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Overall mental distress and health-related quality of life after solid-organ transplantation: results from a retrospective follow-up study.

Sat, 02/09/2013 - 13:45
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Overall mental distress and health-related quality of life after solid-organ transplantation: results from a retrospective follow-up study.

Health Qual Life Outcomes. 2013 Feb 8;11(1):15

Authors: Baranyi A, Krauseneck T, Rothenhäusler HB

Abstract
ABSTRACT: BACKGROUND: Our retrospective follow-up study aimed to explore the degree of overall mental distress in a cohort of solid-organ transplantation (SOT) recipients after liver, heart or lung transplantation. Furthermore, we investigated how overall mental distress is linked to health-related quality of life. METHODS: 123 SOT patients treated during the study period were enrolled in this investigation at a mean of 24.6 months (SD=11.6) after transplantation. Before transplantation, the Transplant Evaluation Rating Scale (TERS) was used to classify the level of adjustment in psychosocial functioning among transplantation candidates. After transplantation, recipients completed a research battery, which included the SCL-90-R, and the SF-36. RESULTS: 39 (31.7 %) transplantation recipients had clinically significant overall mental distress as measured on the Global Severity Index of the SCL-90-R. Obsessive-compulsive symptoms (92.3%), somatization symptoms (87.2%), anxiety symptoms (84.6%), depression symptoms (82.1%) and phobic anxiety symptoms (69.2%) were a frequent finding.Transplantation recipients with overall mental distress had significant lower levels of adjustment in psychosocial functioning before transaplantation than those without overall mental distress as measured in the TERS. Transplantation-related overall mental distress symptomatology was associated with maximal decrements in health-related quality of life. CONCLUSION: Transplantation recipients may face major transplantation- and treatment-related overall mental distress and impairments to their health-related quality of life. Further, overall mental distress is a high-risk factor in intensifying impairments to patients' overall quality of life.

PMID: 23391215 [PubMed - as supplied by publisher]

Pulmonary manifestations of chronic granulomatous disease.

Sat, 02/09/2013 - 13:45
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Pulmonary manifestations of chronic granulomatous disease.

Expert Rev Clin Immunol. 2013 Feb;9(2):153-60

Authors: Mahdaviani SA, Mohajerani SA, Rezaei N, Casanova JL, Mansouri SD, Velayati AA

Abstract
Chronic granulomatous disease (CGD) is an inherited disorder, characterized by defects in superoxide-generating NADPH oxidase of phagocytes. The genetic defects in CGD induce failure to activate the respiratory burst in the phagocytes, leading to severe recurrent infections and unexplained prolonged inflammatory reactions that may produce granulomatous lesions. A noble advance in curative therapy for CGD is hematopoietic stem cell transplantation. Since the most common site of involvement in CGD is the lung, the pulmonologists (pediatrics or adult) may be among the first to recognize the pattern of infection, inflammation and granuloma formation, leading to diagnosis of CGD. Pulmonologists need to be aware of different lung manifestations of CGD.

PMID: 23390946 [PubMed - in process]

Recurrent spontaneous pneumothorax in a 42 years old woman with pulmonary lymphangioleiomyomatosis: insights and pitfalls of the surgical treatment.

Fri, 02/08/2013 - 12:14

Recurrent spontaneous pneumothorax in a 42 years old woman with pulmonary lymphangioleiomyomatosis: insights and pitfalls of the surgical treatment.

J Clin Med Res. 2013 Feb;5(1):70-4

Authors: Spiliopoulos K, Tsantsaridou A, Papamichali R, Kimpouri K, Salemis NS, Koukoulis GK, Tsilimingas NB

Abstract
Lymphangioleiomyomatosis (LAM) is a rare disease that occurs predominantly in females between the ages of 30 and 50 years and is clinically characterized by progressive dyspnoea on exertion, recurrent pneumothoraces, abdominal and thoracic lymphadenopathy, as well tumors-like angiomyolipomas and lymphangiomyomas. We present the case of a 42-year-old woman, who developed recurrent pneumothoraces and was subsequently diagnosed with LAM. Although pneumothorax is a common complication of the disease, its optimal approach to treatment and prevention remains unclear. Chemical or surgical pleurodesis are often performed in order to prevent recurrence, but may predispose to perioperative complications in the event of future lung transplantation.

