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Prof. Dr. med. habil. Thiha Aung, MHBA (Univ.)

Faculty of Applied Healthcare Sciences

Professors

Professor

LA 27-2.17

0991/3615-8253

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Journal article
  • Thiha Aung
  • B. Chapuy
  • D. Vogel
  • D. Wenzel
  • M. Oppermann
  • M. Lahmann
  • et al.

Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3.

In: Proceedings of the National Academy of Sciences of the United States of America vol. 108 pg. 15336-41

  • 25.08.2011 (2011)

DOI: 10.1073/pnas.1102855108

show abstract

Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.
Journal article
  • R. Koch
  • M. Demant
  • Thiha Aung
  • N. Diering
  • A. Cicholas
  • B. Chapuy
  • et al.

Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma.

In: Blood vol. 123 pg. 2189-98

  • 21.02.2014 (2014)

DOI: 10.1182/blood-2013-08-523886

show abstract

Tumors are composed of phenotypically heterogeneous cell populations. The nongenomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show that diffuse large B-cell lymphomas possess a self-organized infrastructure comprising side population (SP) and non-SP cells, where transitions between clonogenic states are modulated by exosome-mediated Wnt signaling. DNA methylation modulated SP-non-SP transitions and was correlated with the reciprocal expressions of Wnt signaling pathway agonist Wnt3a in SP cells and the antagonist secreted frizzled-related protein 4 in non-SP cells. Lymphoma SP cells exhibited autonomous clonogenicity and exported Wnt3a via exosomes to neighboring cells, thus modulating population equilibrium in the tumor.
Journal article
  • R. Koch
  • Thiha Aung
  • D. Vogel
  • B. Chapuy
  • D. Wenzel
  • S. Becker
  • et al.

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone.

In: Clinical Cancer Research (American Association for Cancer Research) vol. 22 pg. 395-404

  • 14.09.2015 (2016)

DOI: 10.1158/1078-0432.CCR-15-0577

show abstract

PURPOSE Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas. EXPERIMENTAL DESIGN We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment. RESULTS We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay. CONCLUSIONS We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones.
Journal article
  • H. Blesinger
  • S. Kaulfuß
  • Thiha Aung
  • S. Schwoch
  • L. Prantl
  • J. Rößler
  • et al.

PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations.

In: PLoS One vol. 13 pg. e0200343

  • 09.07.2018 (2018)

DOI: 10.1371/journal.pone.0200343

show abstract

Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic vessels during pre- and postnatal development. Macrocystic, microcystic and combined forms of LM are known. The cysts are lined by lymphatic endothelial cells (LECs). Resection and sclerotherapy are the most common treatment methods. Recent studies performed on LM specimens in the United States of America have identified activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but not isolated cell types were studied. Here, we studied LM tissues resected at the University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21 of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6 LM-derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A; p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived fibroblasts did not possess such mutations, showing cell-type specificity of the gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones with newly identified mutations), as compared to normal LECs. Additionally, hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one with Glu109del. In vitro, the small molecule kinase inhibitors Buparlisib/BKM-120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101 (inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of LM-derived LECs in a concentration-dependent manner, but also blocked proliferation of normal LECs. However, MK-2206 appeared to be more specific for mutated LECs, except in case of Glu109 deletion. In sum, children that are, or will be, treated with kinase inhibitors must be monitored closely.
Contribution
  • Thiha Aung
  • S. Härteis
  • L. Prantl

Lymphozele und Lymphfistel.

In: Klinische Angiologie. (Springer Reference Medizin) pg. 1-5

  • Eds.:
  • E. Freisinger
  • M. Czihal
  • N. Weiss
  • B. Linnemann
  • U. Hoffmann

Springer Berlin Heidelberg, Imprint: Springer Berlin; Heidelberg

  • (2020)

show abstract

Bei Lymphozelen handelt es sich um eine Ansammlung von klarer Lymphflüssigkeit, in einem anatomisch dafür nicht vorgesehenen Raum. Zur Bildung von Lymphozelen kommt es beispielsweise nach Lymphknotendissektionen oder gefäßchirurgischen Eingriffen. Zur Behandlung von Lymphozelen wurden unterschiedliche Therapien beschrieben, wozu konservative Therapie, niedrig-dosierte Radiotherapie, sklerosierend wirkende Substanzen und die sehr erfolgversprechende Therapieoption der (supra-)mikrochirurgischen Resektion der Lymphozelen mit Einsatz von Indocyanin-Grün-Lymphographie zählen.
Journal article
  • A.-L. Feder
  • E. Pion
  • J. Troebs
  • U. Lenze
  • L. Prantl
  • M. Htwe
  • A. Phyo
  • Silke Härteis
  • Thiha Aung

Extended analysis of intratumoral heterogeneity of primary osteosarcoma tissue using 3D-in-vivo-tumor-model.

