheng G, Luan Y

Abstract
In the present study, we carried out intratracheal administration of bone marrow-derived mononuclear cells (BM-MNCs) to dehydromonocrotaline (DMCT)-induced canine pulmonary artery hypertension (PH) of rat model to examine the security and feasibility, and the aim was to discuss the mechanism. All animals (n=30) were randomly divided into 3 groups (n=10 in each group), i. e. control group, PH group and BM-MNCs group. Six weeks after the transplantation, the hemodynamic data and right ventricle weight ratio were significantly improved for those in BM-MNCs group compared with those in PH group. The lung mRNA levels of vascular endothelial growth factor (VEGF) were higher, while preproendothelin-1 (ppET-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were lower compared with those in the PH group (P<0. 05). Immunofluorescence and histochemical results confirmed that 6 weeks after the administration, transplanted BM-MNCs were still alive and could differentiate into pulmonary vascular endothelial cells. These results showed that intratracheal administration of BM-MNCs could obviously reduce or even reverse the DMCT induction of PAH process. The mechanism could be explained as that the function was mainly through the paracrine effect to promote renewable and reduce inflammation.

PMID: 23865327 [PubMed - in process]

SHP-1 regulation of mast cell function in allergic inflammation and anaphylaxis.

Sat, 07/20/2013 - 10:12
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SHP-1 regulation of mast cell function in allergic inflammation and anaphylaxis.

PLoS One. 2013;8(2):e55763

Authors: Zhou L, Oh SY, Zhou Y, Yuan B, Wu F, Oh MH, Wang Y, Takemoto C, Van Rooijen N, Zheng T, Zhu Z

Abstract
Allergic inflammation and severe allergic reactions (anaphylaxis) are important in allergen induced diseases. Bacterial products such as lipopolysaccharide (LPS) are ubiquitous and can facilitate allergen induced Th2 immune responses. Phosphatase SHP-1 is critical in regulating immunological homeostasis and in allergen induced Th2 immune responses in the lung. However, the mechanisms underlying the initiation of allergic inflammation and allergen induced anaphylaxis are still not completely elucidated and it is unclear whether SHP-1 plays any role in LPS-induced airway inflammation and in allergen-induced anaphylaxis. In this study we tested the hypothesis that phosphatase SHP-1 plays an important role in allergic inflammation and anaphylaxis and determined whether its effects are through regulation of mast cell functions. SHP-1 deficient (mev/+ and mev/mev) and mast cell deficient (Kit(W-sh)) mice were examined in their responses to LPS airway stimulation and to ovalbumin (OVA) allergen induced systemic anaphylaxis. Compared to wild type mice, mev/+ mice had significantly enhanced LPS induced airway inflammation and OVA induced anaphylactic responses, including hypothermia and clinical symptoms. These changes were mast cell dependent as Kit(W-sh) mice had reduced responses whereas adoptive transfer of mast cells restored the responses. However, T and B cells were not involved and macrophages did not play a significant role in LPS induced airway inflammation. Interestingly, basophil differentiation from SHP-1 deficient bone marrow cells was significantly reduced. These findings provided evidence that through regulation of mast cell functions SHP-1 plays a critical role as a negative regulator in allergic inflammation and in allergen induced anaphylaxis. In addition, SHP-1 seems to be required for normal basophil development.

PMID: 23390550 [PubMed - indexed for MEDLINE]

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