PMID: 23390481 [PubMed - in process]

Key Diagnostic Features of Granulomatous Interstitial Nephritis Due to Encephalitozoon cuniculi in a Lung Transplant Recipient.

Fri, 02/08/2013 - 12:14

Key Diagnostic Features of Granulomatous Interstitial Nephritis Due to Encephalitozoon cuniculi in a Lung Transplant Recipient.

Am J Surg Pathol. 2013 Mar;37(3):447-52

Authors: Levine DJ, Riley DJ, Jorgensen JH, McClain WD, Tio F, Visvesvara GS, Abboud-Werner SL

Abstract
Microsporidia are increasingly recognized as opportunistic pathogens in immunocompromised organ transplant recipients (OTR). Disseminated infection due to Encephalitozoon sp. is reported mainly in human immunodeficiency virus (HIV)-positive patients and rarely in HIV-negative OTR. The clinical spectrum ranges from keratoconjunctivitis, to pneumonitis, to acute kidney injury. The kidney is a common site for disseminated infection; however, specialized techniques are required for definitive diagnosis. We report the first case of disseminated Encephalitozoon cuniculi infection in an HIV-negative lung transplant recipient diagnosed on renal biopsy. Five months after transplant, he presented with fever and a lung infiltrate and developed acute kidney injury. Renal biopsy showed granulomatous interstitial nephritis with gram-positive rod-shaped organisms with a "belt-like stripe" in tubular epithelial cells. Electron microscopy, polymerase chain reaction, and mammalian cell cultures of the urine sediment confirmed E. cuniculi infection. Retrospective review of a previous lung biopsy showed similar organisms. On the basis of electron microscopy findings, the patient was treated with albendazole, and immunosuppressive therapy was reduced. However, the patient expired due to Aspergillus pneumonia and disseminated E. cuniculi infection. Microsporidia should be considered in cases of fever of unknown origin and/or multiorgan infection in HIV-negative OTR when other causes have been excluded, as successful treatment requires early detection.

PMID: 23388129 [PubMed - in process]

Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis.

Fri, 02/08/2013 - 12:14

Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis.

Transpl Infect Dis. 2013 Feb 6;

Authors: Sayah DM, Schwartz BS, Kukreja J, Singer JP, Golden JA, Leard LE

Abstract
Despite the adoption of antifungal prophylaxis, fungal infections remain a significant concern in lung transplant recipients. Indeed, some concern exists that such prophylaxis may increase the risk of infection with drug-resistant fungal organisms. Here, we describe a case of disseminated Scedosporium prolificans infection, presenting as pericarditis, which developed in a lung transplant patient receiving prophylactic voriconazole for 8 months. The epidemiology and clinical presentation of S. prolificans infections are reviewed, and controversies surrounding antifungal prophylaxis and the development of resistant infections are discussed.

PMID: 23387799 [PubMed - as supplied by publisher]

Effect of positive end-expiratory pressure after porcine unilateral left lung transplant.

Fri, 02/08/2013 - 12:14

Effect of positive end-expiratory pressure after porcine unilateral left lung transplant.

Exp Clin Transplant. 2013 Feb;11(1):50-5

Authors: Madke GR, Forgiarini LA, Grün G, Fontena E, Pereira RB, de Moraes MM, Mariano R, Cardoso PF, Felix EA, Andrade CF

