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Article: Reverting Immune Suppression to Enhance Cancer Immunotherapy.

Guerrouahen, Bella S / Maccalli, Cristina / Cugno, Chiara / Rutella, Sergio / Akporiaye, Emmanuel T

2020 Volume 9, Page(s) 1554

Abstract: Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, ... ...

Abstract	Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD8
Language	English
Publishing date	2020-01-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.01554
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Enhancing Mesenchymal Stromal Cell Immunomodulation for Treating Conditions Influenced by the Immune System.

Guerrouahen, Bella S / Sidahmed, Heba / Al Sulaiti, Asma / Al Khulaifi, Moza / Cugno, Chiara

Stem cells international

2019 Volume 2019, Page(s) 7219297

Abstract: Mesenchymal stromal cells (MSCs), formerly known as mesenchymal stem cells, are nonhematopoietic multipotent cells and are emerging worldwide as the most clinically used and promising source for allogeneic cell therapy. MSCs, initially obtained from bone ...

Abstract	Mesenchymal stromal cells (MSCs), formerly known as mesenchymal stem cells, are nonhematopoietic multipotent cells and are emerging worldwide as the most clinically used and promising source for allogeneic cell therapy. MSCs, initially obtained from bone marrow, can be derived from several other tissues, such as adipose tissue, placenta, and umbilical cord. Diversity in tissue sourcing and manufacturing procedures has significant effects on MSC products. However, in 2006, a minimal set of standard criteria has been issued by the International Society of Cellular Therapy for defining derived MSCs. These include adherence to plastic in conventional culture conditions, particular phenotype, and multilineage differentiation capacity
Language	English
Publishing date	2019-08-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2573856-2
ISSN	1687-9678 ; 1687-966X
ISSN (online)	1687-9678
ISSN	1687-966X
DOI	10.1155/2019/7219297
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Article ; Online: Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4

Polanczyk, Magdalena J / Walker, Edwin / Haley, Daniel / Guerrouahen, Bella S / Akporiaye, Emmanuel T

Journal of translational medicine

2019 Volume 17, Issue 1, Page(s) 219

Abstract: Background: The pleiotropic cytokine, transforming growth factor (TGF)-β, and CD4: Methods: Using BALB/c, FoxP3eGFP and Rag: Results: SM16 abrogates TGF-β-induced Treg generation in vitro but does not prevent global homeostatic expansion of CD4: ...

Abstract	Background: The pleiotropic cytokine, transforming growth factor (TGF)-β, and CD4 Methods: Using BALB/c, FoxP3eGFP and Rag Results: SM16 abrogates TGF-β-induced Treg generation in vitro but does not prevent global homeostatic expansion of CD4 Conclusions: These findings suggest that blockade of TGF-β signaling is a potentially useful strategy for blunting Treg function to enhance the anti-tumor response. Our data further suggest that the overall dampening of Treg function may involve the expansion of a quiescent Treg precursor population, which is CD4
MeSH term(s)	Animals ; Antineoplastic Agents/metabolism ; CD4 Antigens/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Cell Count ; Cell Line, Tumor ; Cell Proliferation ; Female ; Forkhead Transcription Factors/metabolism ; Homeostasis ; Interferon-gamma/metabolism ; Interleukin-2 Receptor alpha Subunit/metabolism ; Lymph Nodes/cytology ; Mice, Knockout ; Neoplasms/pathology ; Signal Transduction ; Spleen/cytology ; T-Lymphocytes, Regulatory/immunology ; Transforming Growth Factor beta/metabolism ; Tumor Burden
Chemical Substances	Antineoplastic Agents ; CD4 Antigens ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Interleukin-2 Receptor alpha Subunit ; Transforming Growth Factor beta ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2019-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-019-1967-3
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Article ; Online: Nesting of colon and ovarian cancer cells in the endothelial niche is associated with alterations in glycan and lipid metabolism.

Halama, Anna / Guerrouahen, Bella S / Pasquier, Jennifer / Satheesh, Noothan J / Suhre, Karsten / Rafii, Arash

Scientific reports

2017 Volume 7, Page(s) 39999

Abstract: The metabolic phenotype of a cancer cell is determined by its genetic makeup and microenvironment, which dynamically modulates the tumor landscape. The endothelial cells provide both a promoting and protective microenvironment - a niche for cancer cells. ...