In: Clinical Hemorheology and Microcirculation vol. 76 pg. 133-141

  • (2020)

DOI: 10.3233/CH-209204

show abstract

BACKGROUND Osteosarcomas are a rare, heterogeneous and malignant group of bone tumors that have a high potential for metastasis and aggressive growth patterns. Treatment of metastasized osteosarcoma is often insufficient and research is compromised by problems encountered when culturing cells or analyzing genetic alterations due to the high level of intratumoral and intertumoral heterogeneity. The chick chorioallantoic membrane (CAM) model, a 3D-in-vivo-tumor-model, could potentially facilitate the investigation of osteosarcoma heterogeneity at an individual and highly specified level. OBJECTIVE Objective was to establish the grafting and transplantation of different primary osteosarcoma tissue parts onto several consecutive CAMs for tumor profiling and investigation of osteosarcoma heterogeneity. METHODS Various parts of primary osteosarcoma tissue were grafted onto CAMs and were transplanted onto another CAM for five to seven consecutive times, enabling further experimental analyzes. RESULTS Primary osteosarcoma tissue parts exhibited satisfactory growth patterns and displayed angiogenic development on the CAM. It was possible to graft and transplant different tumor parts several times while the tissue viability was still high and tumor profiling was performed. CONCLUSIONS Primary osteosarcoma tissue grew on several different CAMs for an extended time period and neovascularization of serial transplanted tumor parts was observed, improving the versatility of the 3D-in-vivo-tumor-model.
Journal article
  • I. Zucal
  • S. Geis
  • L. Prantl
  • S. Härteis
  • Thiha Aung

Indocyanine Green for Leakage Control in Isolated Limb Perfusion.

In: Journal of Personalized Medicine vol. 11

  • 05.11.2021 (2021)

DOI: 10.3390/jpm11111152

show abstract

Sarcomas are characterized by a high metastatic potential and aggressive growth. Despite surgery, chemotherapy plays an important role in the treatment of these tumors. Optimal anti-cancer therapy with maximized local efficacy and minimized systemic side effects has been the object of many studies for a long time. To improve the local efficacy of anti-tumor therapy, isolated limb perfusion with high-dose cytostatic agents has been introduced in surgical oncology. In order to control the local distribution of substances, radiolabeled cytostatic drugs or perfusion solutions have been applied but often require the presence of specialized personnel and result in a certain exposure to radiation. In this study, we present a novel strategy using indocyanine green to track tumor perfusion with high-dose cytostatic therapy. In a rat cadaver model, the femoral vessels were cannulated and connected to a peristaltic pump to provide circulation within the selected limb. The perfusion solution contained indocyanine green and high-dose doxorubicin. An infrared camera enabled the visualization of indocyanine green during limb perfusion, and subsequent leakage control was successfully performed. Histologic analysis of sections derived proximally from the injection site excluded systemic drug dispersion. In this study, the application of indocyanine green was proven to be a safe and cost- and time-efficient method for precise leakage control in isolated limb perfusion with a high-dose cytostatic agent.
Contribution
  • Thiha Aung
  • S. Härteis
  • V. Brebant
  • L. Prantl

Indocyaningrün(ICG)-Lymphografie in der Lymphchirurgie.

In: Bildgebung Lymphologie. Sonographie, Lymphangiographie, MR und Nuklearmedizin (Springer eBook Collection) pg. 185-197

  • Eds.:
  • W. Brauer

Springer Berlin Heidelberg, Imprint Springer Berlin; Heidelberg

  • (2021)

show abstract

Die Indocyaningrün (ICG)-Lymphografie ist eine wenig belastende, minimal-invasive Untersuchungstechnik, die eine Realtime-Darstellung der Lymphgefäße ermöglicht und den Schweregrad der Lymphödeme widerspiegelt. Sie wird sowohl in der Diagnostik von Lymphgefäßerkrankungen als auch zur präoperativen Planung lymphchirurgischer Eingriffe (u. a. bei lympho-venösen Anastomosen oder Lymphknoten-Transplantationen) angewandt. Intraoperativ wird die ICG-Lymphangiografie zur Visualisierung des rekonstruierten Lymphabflusses (patency test) eingesetzt. Niedrige Komplikationsraten, einfache Handhabung, hohe Spezifität und Sensitivität machen die ICG-Lymphografie zu einem sicheren diagnostischen Verfahren.
Journal article
  • E. Pion
  • C. Asam
  • A.-L. Feder
  • O. Felthaus
  • P. Heidekrueger
  • L. Prantl
  • S. Härteis
  • Thiha Aung

Laser speckle contrast analysis (LASCA) technology for the semiquantitative measurement of angiogenesis in in-ovo-tumor-model.