Abstract
OBJECTIVES: To evaluate the effects of 2 different levels of positive end-expiratory pressure on pigs who had unilateral lung transplants.
MATERIALS AND METHODS: A left lung transplant was performed in 12 pigs. The animals were randomized into 2 groups based on positive end-expiratory pressure: group 1 (5 cm H2O) and group 2 (10 cm H2O). Hemodynamics, gas exchange, and respiratory mechanics were measured before and after surgery. Cytokines, oxidative stress, and histologic scores were assessed in the lung tissue of each pig.
RESULTS: Pigs in group 2 exhibited a significantly higher mean heart rate (P = .006), static compliance (P = .001), lower mean arterial pressure (P = .003), and airway resistance (P = .001) than did pigs in group 1. There were no postoperative differences between the groups in concentrations of thiobarbituric acid reactive substances, superoxide dismutase, and interleukin 8. At the end of the observation period, pigs in group 2 had higher levels of thiobarbituric acid reactive substances (P = .001) and interleukin 8 (P = .05), and pigs in group 1 had higher levels of superoxide dismutase (P = .05) than they did at baseline.
CONCLUSIONS: After unilateral lung transplant, higher positive end-expiratory pressure was associated with improved respiratory mechanics, a negative effect on hemodynamics, a stronger inflammatory response, and increased production of reactive oxygen species, but no effect on gas exchange.

PMID: 23387542 [PubMed - in process]

Ischemic postconditioning reduces ischemic reperfusion injury of non-heart-beating donor grafts in a rat lung transplant.

Fri, 02/08/2013 - 12:14

Ischemic postconditioning reduces ischemic reperfusion injury of non-heart-beating donor grafts in a rat lung transplant.

Exp Clin Transplant. 2013 Feb;11(1):44-9

Authors: Hu QH, Luo FY, Luo WJ, Wang L

Abstract
OBJECTIVES: This study was designed to see if ischemic postconditioning could attenuate ischemic reperfusion injury of transplanted lungs recovered from non-heart-beating donors.
MATERIALS AND METHODS: Forty Sprague-Dawley rats were randomized into 2 groups: the control group and the ischemic postconditioning group, with 10 donor rats paired with 10 recipient rats in each group. Twenty rats underwent a left lung transplant from non-heart-beating donors with a warm ischemia time of 36.7 ± 5.62 minutes. In the ischemic postconditioning group, 5 cycles of 1-minute reperfusion and 1-minute reocclusion at the onset of reperfusion were applied as postconditioning. Arterial blood gas, wet-to-dry lung weight ratio, activities of malondialdehyde and superoxide dismutase, and expressions of apoptosis and ICAM-1 mRNA were compared.
RESULTS: When compared with the control group 4 hours after reperfusion, PaO2 was higher, and wet-to-dry lung weight ratio was lower, in the ischemic postconditioning group, and expression of apoptosis and ICAM-1 mRNA as well as activity of malondialdehyde were lower, while superoxide dismutase activity was higher in the ischemic postconditioning group.
CONCLUSIONS: Ischemic postconditioning can reduce ischemic reperfusion injury of lungs recovered from non-heart-beating donors and preserve lung function by reducing reactive oxygen species and inhibiting apoptosis and inflammation.

PMID: 23387541 [PubMed - in process]

Stem cell transplantation as a therapy for cardiac fibrosis.

Fri, 02/08/2013 - 12:14
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Stem cell transplantation as a therapy for cardiac fibrosis.

J Pathol. 2013 Jan;229(2):347-54

Authors: Elnakish MT, Kuppusamy P, Khan M

Abstract
Cardiac fibrosis is a fundamental constituent of most cardiac pathologies and represents the upshot of nearly all types of cardiac injury. Generally, fibrosis is a scarring process, characterized by accumulation of fibroblasts and deposition of increasing amounts of extracellular matrix (ECM) proteins in the myocardium. Therapeutic approaches that control fibroblast activity and evade maladaptive processes could represent a potential strategy to attenuate progression towards heart failure. Currently, cell therapy is actively perceived as an alternative to traditional pharmacological management of myocardial infarction (MI). The majority of the studies applying stem cell therapy following MI have demonstrated a decline in fibrosis. However, it was not clearly recognized whether the decline in cardiac fibrosis was due to replacement of dead cardiomyocytes or because of the direct effects of paracrine factors released from the transplanted stem cells on the ECM. Therefore, the main focus of this review is to discuss the impact of different types of stem cells on cardiac fibrosis and associated cardiac remodelling in a variety of experimental models of heart failure, particularly MI.

