154 research outputs found
Uterine NK cells are critical in shaping DC immunogenic functions compatible with pregnancy progression.
Dendritic cell (DC) and natural killer (NK) cell interactions are important for the regulation of innate and adaptive immunity, but their relevance during early pregnancy remains elusive. Using two different strategies to manipulate the frequency of NK cells and DC during gestation, we investigated their relative impact on the decidualization process and on angiogenic responses that characterize murine implantation. Manipulation of the frequency of NK cells, DC or both lead to a defective decidual response characterized by decreased proliferation and differentiation of stromal cells. Whereas no detrimental effects were evident upon expansion of DC, NK cell ablation in such expanded DC mice severely compromised decidual development and led to early pregnancy loss. Pregnancy failure in these mice was associated with an unbalanced production of anti-angiogenic signals and most notably, with increased expression of genes related to inflammation and immunogenic activation of DC. Thus, NK cells appear to play an important role counteracting potential anomalies raised by DC expansion and overactivity in the decidua, becoming critical for normal pregnancy progression
Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer
<p>Abstract</p> <p>Background</p> <p>Selection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer.</p> <p>Methods</p> <p>A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8.</p> <p>Results</p> <p>The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same.</p> <p>Conclusion</p> <p>Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.</p
Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer?
Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer
Targeting Tumor Vascular CD99 Inhibits Tumor Growth
CD99 (MIC2; single-chain type-1 glycoprotein) is a heavily O-glycosylated transmembrane protein (32 kDa) present on leukocytes and activated endothelium. Expression of CD99 on endothelium is important in lymphocyte diapedesis. CD99 is a diagnostic marker for Ewing's Sarcoma (EWS), as it is highly expressed by these tumors. It has been reported that CD99 can affect the migration, invasion and metastasis of tumor cells. Our results show that CD99 is also highly expressed in the tumor vasculature of most solid tumors. Furthermore, we found that in vitro CD99 expression in cultured endothelial cells is induced by starvation. Targeting of murine CD99 by a conjugate vaccine, which induced antibodies against CD99 in mice, resulted in inhibition of tumor growth in both a tumor model with high CD99 (Os-P0109 osteosarcoma) and low CD99 (CT26 colon carcinoma) expression. We demonstrated that vaccination against CD99 is safe, since no toxicity was observed in mice with high antibody titers against CD99 in their sera during a period of almost 11 months. Targeting of CD99 in humans is more complicated due to the fact that the human and mouse CD99 protein are not identical. We are the first to show that growth factor activated endothelial cells express a distinct human CD99 isoform. We conclude that our observations provide an opportunity for specific targeting of CD99 isoforms in human tumor vasculature
Left and right ventricular longitudinal strain-volume/area relationships in elite athletes.
We propose a novel ultrasound approach with the primary aim of establishing the temporal relationship of structure and function in athletes of varying sporting demographics. 92 male athletes were studied [Group IA, (low static-low dynamic) (n = 20); Group IC, (low static-high dynamic) (n = 25); Group IIIA, (high static-low dynamic) (n = 21); Group IIIC, (high static-high dynamic) (n = 26)]. Conventional echocardiography of both the left ventricles (LV) and right ventricles (RV) was undertaken. An assessment of simultaneous longitudinal strain and LV volume/RV area was provided. Data was presented as derived strain for % end diastolic volume/area. Athletes in group IC and IIIC had larger LV end diastolic volumes compared to athletes in groups IA and IIIA (50 ± 6 and 54 ± 8 ml/(m(2))(1.5) versus 42 ± 7 and 43 ± 2 ml/(m(2))(1.5) respectively). Group IIIC also had significantly larger mean wall thickness (MWT) compared to all groups. Athletes from group IIIC required greater longitudinal strain for any given % volume which correlated to MWT (r = 0.4, p < 0.0001). Findings were similar in the RV with the exception that group IIIC athletes required lower strain for any given % area. There are physiological differences between athletes with the largest LV and RV in athletes from group IIIC. These athletes also have greater resting longitudinal contribution to volume change in the LV which, in part, is related to an increased wall thickness. A lower longitudinal contribution to area change in the RV is also apparent in these athletes
Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy
Background and aim: A photosensitizer (PS) delivery and comprehensive tumor targeting platform was developed that is centered on the photosensitization of key pharmacological targets in solid tumors (cancer cells, tumor vascular endothelium, and cellular and non-cellular components of the tumor microenvironment) before photodynamic therapy (PDT). Interstitially targeted liposomes (ITLs) encapsulating zinc phthalocyanine (ZnPC) and aluminum phthalocyanine (AlPC) were formulated for passive targeting of the tumor microenvironment. In previous work it was established that the PEGylated ITLs were taken up by cultured cholangiocarcinoma cells. The aim of this study was to verify previous results in cancer cells and to determine whether the ITLs can also be used to photosensitize cells in the tumor microenvironment and vasculature. Following positive results, rudimentary in vitro and in vivo experiments were performed with ZnPC-ITLs and AlPC-ITLs as well as their water-soluble tetrasulfonated derivatives (ZnPCS4 and AlPCS4) to assemble a research dossier and bring this platform closer to clinical transition. Methods: Flow cytometry and confocal microscopy were employed to determine ITL uptake and PS distribution in cholangiocarcinoma (SK-ChA-1) cells, endothelial cells (HUVECs), fibroblasts (NIH-3T3), and macrophages (RAW 264.7). Uptake of ITLs by endothelial cells was verified under flow conditions in a flow chamber. Dark toxicity and PDT efficacy were determined by cell viability assays, while the mode of cell death and cell cycle arrest were assayed by flow cytometry. In vivo systemic toxicity was assessed in zebrafish and chicken embryos, whereas skin phototoxicity was determined in BALB/c nude mice. A PDT efficacy pilot was conducted in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts. Results: The key findings were that (1) photodynamically active PSs (i.e., all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells; (2) following PDT, photodynamically active PSs were highly toxic-to-potent as per anti-cancer compound classification; (3) the photodynamically active PSs did not elicit notable systemic toxicity in zebrafish and chicken embryos; (4) ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum-containing PSs did not exert detectable skin phototoxicity; and (5) ITL-delivered ZnPC and AlPC were equally effective in their tumor-killing capacity in human tumor breast cancer xenografts and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis. Conclusions: AlPC(S4) are the safest and most effective PSs to integrate into the comprehensive tumor targeting and PS delivery platform. Pending further in vivo validation, these third-generation PSs may be used for multi-compartmental tumor photosensitization
The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future
Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy
Background and aim: A photosensitizer (PS) delivery and comprehensive tumor targeting platform was developed that is centered on the photosensitization of key pharmacological targets in solid tumors (cancer cells, tumor vascular endothelium, and cellular and non-cellular components of the tumor microenvironment) before photodynamic therapy (PDT). Interstitially targeted liposomes (ITLs) encapsulating zinc phthalocyanine (ZnPC) and aluminum phthalocyanine (AlPC) were formulated for passive targeting of the tumor microenvironment. In previous work it was established that the PEGylated ITLs were taken up by cultured cholangiocarcinoma cells. The aim of this study was to verify previous results in cancer cells and to determine whether the ITLs can also be used to photosensitize cells in the tumor microenvironment and vasculature. Following positive results, rudimentary in vitro and in vivo experiments were performed with ZnPC-ITLs and AlPC-ITLs as well as their water-soluble tetrasulfonated derivatives (ZnPCS4 and AlPCS4) to assemble a research dossier and bring this platform closer to clinical transition. Methods: Flow cytometry and confocal microscopy were employed to determine ITL uptake and PS distribution in cholangiocarcinoma (SK-ChA-1) cells, endothelial cells (HUVECs), fibroblasts (NIH-3T3), and macrophages (RAW 264.7). Uptake of ITLs by endothelial cells was verified under flow conditions in a flow chamber. Dark toxicity and PDT efficacy were determined by cell viability assays, while the mode of cell death and cell cycle arrest were assayed by flow cytometry. In vivo systemic toxicity was assessed in zebrafish and chicken embryos, whereas skin phototoxicity was determined in BALB/c nude mice. A PDT efficacy pilot was conducted in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts. Results: The key findings were that (1) photodynamically active PSs (i.e., all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells; (2) following PDT, photodynamically active PSs were highly toxic-to-potent as per anti-cancer compound classification; (3) the photodynamically active PSs did not elicit notable systemic toxicity in zebrafish and chicken embryos; (4) ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum-containing PSs did not exert detectable skin phototoxicity; and (5) ITL-delivered ZnPC and AlPC were equally effective in their tumor-killing capacity in human tumor breast cancer xenografts and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis. Conclusions: AlPC(S4) are the safest and most effective PSs to integrate into the comprehensive tumor targeting and PS delivery platform. Pending further in vivo validation, these third-generation PSs may be used for multi-compartmental tumor photosensitization
Consensus guidelines for the use and interpretation of angiogenesis assays
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference
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