In: Microvascular Research vol. 133 pg. 104072

  • 17.09.2020 (2021)

DOI: 10.1016/j.mvr.2020.104072

show abstract

BACKGROUND The process of angiogenesis is a key element for tumor growth and proliferation and therefore one of the determining factors for aggressiveness and malignancy. A better understanding of the underlying processes of tumor induced angiogenesis is crucial for superior cancer treatment. Furthermore, the PeriCam perfusion speckle imager (PSI) system high resolution (HR) model by PERIMED presents a noninvasive method for semi-quantitative measurement of blood perfusion, based on laser speckle contrast analysis (LASCA). Aim of the present study was to utilize the chick chorioallantoic membrane (CAM) model as an in-ovo-tumor-model which enables rapid neovascularization of tumors while allowing real-time observation of the microcirculation via LASCA. METHODS Fertilized chicken eggs were grafted with embryonal/alveolar rhabdomyosarcoma cells or primary sarcoma tumors. The blood perfusion was measured before and after tumor growth using LASCA. The procedure is accelerated and simplified through the integrated PIMSoft software which provides real-time graphs and color-coded images during the measurement. RESULTS Sarcoma cells and primary sarcoma tumors exhibited satisfactory growth processes on the CAM. LASCA visualized microcirculation accurately and enabled an extensive investigation of the angiogenic potential of sarcoma cells on the CAM. We were able to show that sarcoma cells and primary sarcoma tumors induced larger quantities of neovasculature on the CAM than the controls. CONCLUSIONS The utilization of LASCA for the investigation of tumor angiogenesis within the CAM model appears to be a highly beneficial, cost-efficient and easily practicable procedure. The proposed model can be used as a drug-screening model for individualized cancer therapy, especially with regards to anti-angiogenic agents.
Journal article
  • K. Drexler
  • B. Schwertner
  • S. Härteis
  • Thiha Aung
  • M. Berneburg
  • E. Geissler
  • M. Mycielska
  • S. Haferkamp

The Role of Citrate Homeostasis in Merkel Cell Carcinoma Pathogenesis.

In: Cancers vol. 14

  • 14.07.2022 (2022)

DOI: 10.3390/cancers14143425

show abstract

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin with a poor prognosis. The factors driving this cancer must be better understood in order to discover novel targets for more effective therapies. In the search for targets, we followed our interest in citrate as a central and critical metabolite linked to fatty acid synthesis in cancer development. A key to citrate uptake in cancer cells is the high expression of the plasma membrane citrate transporter (pmCiC), which is upregulated in the different adenocarcinoma types tested so far. In this study, we show that the pmCiC is also highly expressed in Merkel cell carcinoma cell lines by western blot and human tissues by immunohistochemistry staining. In the presence of extracellular citrate, MCC cells show an increased proliferation rate in vitro; a specific pmCiC inhibitor (Na+-gluconate) blocks this citrate-induced proliferation. Furthermore, the 3D in vivo Chick Chorioallantoic Membrane (CAM) model showed that the application of Na+-gluconate also decreases Merkel cell carcinoma growth. Based on our results, we conclude that pmCiC and extracellular citrate uptake should be considered further as a potential novel target for the treatment of Merkel cell carcinoma.
Journal article
  • E. Pion
  • J. Karnosky
  • S. Boscheck
  • B. Wagner
  • K. Schmidt
  • S. Brunner
  • H. Schlitt
  • Thiha Aung
  • C. Hackl
  • S. Härteis

3D In Vivo Models for Translational Research on Pancreatic Cancer: The Chorioallantoic Membrane (CAM) Model.

In: Cancers vol. 14

  • 31.07.2022 (2022)

DOI: 10.3390/cancers14153733

show abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with adverse outcomes that have barely improved over the last decade. About half of all patients present with metastasis at the time of diagnosis, and the 5-year overall survival rate across all stages is only 6%. Innovative in vivo research models are necessary to combat this cancer and to discover novel treatment strategies. The chorioallantoic membrane (CAM) model represents one 3D in vivo methodology that has been used in a large number of studies on different cancer types for over a century. This model is based on a membrane formed within fertilized chicken eggs that contain a dense network of blood vessels. Because of its high cost-efficiency, simplicity, and versatility, the CAM model appears to be a highly valuable research tool in the pursuit of gaining more in-depth insights into PDAC. A summary of the current literature on the usage of the CAM model for the investigation of PDAC was conducted and subdivided into angiogenesis, drug testing, modifications, personalized medicine, and further developments. On this comprehensive basis, further research should be conducted on PDAC in order to improve the abysmal prognosis of this malignant disease.
Journal article
  • P. Kuri
  • E. Pion
  • L. Mahl
  • P. Kainz
  • S. Schwarz
  • C. Brochhausen
  • Thiha Aung
  • S. Härteis

Deep Learning-Based Image Analysis for the Quantification of Tumor-Induced Angiogenesis in the 3D In Vivo Tumor Model-Establishment and Addition to Laser Speckle Contrast Imaging (LSCI).