PMID: 23011894 [PubMed - indexed for MEDLINE]

Dietary supplementation with curcumin enhances metastatic growth of Lewis lung carcinoma in mice.

Fri, 02/08/2013 - 12:14
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Dietary supplementation with curcumin enhances metastatic growth of Lewis lung carcinoma in mice.

Int J Cancer. 2013 Jan 15;132(2):269-75

Authors: Yan L

Abstract
Our study investigated the effects of dietary supplementation with curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] on spontaneous metastasis of Lewis lung carcinoma (LLC) in C57BL/6 mice. Mice were fed with the AIN93G control diet or with the diet supplemented with 2 or 4% curcumin for 5 weeks at which time they were injected subcutaneously with 2.5 × 10(5) viable LLC cells. The subcutaneous primary tumor was surgically removed when it reached ~ 8 mm in diameter, and the experiment was terminated 10 days after the surgery. There was no difference in pulmonary metastatic yield among the groups. Curcumin supplementation at either dietary level did not significantly increase the size of metastatic tumors; however, the combined data from both curcumin groups showed that curcumin treatment increased metastatic tumor cross-sectional area by 46% (p < 0.05) and volume by 70% (p < 0.05) compared to the controls. Curcumin supplementation increased plasma concentrations of angiogenic factors angiogenin (p < 0.05), basic fibroblast growth factor (p < 0.05) and vascular endothelial growth factor (p < 0.05), as well as inflammatory cytokines interleukin-1β (p < 0.05) and monocyte chemotactic protein-1 (p < 0.05), compared to the controls. These results demonstrate that curcumin does not prevent metastasis and indicate that it can enhance metastatic growth of LLC in mice, perhaps through upregulation of angiogenesis and inflammation.

PMID: 22729592 [PubMed - indexed for MEDLINE]

G-CSF rescues tumor growth and neo-angiogenesis during liver metastasis under host angiopoietin-2 deficiency.

Fri, 02/08/2013 - 12:14
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G-CSF rescues tumor growth and neo-angiogenesis during liver metastasis under host angiopoietin-2 deficiency.

Int J Cancer. 2013 Jan 15;132(2):315-26

Authors: Im JH, Tapmeier T, Balathasan L, Gal A, Yameen S, Hill S, Smart S, Noterdaeme O, Kelly M, Brady M, Fu W, Kruse K, Bernhard EJ, Augustin HG, Muschel RJ

Abstract
Suppression of neo-angiogenesis is a clinically used anti-tumor strategy with new targets such as angiopoietin-2 (Ang2) being proposed. However, the functions of Ang2 in vascular remodeling, inflammation and tumor growth are not consistent. We examined effect of depletion of host Ang2 on liver colony formation using Ang2 deficient (Ang2(-/-)) mice. Surprisingly, the metastatic colonies formed in Ang2(-/-) mice were larger than those in the wild type. These colonies had greater vascular density with more pericyte coverage than the vessels in liver colonies in the wild type. Liver VEGF concentration in both genotypes was equivalent, and thus, the differences appeared VEGF independent. However, after colony formation, the serum concentration of granulocyte-colony stimulating factor (G-CSF) and CXCL1 in Ang2(-/-) mice was 12 and 6 times greater than after colony formation in wild type. Increase of these two cytokines was associated with two times greater numbers of neutrophils recruited to the liver. Two times more Tie2+/CD11b+/CD31- cells were present in the tumors in Ang2(-/-) than in the wild type livers. These results suggest that the depletion of host Ang2 induced compensatory VEGF-independent angiogenic mechanisms and thus enhanced liver metastatic colony growth and colony vascularity. They further indicate organotypic differences in response to tumor metastasis. In contrast, Ang2 deficiency inhibited tumor growth during metastatic colony formation in the lung, consistent with the reports of decreased pulmonary seeding of tumor cells after pharmacological inhibition of Ang2. Further studies are thus required to assess the effects of pharmacological Ang2 blockade for cancer patients particularly in the liver.

PMID: 22699974 [PubMed - indexed for MEDLINE]

The role of CXCR3 and CXCR4 in colorectal cancer metastasis.