Abstract	The metabolic phenotype of a cancer cell is determined by its genetic makeup and microenvironment, which dynamically modulates the tumor landscape. The endothelial cells provide both a promoting and protective microenvironment - a niche for cancer cells. Although metabolic alterations associated with cancer and its progression have been fairly defined, there is a significant gap in our understanding of cancer metabolism in context of its microenvironment. We deployed an in vitro co-culture system based on direct contact of cancer cells with endothelial cells (E4
MeSH term(s)	Cell Line, Tumor ; Coculture Techniques ; Colonic Neoplasms/metabolism ; Endothelial Cells/metabolism ; Female ; Glycosylation ; Humans ; Lipid Metabolism ; Ovarian Neoplasms/metabolism ; Polysaccharides/metabolism ; Tumor Microenvironment
Chemical Substances	Polysaccharides
Language	English
Publishing date	2017-01-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep39999
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Article ; Online: GMP-grade α-TEA lysine salt: a 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs.

Guerrouahen, Bella S / Hahn, Tobias / Alderman, Zefora / Curti, Brendan / Urba, Walter / Akporiaye, Emmanuel T

BMC cancer

2016 Volume 16, Page(s) 199

Abstract: Background: Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti- ...

Abstract	Background: Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade α-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. Methods: Male and female beagle dogs received capsules of α-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. α-TEA plasma levels were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. Results: Our findings showed that there was no α-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to α-TEA-treatment. Conclusion: We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of α-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of α-TEA in patients with advanced cancer.
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/toxicity ; Biopsy ; Blood Cell Count ; Blood Chemical Analysis ; Blood Coagulation/drug effects ; Blood Coagulation Tests ; Dogs ; Female ; Lysine ; Male ; Salts ; Time Factors ; Tocopherols/administration & dosage ; Tocopherols/chemistry ; Tocopherols/pharmacokinetics ; Tocopherols/toxicity ; Toxicity Tests ; Toxicokinetics ; Urinalysis
Chemical Substances	Antineoplastic Agents ; Salts ; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (JW7FJR3ZLY) ; Lysine (K3Z4F929H6) ; Tocopherols (R0ZB2556P8)
Language	English
Publishing date	2016-03-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-016-2220-6
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Article ; Online: Osteoblastic and vascular endothelial niches, their control on normal hematopoietic stem cells, and their consequences on the development of leukemia.

Guerrouahen, Bella S / Al-Hijji, Ibrahim / Tabrizi, Arash Rafii

Stem cells international

2011 Volume 2011, Page(s) 375857

Abstract: Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called "niches." The best-characterized stem cell is the hematopoietic stem cell (HSC). Self-renewal and differentiation ability ... ...

Abstract	Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called "niches." The best-characterized stem cell is the hematopoietic stem cell (HSC). Self-renewal and differentiation ability of HSC are regulated by two major elements: endosteal and vascular regulatory elements. The osteoblastic niche localized at the inner surface of the bone cavity might serve as a reservoir for long-term HSC storage in a quiescent state. Whereas the vascular niche, which consists of sinusoidal endothelial cell lining blood vessel, provides an environment for short-term HSC proliferation and differentiation. Both niches act together to maintain hematopoietic homeostasis. In this paper, we provide some principles applying to the hematopoietic niches, which will be useful in the study and understanding of other stem cell niches. We will discuss altered microenvironment signaling leading to myeloid lineage disease. And finally, we will review some data on the development of acute myeloid leukemia from a subpopulation called leukemia-initiating cells (LIC), and we will discuss on the emerging evidences supporting the influence of the microenvironment on chemotherapy resistance.
Language	English
Publishing date	2011-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2573856-2
ISSN	1687-9678 ; 1687-966X
ISSN (online)	1687-9678
ISSN	1687-966X
DOI	10.4061/2011/375857
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Article ; Online: Breast cancer cells promote a notch-dependent mesenchymal phenotype in endothelial cells participating to a pro-tumoral niche.