In: Cells vol. 11

  • 28.07.2022 (2022)

DOI: 10.3390/cells11152321

show abstract

(1) Background: angiogenesis plays an important role in the growth and metastasis of tumors. We established the CAM assay application, an image analysis software of the IKOSA platform by KML Vision, for the quantification of blood vessels with the in ovo chorioallantoic membrane (CAM) model. We added this proprietary deep learning algorithm to the already established laser speckle contrast imaging (LSCI). (2) Methods: angiosarcoma cell line tumors were grafted onto the CAM. Angiogenesis was measured at the beginning and at the end of tumor growth with both measurement methods. The CAM assay application was trained to enable the recognition of in ovo CAM vessels. Histological stains of the tissue were performed and gluconate, an anti-angiogenic substance, was applied to the tumors. (3) Results: the angiosarcoma cells formed tumors on the CAM that appeared to stay vital and proliferated. An increase in perfusion was observed using both methods. The CAM assay application was successfully established in the in ovo CAM model and anti-angiogenic effects of gluconate were observed. (4) Conclusions: the CAM assay application appears to be a useful method for the quantification of angiogenesis in the CAM model and gluconate could be a potential treatment of angiosarcomas. Both aspects should be evaluated in further research.
Journal article
  • L. Sommerauer
  • A. Phyo
  • E. Pion
  • I. Zucal
  • E. Klingelhoefer
  • S. Thu
  • T. Win
  • S. Khin
  • T. Kyaw
  • H. Zaw
  • M. Htwe
  • N. Fabbri
  • S. Härteis
  • Thiha Aung

Modified Borggreve-Van Nes-Winkelmann rotationplasty for surgery in developing countries.

In: BMC Surgery vol. 22 pg. 333

  • 07.09.2022 (2022)

DOI: 10.1186/s12893-022-01780-z

show abstract

BACKGROUND Amputation is still the most common therapy for patients suffering from osteosarcoma in Myanmar, despite the fact that limb salvage surgery e.g. Borggreve-Van Nes-Winkelmann rotationplasty for malignant tumors located within the distal femur or proximal tibia is the current state-of-the-art reconstructive procedure. A safe and reliable operation technique is crucial in order to perform a complex surgical procedure like the rotationplasty in lower-middle income economies with limited infrastructure and resources. The authors present seven cases of patients with osteosarcomas that received a Borggreve-Van Nes-Winkelmann rotationplasty with an evaluation of the procedures focusing on safety and sustainability. METHODS From 2019 until 2020, seven young patients with osteosarcomas of the distal femur or proximal tibia were treated with Borggreve-Van Nes-Winkelmann rotationplasties in the Orthopaedic Hospital in Mandalay, Myanmar. As modification of the standard procedure the dissection and subsequent clamping of the femoral artery in order to minimize blood loss as well as the formation of an adipocutaneous flap that minimizes swelling and decreases the pressure on the vessels were successfully performed. This modified procedure resembles a safe and simplified surgical technique that is feasible under the circumstances of lower-middle income economies with good outcomes. RESULTS All patients showed good functional and aesthetic results. One of the seven patients needed secondary wound closure due to wound dehiscence. CONCLUSIONS A simplified and safe operation technique for the performance of the Van Nes-Borggreve rotationplasty was adapted to the given constraints in lower-middle income economies and proved to be successful. Trial registration All patients approved to participate in the study and have given consent to publication.
Journal article
  • E.-M. Bichlmayer
  • L. Mahl
  • L. Hesse
  • E. Pion
  • V. Haller
  • A. Moehwald
  • C. Hackl
  • J. Werner
  • H. Schlitt
  • S. Schwarz
  • P. Kainz
  • C. Brochhausen
  • C. Groeger
  • F. Steger
  • O. Kölbl
  • C. Daniel
  • K. Amann
  • A. Kraus
  • B. Buchholz
  • Thiha Aung
  • S. Härteis

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices.

In: Cells vol. 11

  • 22.07.2022 (2022)