Fri, 02/08/2013 - 12:14
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The role of CXCR3 and CXCR4 in colorectal cancer metastasis.

Int J Cancer. 2013 Jan 15;132(2):276-87

Authors: Murakami T, Kawada K, Iwamoto M, Akagami M, Hida K, Nakanishi Y, Kanda K, Kawada M, Seno H, Taketo MM, Sakai Y

Abstract
Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4-mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3-, CXCR4-, and CXCR3/CXCR4 double-knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3- and CXCR3/CXCR4 double-knockdowns. In addition, CXCR3- and CXCR3/CXCR4 double-knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.

PMID: 22689289 [PubMed - indexed for MEDLINE]

Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo.

Fri, 02/08/2013 - 12:14
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Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo.

Breast Cancer Res. 2012;14(1):R36

Authors: Lahlou H, Sanguin-Gendreau V, Frame MC, Muller WJ

Abstract
INTRODUCTION: Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer.
METHODS: To directly evaluate the role of FAK in mammary tumour progression, we have used a conditional FAK mouse model and mouse mammary tumour virus (MMTV)-driven Cre recombinase strain to inactivate FAK in the mammary epithelium of a transgenic mouse model of ErbB2 breast cancer.
RESULTS: Although mammary epithelial disruption of FAK in this model resulted in both a delay in onset and a decrease in the number of neoplastic lesions, mammary tumours occurred in 100% of virgin female mice. All of the tumours and derived metastases that developed were proficient for FAK due to the absence of Cre recombinase expression. The hyperplastic epithelia where Cre-mediated recombination of FAK could be detected exhibited a profound proliferative defect. Consistent with these observations, disruption of FAK in established tumour cells resulted in reduced tumour growth that was associated with impaired proliferation. To avoid the selection for FAK-proficient ErbB2 tumour epithelia through escape of Cre-mediated recombination, we next intercrossed the FAK conditional mice with a separate MMTV-driven ErbB2 strain that co-expressed ErbB2 and Cre recombinase on the same transcriptional unit.
CONCLUSIONS: While a delay in tumour induction was noted, FAK-deficient tumours arose in 100% of female animals indicating that FAK is dispensable for ErbB2 tumour initiation. In addition, the FAK-null ErbB2 tumours retained their metastatic potential. We further demonstrated that the FAK-related Pyk2 kinase is still expressed in these tumours and is associated with its downstream regulator p130Cas. These observations indicate that Pyk2 can functionally substitute for FAK in ErbB2 mammary tumour progression.

PMID: 22373082 [PubMed - indexed for MEDLINE]

Contribution of CXCL12 secretion to invasion of breast cancer cells.

Fri, 02/08/2013 - 12:14
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Contribution of CXCL12 secretion to invasion of breast cancer cells.

Breast Cancer Res. 2012;14(1):R23

Authors: Boimel PJ, Smirnova T, Zhou ZN, Wyckoff J, Park H, Coniglio SJ, Qian BZ, Stanley ER, Cox D, Pollard JW, Muller WJ, Condeelis J, Segall JE

Abstract
INTRODUCTION: Neu (HER2/ErbB2) is overexpressed in 25% to 30% of human breast cancer, correlating with a poor prognosis. Researchers in previous studies who used the mouse mammary tumor virus Neu-transgenic mouse model (MMTV-Neu) demonstrated that the Neu-YB line had increased production of CXCL12 and increased metastasis, whereas the Neu-YD line had decreased metastasis. In this study, we examined the role of increased production of CXCL12 in tumor cell invasion and malignancy.
METHODS: We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or by increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony-stimulating factor 1 receptor (CSF-1R) blocking antibody.
RESULTS: The Neu-YD strain was reduced in invasion, intravasation and metastasis compared to the Neu-YB and Neu deletion mutant (activated receptor) strains. Remarkably, in the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12-CXCR4 and CSF1-CSF-1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Overexpression of CXCL12 in rat mammary adenocarcinoma cells increased in vivo invasion as well as microvessel and macrophage density.
CONCLUSIONS: Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.

PMID: 22314082 [PubMed - indexed for MEDLINE]

Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers.