Ghiabi, Pegah / Jiang, Jie / Pasquier, Jennifer / Maleki, Mahtab / Abu-Kaoud, Nadine / Halabi, Najeeb / Guerrouahen, Bella S / Rafii, Shahin / Rafii, Arash

Journal of translational medicine

2015 Volume 13, Page(s) 27

Abstract: Background: Endothelial cells (ECs) are responsible for creating a tumor vascular niche as well as producing angiocrine factors. ECs demonstrate functional and phenotypic heterogeneity when located under different microenvironments. Here, we describe a ... ...

Abstract	Background: Endothelial cells (ECs) are responsible for creating a tumor vascular niche as well as producing angiocrine factors. ECs demonstrate functional and phenotypic heterogeneity when located under different microenvironments. Here, we describe a tumor-stimulated mesenchymal phenotype in ECs and investigate its impact on tumor growth, stemness, and invasiveness. Methods: Xenograft tumor assay in NOD/SCID mice and confocal imaging were conducted to show the acquisition of mesenchymal phenotype in tumor-associated ECs in vivo. Immunocytochemistry, qPCR and flow cytometry techniques showed the appearance of mesenchymal traits in ECs after contact with breast tumor cell lines MDA-MB231 or MCF-7. Cell proliferation, cell migration, and sphere formation assays were applied to display the functional advantages of mesenchymal ECs in tumor growth, invasiveness, and enrichment of tumor initiating cells. qPCR and western blotting were used to investigate the mechanisms underlying EC mesenchymal transition. Results: Our results showed that co-injection of ECs and tumor cells in NOD/SCID mice significantly enhanced tumor growth in vivo with tumor-associated ECs expressing mesenchymal markers while maintaining their intrinsic endothelial trait. We also showed that a mesenchymal phenotype is possibly detectable in human neoplastic breast biopsies as well as ECs pre-exposed to tumor cells (ECs(Mes)) in vitro. The ECs(Mes) acquired prolonged survival, increased migratory behavior and enhanced angiogenic properties. In return, ECs(Mes) were capable of enhancing tumor survival and invasiveness. The mesenchymal phenotypes in ECs(Mes) were the result of a contact-dependent transient phenomenon and reversed upon removal of the neoplastic contexture. We showed a synergistic role for TGFβ and notch pathways in this phenotypic change, as simultaneous inhibition of notch and TGFβ down-regulated Smad1/5 phosphorylation and Jag1(KD) tumor cells were unable to initiate the process. Conclusions: Overall, our data proposed a crosstalk mechanism between tumor and microenvironment where tumor-stimulated mesenchymal modulation of ECs enhanced the constitution of a transient mesenchymal/endothelial niche leading to significant increase in tumor proliferation, stemness, and invasiveness. The possible involvement of notch and TGFβ pathways in the initiation of mesenchymal phenotype may propose new stromal targets.
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Mesoderm/metabolism ; Mesoderm/pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Phenotype ; Receptors, Notch/metabolism ; Signal Transduction/genetics ; Transcriptome/genetics ; Transforming Growth Factor beta/metabolism ; Tumor Microenvironment ; Xenograft Model Antitumor Assays
Chemical Substances	Receptors, Notch ; Transforming Growth Factor beta
Language	English
Publishing date	2015-01-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-015-0386-3
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Article ; Online: Metabolic signatures differentiate ovarian from colon cancer cell lines.

Halama, Anna / Guerrouahen, Bella S / Pasquier, Jennifer / Diboun, Ilhem / Karoly, Edward D / Suhre, Karsten / Rafii, Arash

Journal of translational medicine

2015 Volume 13, Page(s) 223

Abstract: Background: In this era of precision medicine, the deep and comprehensive characterization of tumor phenotypes will lead to therapeutic strategies beyond classical factors such as primary sites or anatomical staging. Recently, "-omics" approached have ... ...