DOI: 10.3390/cells11152269

show abstract

(1) Background: Autosomal dominant polycystic kidney disease (ADPKD) is a frequent monogenic disorder that leads to progressive renal cyst growth and renal failure. Strategies to inhibit cyst growth in non-human cyst models have often failed in clinical trials. There is a significant need for models that enable studies of human cyst growth and drug trials. (2) Methods: Renal tissue from ADPKD patients who received a nephrectomy as well as adult mouse kidney slices were cultured on a chorioallantoic membrane (CAM) for one week. The cyst volume was monitored by microscopic and CT-based applications. The weight and angiogenesis were quantified. Morphometric and histological analyses were performed after the removal of the tissues from the CAM. (3) Results: The mouse and human renal tissue mostly remained vital for about one week on the CAM. The growth of cystic tissue was evaluated using microscopic and CT-based volume measurements, which correlated with weight and an increase in angiogenesis, and was accompanied by cyst cell proliferation. (4) Conclusions: The CAM model might bridge the gap between animal studies and clinical trials of human cyst growth, and provide a drug-testing platform for the inhibition of cyst enlargement. Real-time analyses of mouse kidney tissue may provide insights into renal physiology and reduce the need for animal experiments.
Journal article
  • I. Zucal
  • A.-L. Feder
  • T. Kyaw
  • S. Khin
  • P. Heidekrueger
  • L. Prantl
  • S. Härteis
  • Thiha Aung

An Innovative Simulation Model for Microvascular Training.

In: Plastic and Reconstructive Surgery (Journal of the American Society of Plastic Surgeons) vol. 150 pg. 189e-193e

  • 29.06.2022 (2022)

DOI: 10.1097/PRS.0000000000009209

show abstract

Preclinical/clinical microsurgical training is essential for clinical practice. Therefore, various training models have been established, such as synthetic and cadaveric models. The most common limitation of these models is the lack of circulation, which limits the simulation of real intraoperative circumstances. Thus, the authors aimed to create a novel model that provides blood circulation with an extracorporeal perfusion device that they attached to rat cadavers for the reestablishment of a circulatory system. Patent blue and heparin were added to the perfusion fluid to visualize circulation and to dissolve thrombosis, and indocyanine green fluorescent imaging was applied to show the perfusion of the entire body. The femoral and brachial vessels were dissected, and an end-to-end anastomosis was performed on the femoral artery. The patency of the operated vessel was visualized with indocyanine green fluorescent imaging. Indocyanine green fluorescent imaging showed appropriate vessel patency and extremity perfusion through the anastomosis. The use of this novel rat model enables a solution for ethical problems encountered when using rats for surgical training courses. By practicing on these animal-sparing models with intact circulation, microsurgical skills can be improved. Future studies on further microsurgical techniques and vascular perfusion of organs or tumors may benefit from our model.
Journal article
  • L. Mahl
  • J. Ollig
  • V. Schweihofer
  • L. Wiegand
  • Phillipp Torkler
  • S. Härteis
  • Thiha Aung

Importance and implications of exosomes in nephrology and urology.

In: Pflügers Archiv : European Journal of Physiology

  • 18.11.2022 (2022)

DOI: 10.1007/s00424-022-02771-y

show abstract

Exosomes are extracellular vesicles that are formed by two invaginations of the plasma membrane and can be released by all eukaryotic cells. Because of their bioactive contents, including nucleic acids and proteins, exosomes can activate a variety of functions in their recipient cells. Due to the plethora of physiological and pathophysiological functions, exosomes have received a lot of attention from researchers over the past few years. However, there is still no consensus regarding isolation and characterization protocols of exosomes and their subtypes. This heterogeneity poses a lot of methodical challenges but also offers new clinical opportunities simultaneously. So far, exosome-based research is still mostly limited to preclinical experiments and early-stage clinical trials since the translation of experimental findings remains difficult. Exosomes could potentially play an important role as future diagnostic and prognostic agents and might also be part of the development of new treatment strategies. Therefore, they have previously been investigated in a variety of nephrological and urological conditions such as acute kidney injury or prostate cancer.
Journal article
  • C. Kohl
  • Thiha Aung
  • S. Härteis
  • A. Ignatov
  • O. Ortmann
  • T. Papathemelis

The 3D in vivo chorioallantoic membrane model and its role in breast cancer research.

In: Journal of Cancer Research and Clinical Oncology vol. 148 pg. 1033-1043

  • 05.02.2022 (2022)

DOI: 10.1007/s00432-022-03936-z

show abstract

PURPOSE We aimed to evaluate the role of the chorioallantoic membrane model (CAM) in breast cancer research. METHODS The following is an overview of the use of the CAM in the field of breast cancer research based on a PubMed literature query. RESULTS The CAM is a 3D in vivo model that can be used for the analysis of tumor growth, biology and angiogenesis of primary tumor tissue or tumor cell lines. The CAM model has been used in breast cancer research for drug testing, migration assays and the evaluation of vascularization, amongst others. The CAM model is a valuable method that offers a better imitation of the physiological phenomena compared to 2D or 3D in vitro models. CONCLUSION The CAM model has primarily and successfully been utilized for the assessment of the tumor biology of established breast cancer cell lines. Further, the CAM model is a promising method to analyze patient derived primary tumor material and could be used as a "patient-specific 3D-tumor-therapy-model" for the cost-efficient evaluation of anti-cancer drugs to find the optimal treatment for breast cancer patients.
Journal article
  • E. Pion
  • I. Zucal
  • J. Troebs
  • A.-L. Feder
  • T. Kyaw
  • S. Khin
  • P. Heidekrueger
  • L. Prantl
  • S. Härteis
  • Thiha Aung

New, Innovative, Three-Dimensional In Vivo Model for High-Level Microsurgical and Supermicrosurgical Training: A Replacement for Animal Models.