Fri, 02/08/2013 - 12:14
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Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers.

Breast Cancer Res. 2012;14(1):R18

Authors: Weng D, Penzner JH, Song B, Koido S, Calderwood SK, Gong J

Abstract
INTRODUCTION: It is still uncertain whether metastasis is predominantly an early or late event in tumor progression. The detection of early metastases and cells responsible for the dissemination may therefore have significant clinical implications.
METHODS: Lung dissemination and/or metastasis were investigated in mice carrying the polyomavirus middle-T oncogene (PyMT) during different stages of mammary tumorigenesis using the colony forming assay. Immunocytochemical or immunohistochemical staining was used to identify subpopulations of cells responsible for lung dissemination and metastasis. Histological examination was used to show primary and metastatic tumors. The tumor-initiating and metastatic capacity of cells expressing stem cell markers was assessed in syngeneic wild-type (WT) mice whose mammary fat pads were injected with these cells.
RESULTS: Metastatic mammary epithelial cells were detected in the lungs of mice carrying the PyMT oncogene (MMT mice). These cells were observed early in breast tumorigenesis when the mammary tree appeared by histological inspection to be normal (or at a premalignant stage), suggesting the possession of disseminating and metastatic capacity even before full malignant transformation. Some of the disseminated cells and lung metastases displayed surface stem cell markers. These findings suggest that stem cells from apparently precancerous primary lesions could be a source of metastasis. Indeed, injection of lung tissue cells from MMT mice into syngeneic WT mice resulted in the formation of mammary tumors. These tumors resembled their parent mammary tumors in the MMT donors as well as grafted tumors derived from mammary tumor cells. Furthermore, when we injected lung tissue cells from GFP MMT mice into the fat pads of recipient WT mice, disseminated or metastatic GFP-expressing cells were detected in the lungs, lymph nodes and blood of the recipient WT mice. We finally identified a subpopulation of mammary epithelial/tumor cells expressing CD44 and Sca1 that was largely responsible for dissemination and metastasis in MMT mice.
CONCLUSIONS: The tumorigenic and metastatic potential of a subpopulation of mammary epithelial/tumor cells in MMT mice is endowed relatively early in mammary neoplasms and suggests a potential role for cancer stem cell sub-populations in metastasis.

PMID: 22277639 [PubMed - indexed for MEDLINE]

Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes.

Fri, 02/08/2013 - 12:14
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Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes.

Breast Cancer Res. 2012;14(1):R8

Authors: Ferguson RD, Novosyadlyy R, Fierz Y, Alikhani N, Sun H, Yakar S, Leroith D

Abstract
INTRODUCTION: Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.
METHODS: Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases.
RESULTS: We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels.
CONCLUSIONS: Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.

PMID: 22226054 [PubMed - indexed for MEDLINE]

Acyclovir-resistant herpetic keratitis in a solid-organ transplant recipient on systemic immunosuppression.

Thu, 02/07/2013 - 12:27

Acyclovir-resistant herpetic keratitis in a solid-organ transplant recipient on systemic immunosuppression.

Clin Ophthalmol. 2013;7:229-32

Authors: Turner LD, Beckingsale P

Abstract
PURPOSE: To report a case of acyclovir-resistant herpetic keratitis in a solid-organ lung transplant recipient that was effectively treated with topical trifluridine.
METHODS: A case of a 35-year-old female with herpetic epithelial keratitis resistant to acyclovir is described. The patient presented following treatment for 4 weeks with topical acyclovir ointment five times per day and oral valacyclovir 1 g three times per day for herpetic keratitis with no resolution of the epithelial defect or symptoms. Corneal scrapes and swabs were taken for confirmation of the diagnosis and resistance testing. The results were positive for herpes simplex virus 1 and showed acyclovir resistance (inhibitor concentration 90 = 200 μg/mL) and foscarnet sensitivity (inhibitor concentration 90 = 200 μg/mL). The patient was treated with topical trifluridine 2-hourly for 3 weeks and weaned off the drops over the following week.
RESULTS: The patient showed resolution of the epithelial defect, but did have significant corneal toxicity associated with the use of the trifluridine. At 8 weeks, the patient had some stromal shadowing associated with the recent active infection, but symptoms had settled.
CONCLUSION: This case documents the effective use of topical trifluridine in proven acyclovir-resistant herpetic keratitis. It highlights three things: (1) the importance of considering topical trifluridine as an alternative to topical acyclovir in unresponsive disease; (2) the need to consider solid-organ transplant recipients in the immunocompromised population with resistant herpetic disease, and (3) the need to look for alternatives to treatment of resistant herpetic disease.