Abstract	Background: In this era of precision medicine, the deep and comprehensive characterization of tumor phenotypes will lead to therapeutic strategies beyond classical factors such as primary sites or anatomical staging. Recently, "-omics" approached have enlightened our knowledge of tumor biology. Such approaches have been extensively implemented in order to provide biomarkers for monitoring of the disease as well as to improve readouts of therapeutic impact. The application of metabolomics to the study of cancer is especially beneficial, since it reflects the biochemical consequences of many cancer type-specific pathophysiological processes. Here, we characterize metabolic profiles of colon and ovarian cancer cell lines to provide broader insight into differentiating metabolic processes for prospective drug development and clinical screening. Methods: We applied non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography and gas chromatography for the metabolic phenotyping of four cancer cell lines: two from colon cancer (HCT15, HCT116) and two from ovarian cancer (OVCAR3, SKOV3). We used the MetaP server for statistical data analysis. Results: A total of 225 metabolites were detected in all four cell lines; 67 of these molecules significantly discriminated colon cancer from ovarian cancer cells. Metabolic signatures revealed in our study suggest elevated tricarboxylic acid cycle and lipid metabolism in ovarian cancer cell lines, as well as increased β-oxidation and urea cycle metabolism in colon cancer cell lines. Conclusions: Our study provides a panel of distinct metabolic fingerprints between colon and ovarian cancer cell lines. These may serve as potential drug targets, and now can be evaluated further in primary cells, biofluids, and tissue samples for biomarker purposes.
MeSH term(s)	Cell Line, Tumor ; Colonic Neoplasms/metabolism ; Female ; Humans ; Metabolic Networks and Pathways ; Metabolome ; Metabolomics/methods ; Ovarian Neoplasms/metabolism
Language	English
Publishing date	2015-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-015-0576-z
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Article ; Online: Tailoring cells for clinical needs: Meeting report from the Advanced Therapy in Healthcare symposium (October 28-29 2017, Doha, Qatar).

Deola, Sara / Guerrouahen, Bella S / Sidahmed, Heba / Al-Mohannadi, Anjud / Elnaggar, Muhammad / Elsadig, Ramaz / Abdelalim, Essam M / Petrovski, Goran / Gadina, Massimo / Thrasher, Adrian / Wels, Winfried S / Hunger, Stephen P / Wang, Ena / Marincola, Francesco M / Maccalli, Cristina / Cugno, Chiara

Journal of translational medicine

2018 Volume 16, Issue 1, Page(s) 276

Abstract: New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, ...

Abstract	New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called "living drugs". Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.
MeSH term(s)	Cell- and Tissue-Based Therapy ; Genetic Therapy ; Humans ; Immunotherapy ; Molecular Targeted Therapy ; Neoplasms/immunology ; Neoplasms/therapy ; Precision Medicine ; Qatar
Language	English
Publishing date	2018-10-10
Publishing country	England
Document type	Congress ; Research Support, Non-U.S. Gov't
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/s12967-018-1652-y
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Article ; Online: P-glycoprotein-activity measurements in multidrug resistant cell lines: single-cell versus single-well population fluorescence methods.

Pasquier, Jennifer / Rioult, Damien / Abu-Kaoud, Nadine / Marie, Sabine / Rafii, Arash / Guerrouahen, Bella S / Le Foll, Frank

BioMed research international

2013 Volume 2013, Page(s) 676845

Abstract: Background: P-gp expression has been linked to the efflux of chemotherapeutic drugs in human cancers leading to multidrug resistance. Fluorescence techniques have been widely applied to measure the P-gp activity. In this paper, there is a comparison ... ...

Abstract	Background: P-gp expression has been linked to the efflux of chemotherapeutic drugs in human cancers leading to multidrug resistance. Fluorescence techniques have been widely applied to measure the P-gp activity. In this paper, there is a comparison between the advantages of two fluorescence approaches of commonly available and affordable instruments: the microplate reader (MPR) and the flow cytometer to detect the P-gp efflux activity using calcein-AM. Results: The selectivity, sensibility, and reproducibility of the two methods have been defined. Our results showed that the MPR is more powerful for the detection of small inhibition, whereas the flow cytometry method is more reliable at higher concentrations of the inhibitors. We showed that to determine precisely the inhibition efficacy the flow cytometry is better; hence, to get the correct E max and EC50 values, we cannot only rely on the MPR. Conclusion: Both techniques can potentially be used extensively in the pharmaceutical industry for high-throughput drug screening and in biology laboratories for academic research, monitoring the P-gp efflux in specific assays.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/metabolism ; Cell Line, Tumor ; Drug Resistance, Multiple/physiology ; Drug Resistance, Neoplasm/physiology ; Fluoresceins/metabolism ; Fluorescence ; Humans ; MCF-7 Cells ; Reproducibility of Results
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; Fluoresceins ; calcein AM (148504-34-1)
Language	English
Publishing date	2013-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2013/676845
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