In: Plastic and Reconstructive Surgery (Journal of the American Society of Plastic Surgeons) vol. 150 pg. 432-436

  • 09.06.2022 (2022)

DOI: 10.1097/PRS.0000000000009330

show abstract

Microsurgery and supermicrosurgery are surgical subdomains necessary for a large variety of surgical disciplines. So far, there is no training model for lymphatic surgery or perforator flap surgery, and the most commonly used microsurgical training models are living animals. However, the ethical principles of replacement, refinement, and reduction (the three Rs) of living animals for training purposes were implemented, highlighting the necessity of an animal-sparing microsurgical training model. Formed during embryogenesis, the chick chorioallantoic membrane resembles a highly vascularized, noninnervated membrane within fertilized chicken eggs. The aim of this study was to utilize the chorioallantoic membrane model as an innovative and versatile training model for supermicrosurgery and microsurgery that can reduce the number of animals used for these purposes. The variety of different sized vessels for the implementation of an anastomosis proved the chorioallantoic membrane model as a well-functioning supermicrosurgical and microsurgical training model. The circulatory system is resilient enough to withstand the mechanical stress applied to the tissue, and the patency of the implemented anastomosis can be tested for the verification of the procedures. In summary, the integration of the chorioallantoic membrane model into a surgical training program can benefit its quality by representing a realistic anatomical and physiological model with a high variety of vascular structures. Moreover, the chorioallantoic membrane model satisfies the principles of replacement, refinement, and reduction as an animal-sparing model, indicating the potential of this model as an innovative microsurgical training model for the improvement of surgical skills.
Lecture
  • Thiha Aung

Bildgebung in der Lymphchirurgie.

In: 45. Jahreskongress der Deutschen Gesellschaft für Lymphologie 2022

Deutsche Gesellschaft für Lymphologie e.V. Hanau

  • 11.06.2022 (2022)
Lecture
  • A. Dorn
  • Thiha Aung
  • S. Härteis

Effects of Punicalagin on Osteosarcoma in the 3D in-vivo tumor model. Abstract.

In: 116th Annual Meeting of the Anatomische Gesellschaft 2022

Berlin

  • 20.-23.09.2022 (2022)
Lecture
  • S. Boscheck
  • Thiha Aung
  • B. Wagner
  • C. Hackl
  • S. Härteis

Analysis of pancreatic cancer cell line and pancreatic cancer biopsies in 3D in-vivo tumor model. Abstract.

In: 116th Annual Meeting of the Anatomische Gesellschaft 2022

Berlin

  • 20.-23.09.2022 (2022)
Lecture
  • V. Haller
  • E.-M. Bichlmayer
  • L. Mahl
  • L. Hesse
  • E. Pion
  • A. Möhwald
  • C. Hackl
  • J. Werner
  • H. Schlitt
  • S. Schwarz
  • P. Kainz
  • C. Brochhausen
  • C. Groeger
  • F. Steger
  • O. Koelbl
  • C. Daniel
  • K. Amann
  • A. Kraus
  • B. Buchholz
  • Thiha Aung
  • S. Härteis

Modulation und Untersuchung des Zystenwachstums bei ADPKD in einem humanen Gewebe-basierten 3D-Zystenmodell. Abstract..

In: 14. Jahrestagung der Deutschen Gesellschaft für Nephrologie (DGfN)

Deutsche Gesellschaft für Nephrologie Berlin

  • 06.10.2022
Lecture
  • Thiha Aung

ICG Fluoreszenz – Lymphographie.

In: 7. Nürnberger Symposium für Lymphologie und Phlebologie 2022

Institut für angewandte Lymphologie und Phlebologie (IaLP), Fürth Nürnberg

  • 03.12.2022 (2022)
Contribution
  • E. Pion
  • S. Härteis
  • Thiha Aung

Application of Laser Speckle Contrast Imaging (LSCI) for the Angiogenesis Measurement of Tumors in the Chorioallantoic Membrane (CAM) Model.