PMID: 23386782 [PubMed - in process]

Are the enzymatic methods currently being used to measure bronchoalveolar lavage bile salt levels fit for purpose?

Thu, 02/07/2013 - 12:27

Are the enzymatic methods currently being used to measure bronchoalveolar lavage bile salt levels fit for purpose?

J Heart Lung Transplant. 2013 Feb 2;

Authors: Parikh S, Brownlee IA, Robertson AG, Manning NT, Johnson GE, Brodlie M, Corris PA, Ward C, Pearson JP

Abstract
BACKGROUND: Microaspiration after gastroesophageal reflux has been implicated in the chronic loss of allograft function in lung transplant patients. Bronchoalveolar lavage fluid (BALF) assessment for pepsin and bile salts is a common method to document reflux and aspiration. Clinically used methods for bile salt analysis include tandem mass spectrometry and diagnostic enzymatic kits designed to measure bile salts in serum. In clinical research, the enzymatic kits have been commonly used for BALF assays in lung transplant recipients, with reports of detection limits of 0.2 μmol/liter, and the levels used to inform clinical decisions. This study assessed the sensitivity of detection by 2 enzymatic assay kits compared with tandem mass spectrometry. METHODS: These 2 kits were used to measure (1) the absorbance changes for 0 to 50 μmol/liter bile salts, (2) levels in gastric juice (10-10,010 μmol/liter), and (3) bile salt levels of 40 BALF samples that were also measured using tandem mass spectrometry (0.01-1.19 μmol/liter). Measurements of pH/impedance were done in 14 of 15 patients. RESULTS: Neither kit had detection limits as low as claimed in previous BALF studies. The kits could be made more sensitive with a longer incubation time, (5 μmol/liter). All patients had detectable lavage bile acids using mass spectroscopy, 71% had pathologic distal gastroesophageal reflux, and 43% had pathologic proximal reflux. CONCLUSIONS: The enzymatic kits are not sensitive enough for use in situations where bile salt levels are much below 5 μmol/liter, which is the case in BALF. In addition, reports in the literature of levels significantly below 5 μmol/liter need reassessing. Tandem mass spectrometry with a lower limit of detection of 0.01 μmol/liter should be the method of choice.

PMID: 23384888 [PubMed - as supplied by publisher]

The effect of age and emphysematous and fibrotic injury on the re-cellularization of de-cellularized lungs.

Thu, 02/07/2013 - 12:27

The effect of age and emphysematous and fibrotic injury on the re-cellularization of de-cellularized lungs.

Biomaterials. 2013 Feb 2;

Authors: Sokocevic D, Bonenfant NR, Wagner DE, Borg ZD, Lathrop MJ, Lam YW, Deng B, Desarno MJ, Ashikaga T, Loi R, Hoffman AM, Weiss DJ

Abstract
Use of de-cellularized cadaveric lungs as 3-dimensional scaffolds for ex vivo lung tissue generation offers a new potential therapeutic approach for clinical lung transplantation. However, it is likely that some of the available cadaveric human lungs may be from older donors or from donors with previously existing structural lung diseases such as emphysema or pulmonary fibrosis. It is not known whether these lungs will be suitable for either de-cellularization or re-cellularization. To investigate this, we assessed the effects of advanced age, representative emphysematous and fibrotic injuries, and the combination of advanced age and emphysematous injury and found significant differences both in histologic appearance and in the retention of extracellular matrix (ECM) and other proteins, as assessed by immunohistochemistry and mass spectrometry, between the different conditions. However, despite these differences, binding, retention and growth of bone marrow-derived mesenchymal stromal cells (MSCs) over a 1-month period following intratracheal inoculation were similar between the different experimental conditions. In contrast, significant differences occurred in the growth of C10 mouse lung epithelial cells between the different conditions. Therefore, age, lung injury, and the cell type used for re-cellularization may significantly impact the usefulness of de-cellularized whole lungs for ex vivo lung tissue regeneration.