In: Tumor Angiogenesis Assays. Methods and Protocols (Methods in Molecular Biology) pg. 141-153

  • Eds.:
  • D. Ribatti

Imprint Humana, Springer US New York, NY

  • (2023)

DOI: 10.1007/978-1-0716-2703-7_11

show abstract

Tumor angiogenesis is one essential aspect for the growth and metastasis of cancer cells, which means that adequate in vivo angiogenesis models are of utmost importance for the investigation of such diseases. The chick chorioallantoic membrane (CAM) model is one established method for this purpose and has already been used for research on multiple cancer types. One important part of the evaluation of tumors grafted onto the CAM is the measurement of tumor-induced angiogenesis. In order to address this central aspect, we utilized the novel PeriCam perfusion speckle imager (PSI) system high resolution (HR) model (Perimed AB, Järfälla, Sweden), which is based on laser speckle contrast imaging (LSCI) for the semiquantitative measurement of blood flow in the CAM model. This method enables a fast and accurate analysis of the angiogenesis of cell line tumors and primary tumors that are grafted onto the CAM. The proposed model can be regarded as a precursor model for personalized cancer therapy.
Lecture
  • Thiha Aung

Modified Borggreve-Van Nes-Winkelmann Rotationplasty for Surgery in Developing Countries.

In: 2023 Annual Meeting of the American Society for Reconstructive Microsurgery

Aventura, FL, USA

  • 20.-24.01.2023 (2023)
Lecture
  • Thiha Aung

Indocyanine Green (ICG) Coloring of the Sciatic, Common Peroneal and Tibial Nerves for Rotationplasty Surgery of Osteosarcoma Patients.

In: 2023 Annual Meeting of the American Society for Reconstructive Microsurgery

Aventura, FL, USA

  • 20.-24.01.2023 (2023)
Lecture
  • Thiha Aung

Indocyanine Green (ICG) Coloring of the sciatic, common peroneal and tibial nerves for rotationplasty surgery of osteosarcoma patients.

In: Deutscher Chirurgenkongress 2023 (DCK2023)

München

  • 26.-28.04.2023 (2023)
Lecture
  • Thiha Aung

Modified Borggreve-Van Nes-Winkelmann rotationplasty for surgery in developing countries.

In: Deutscher Chirurgenkongress 2023 (DCK2023)

München

  • 26.-28.04.2023 (2023)
Journal article
  • A. Ettner-Sitter
  • A. Montagner
  • J. Kuenzel
  • K. Brackmann
  • M. Schäfer
  • R. Schober
  • F. Weber
  • Thiha Aung
  • C. Hackl
  • S. Härteis

Visualization of Vascular Perfusion of Human Pancreatic Cancer Tissue in the CAM Model and Its Impact on Future Personalized Drug Testing.

In: Organoids vol. 3 pg. 1-17

  • (2024)

DOI: 10.3390/organoids3010001

show abstract

Although significant improvements have been made in the treatment of pancreatic cancer, its prognosis remains poor with an overall 5-year survival rate of less than 10%. New experimental approaches are necessary to develop novel therapeutics. In this study, the investigation of pancreatic cancer tissue growth in the chorioallantoic membrane (CAM) model and the subsequent use of indocyanine green (ICG) injections for the verification of intratumoral perfusion was conducted. ICG was injected into the CAM vasculature to visualize the perfusion of the tumor tissue. The presence of metastasis was investigated through PCR for the human-specific ALU element in the liver of the chicken embryo. Additionally, the usage of cryopreserved pancreatic tumors was established. Intratumoral perfusion of tumor tissue on the CAM was observed in recently obtained and cryopreserved tumors. ALU-PCR detected metastasis in the chick embryos’ livers. After cryopreservation, the tissue was still vital, and the xenografts generated from these tumors resembled the histological features of the primary tumor. This methodology represents the proof of principle for intravenous drug testing of pancreatic cancer in the CAM model. The cryopreserved tumors can be used for testing novel therapeutics and can be integrated into the molecular tumor board, facilitating personalized tumor treatment.
Contribution
  • M. Schäfer
  • A. Ettner-Sitter
  • L. Brand
  • S. Lotter
  • F. Vakillipoor
  • Thiha Aung
  • S. Härteis
  • R. Schober

The Chorioallantoic Membrane Model: A 3D in vivo Testbed for Design and Analysis of MC Systems.

In: NANOCOM '24: Proceedings of the 11th Annual ACM International Conference on Nanoscale Computing and Communication.

Association for Computing Machinery New York, NY, USA

  • (2024)

DOI: 10.48550/arXiv.2406.09875

Journal article
  • J. Schueler
  • T. Kuenzel
  • A. Thuesing
  • E. Pion
  • R. Behncke
  • R. Yinghan
  • et int.
  • Thiha Aung
  • S. Härteis

Ultra high frequency ultrasound enables real-time visualization of blood supply from chorioallantoic membrane to human autosomal dominant polycystic kidney tissue.