PMID: 23384794 [PubMed - as supplied by publisher]

In situ lung perfusion is a valuable tool to assess lungs from donation after circulatory death donors category I-II.

Thu, 02/07/2013 - 12:27

In situ lung perfusion is a valuable tool to assess lungs from donation after circulatory death donors category I-II.

Transpl Int. 2013 Feb 6;

Authors: Van De Wauwer C, Munneke AJ, Engels GE, Berga FM, Rakhorst G, Nijsten MW, Mariani MA, Erasmus ME

Abstract
Donations after circulatory death (DCD) lung grafts are an alternative to extend the donor pool in lung transplantation. This study investigates the use of an in situ lung perfusion system (ISLP) in the donor to evaluate category I-II lungs. Pigs were sacrificed by ventricular fibrillation. All animals underwent 20 min of cardiopulmonary resuscitation and 5 min hands-off period after which heparin was administered. In group [WI-1], this was followed by 1 h of warm ischemia (WI) and 2 h of topical cooling (TC). In group [WI-2], 2 h of WI was followed by 1 h of TC. In group [WI-0], there was a minimal period of WI and no TC. In all three groups, the lungs were then evaluated during 60 min with ISLP. [WI-0] lungs showed a significantly higher compliance and Δ PO(2) /FiO(2) compared with [WI-1] and [WI-2]. PaCO(2) and lactate production were higher in [WI-2] versus [WI-0]. Wet/Dry weight ratio was significantly higher in [WI-2] compared with [WI-0] in two lung biopsy locations. A high W/D weight ratio was correlated with a lower compliance, higher lactate production, and a higher PaCO(2) . ISLP is an effective way to assess the quality of lungs from category I-II DCD donors.

PMID: 23384364 [PubMed - as supplied by publisher]

Efficacy and safety of human adipose tissue-derived mesenchymal stem cells for supporting hematopoiesis.

Thu, 02/07/2013 - 12:27
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Efficacy and safety of human adipose tissue-derived mesenchymal stem cells for supporting hematopoiesis.

Int J Hematol. 2012 Sep;96(3):295-300

Authors: Nishiwaki S, Nakayama T, Saito S, Mizuno H, Ozaki T, Takahashi Y, Maruyama S, Nishida T, Murata M, Kojima S, Naoe T

Abstract
We have demonstrated that adipose tissue-derived mesenchymal stem cells (ADSCs) from mice are capable of reconstituting the hematopoietic microenvironment, and facilitate hematopoiesis more effectively than bone marrow-derived mesenchymal stem cells (BMSCs) in mouse. The ready accessibility of fat tissue rich in MSCs and the higher hematopoiesis-supporting capacities of ADSCs suggest that ADSCs might represent a new therapeutic modality for the regeneration of impaired hematopoiesis. As a further step towards their use in clinical practice, we established human BMSCs and ADSCs from healthy volunteers of similar age, and compared their proliferation capacities, hematopoiesis-supporting properties, and safety. In vitro cell proliferation studies revealed that ADSCs have a higher population doubling number than BMSCs. In vitro co-culture assays showed that ADSCs not only support human CD34(+) peripheral blood stem cells (PBSCs), but also yield significantly more non-adherent hematic cells than BMSCs. In vitro progenitor assays revealed that ADSCs promote a higher frequency of early progenitors than do BMSCs. Interestingly, BM cellularity in irradiated mice that had received ADSCs tended to be higher than that of mice treated with BMSCs. When MSCs were injected into the BM cavity of tibiae, we observed no evidence of MSC-induced toxicity either during or after treatment. In addition, no microscopic abnormalities were observed in the bone marrow and major organs.

PMID: 22782260 [PubMed - indexed for MEDLINE]

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