In: Scientific Reports (Nature Publishing Group) vol. 14 pg. 10063

  • 02.05.2024 (2024)

DOI: 10.1038/s41598-024-60783-3

show abstract

Ultra high frequency (UHF) ultrasound enables the visualization of very small structures that cannot be detected by conventional ultrasound. The utilization of UHF imaging as a new imaging technique for the 3D-in-vivo chorioallantoic membrane (CAM) model can facilitate new insights into tissue perfusion and survival. Therefore, human renal cystic tissue was grafted onto the CAM and examined using UHF ultrasound imaging. Due to the unprecedented resolution of UHF ultrasound, it was possible to visualize microvessels, their development, and the formation of anastomoses. This enabled the observation of anastomoses between human and chicken vessels only 12 h after transplantation. These observations were validated by 3D reconstructions from a light sheet microscopy image stack, indocyanine green angiography, and histological analysis. Contrary to the assumption that the nutrient supply of the human cystic tissue and the gas exchange happens through diffusion from CAM vessels, this study shows that the vasculature of the human cystic tissue is directly connected to the blood vessels of the CAM and perfusion is established within a short period. Therefore, this in-vivo model combined with UHF imaging appears to be the ideal platform for studying the effects of intravenously applied therapeutics to inhibit renal cyst growth.
Journal article
  • A. Dorn
  • S. Neff
  • S. Hupp
  • M. Engelhardt
  • E. Pion
  • U. Lenze
  • et int.
  • Thiha Aung
  • S. Härteis

Analysis of Osteosarcoma Cell Lines and Patient Tissue Using a 3D In Vivo Tumor Model—Possible Effects of Punicalagin.

In: Organoids vol. 3 pg. 35-53

  • (2024)

DOI: 10.3390/organoids3010004

show abstract

Osteosarcomas are the most common primary malignant bone tumors and mostly affect children, adolescents, and young adults. Despite current treatment options such as surgery and polychemotherapy, the survival of patients with metastatic disease remains poor. In recent studies, punicalagin has reduced the cell viability, angiogenesis, and invasion in cell culture trials. The aim of this study was to examine the effects of punicalagin on osteosarcomas in a 3D in vivo tumor model. Human osteosarcoma biopsies and SaOs-2 and MG-63 cells, were grown in a 3D in vivo chorioallantoic membrane (CAM) model. After a cultivation period of up to 72 h, the tumors received daily treatment with punicalagin for 4 days. Weight measurements of the CAM tumors were performed, and laser speckle contrast imaging (LSCI) and a deep learning-based image analysis software (CAM Assay Application v.3.1.0) were used to measure angiogenesis. HE, Ki-67, and Caspase-3 staining was performed after explantation. The osteosarcoma cell lines SaOs-2 and MG-63 and osteosarcoma patient tissue displayed satisfactory growth patterns on the CAM. Treatment with punicalagin decreased tumor weight, proliferation, and tumor-induced angiogenesis, and the tumor tissue showed pro-apoptotic characteristics. These results provide a robust foundation for the implementation of further studies and show that punicalagin offers a promising supplementary treatment option for osteosarcoma patients. The 3D in vivo tumor model represents a beneficial model for the testing of anti-cancer therapies.
Journal article
  • B. Wagner
  • A. Ettner-Sitter
  • N. Ihlo
  • M. Behr
  • Sebastian Kölbl
  • S. Brunner
  • F. Weber
  • B. Rau
  • H. Schlitt
  • C. Brochhausen
  • R. Schoenmehl
  • A. Artinger
  • D. Schott
  • M. Pizon
  • K. Pachmann
  • Thiha Aung
  • Silke Härteis
  • C. Hackl

Patient-derived xenografts from circulating cancer stem cells as a preclinical model for personalized pancreatic cancer research.

In: Scientific Reports (Nature Publishing Group) vol. 15 pg. 2896

  • 23.01.2025 (2025)

DOI: 10.1038/s41598-025-87054-z

show abstract

Patient-derived xenografts (PDXs) provide biologically relevant models and potential platforms for the development of treatment strategies for precision medicine in pancreatic cancer. Furthermore, circulating epithelial tumor cells (CETCs/CTCs) are released into the bloodstream by solid tumors and a rare subpopulation-circulating cancer stem cells (cCSCs) - is considered to be responsible for recurrence and plays a key role in metastasis. For the identification of cCSCs, an innovative in vitro assay to generate tumorspheres was established in this study. The number of tumorspheres and CETCs/CTCs was analyzed perioperatively in 25 pancreatic cancer patients. Additionally, an individual in vivo chorioallantoic membrane (CAM) culture system was used to generate PDXs from these tumorspheres. While overall correlations of CETCs/CTCs with clinicopathological parameters did not reach statistical significance, a significant difference in the number of tumorspheres was observed between patient subgroups with lower and higher UICC stages. This finding underscores their potential as biomarkers, providing valuable insights into clinical decision-making and tumor progression. The application of tumorspheres on the CAM successfully established PDXs within 7 days. These xenografts closely resembled the histological features of the primary tumor. Hence, this model represents a novel and fast option for individualized testing of new therapies for PDAC.