1. CXCR4 antagonists as stem cell mobilizers and therapy sensitizers for acute myeloid leukemia and glioblastoma?Vashendriya V. V. Hira, Cornelis J. F. van Noorden, Remco J. Molenaar, 2020, other scientific articles Abstract: Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor–ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α–CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α–CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.
Keywords: glioblastoma, glioblastoma stem cells, niches, acute myeloid leukemia, hematopoietic stem cells, bone marrow, C-X-C receptor type 4, stromal-derived factor-1 ▫$[alpha]$▫, plerixafor
Published in DiRROS: 06.08.2024; Views: 115; Downloads: 155
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2. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell nichesVashendriya V. V. Hira, Cornelis J. F. van Noorden, Hetty E. Carraway, Jaroslaw P. Maciejewski, Remco J. Molenaar, 2017, review article Abstract: Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy.
Keywords: hematopoietic stem cell niche, hijacking, leukemic stem cells, bone marrow, therapy resistance, leukemia
Published in DiRROS: 06.08.2024; Views: 91; Downloads: 116
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3. The importance of flaps in reconstruction of locoregionally advanced lateral skull-base cancer defects : a tertiary otorhinolaryngology referral centre experienceDomen Vozel, Peter Pukl, Aleš Grošelj, Aleksandar Aničin, Primož Strojan, Saba Battelino, 2021, original scientific article Abstract: Background. The aim of the study was to identify the value of extensive resection and reconstruction with flaps in the treatment of locoregionally advanced lateral skull-base cancer.Patients and methods. The retrospective case review of patients with lateral skull-base cancer treated surgically with curative intent between 2011 and 2019 at a tertiary otorhinolaryngology referral centre was made. Results. Twelve patients with locoregionally advanced cancer were analysed. Lateral temporal bone resection was performed in nine (75.0%), partial parotidectomy in six (50.0%), total parotidectomy in one (8.3%), ipsilateral selective neck dissection in eight (66.7%) and ipsilateral modified radical neck dissection in one patient (8.3%). The defect was reconstructed with anterolateral thigh free flap, radial forearm free flap or pectoralis major myocutaneous flap in two patients (17.0%) each. Mean overall survival was 3.1 years (SD = 2.5) and cancer-free survival rate 100%. At the data collection cut-off, 83% of analysed patients and 100% of patients with flap reconstruction were alive. Conclusions. Favourable local control in lateral skull-base cancer, which mainly involves temporal bone is achieved with an extensive locoregional resection followed by free or regional flap reconstruction. Universal cancer registry should be considered in centres treating this rare disease to alleviate analysis and multicentric research.
Keywords: temporal bone, microsurgery, parotid region, free tissue flaps, neoplasm staging, ear
Published in DiRROS: 22.07.2024; Views: 144; Downloads: 120
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4. Compensational role between cathepsinsUrša Pečar Fonović, Janko Kos, Ana Mitrović, 2024, review article Abstract: Cathepsins, a family of lysosomal peptidases, play a crucial role in maintaining cellular homeostasis by regulating protein turnover and degradation as well as many specific regulatory actions that are important for proper cell function and human health. Alterations in the activity and expression of cathepsins have been observed in many diseases such as cancer, inflammation, neurodegenerative disorders, bone remodelling-related conditions and others. These changes are not exclusively harmful, but rather appear to be a compensatory response on the lack of one cathepsin in order to maintain tissue integrity. The upregulation of specific cathepsins in response to the inhibition or dysfunction of other cathepsins suggests a fine-tuned system of proteolytic balance and understanding the compensatory role of cathepsins may improve therapeutic potential of cathepsin's inhibitors. Selectively targeting one cathepsin or modulating their activity could offer new treatment strategies for a number of diseases. This review emphasises the need for comprehensive research into cathepsin biology in the context of disease. The identification of the specific cathepsins involved in compensatory responses, the elucidation of the underlying molecular mechanisms and the development of targeted interventions could lead to innovative therapeutic approaches.
Keywords: lysosomal peptidases, compensation, bone resorption
Published in DiRROS: 23.05.2024; Views: 262; Downloads: 184
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5. Consequence of the introduction of routine FCH PET/CT imaging for patients with prostate cancer : a dual centre surveyMarina Hodolič, Laure Michaud, V. Huchet, S. Balogova, V. Nataf, K. Kerrou, M. Vereb, Jurij Fettich, Jean-Noël Talbot, 2014, original scientific article Abstract: Background. Fluorocholine(18F) (FCH) was introduced at the beginning of April 2010 in France, Slovenia and three other EU member states for the localisation of bone metastases of prostate cancer with PET. The aim of the study was to compare the evolution of diagnostic imaging in patients with prostate cancer using a new radiopharmaceutical FCH, observed in France and in Slovenia, and to quantify the consequence of the results of new imaging modality on the detection rate of abnormal metastases and recurrences of prostate cancer.Patients and methods. In two centres (France/Slovenia), a survey of the number of nuclear medicine examinations in patients with prostate cancer was performed, covering 5 quarters of the year since the introduction of FCH. For each examination, the clinical and biological circumstances were recorded, as well as the detection of bone or soft tissue foci.Results. Six hundred and eighty-eight nuclear medicine examinations were performed impatients with prostate cancer. Nuclear medicine examinations were performed for therapy monitoring and follow-up in 23% of cases. The number of FCH PET/CT grew rapidly between the 1st and 5th period of the observation (+220%), while the number of bone scintigraphies (BS) and fluoride(18F) PET/CTs decreased (-42% and -23% respectively). Fluorodeoxyglucose(18F) (FDG) PET/CT remained limited to few cases of castrate-resistant or metastatic prostate cancer in Paris. The proportion of negative results was significantly lower with FCH PET/CT (14%) than with BS (49%) or fluoride(18F) PET/CT (54%). For bone metastases, the detection rate was similar, but FCH PET/CT was performed on average at lower prostate-specific antigen (PSA) levels and was less frequently doubtful (4% vs. 28% for BS). FCH PET/CT also showed foci in prostatic bed (53% of cases) or in soft tissue (35% of cases).Conclusions. A rapid development of FCH PET/CT was observed in both centres and led to a higher detection rate of prostate cancer lesions.
Keywords: prostate cancer, PET/CT, fluorocholine (FCH), fluoride(18F), bone scintigraphy, indication of imaging, prostata, rak (medicina), slikovna diagnostika
Published in DiRROS: 04.04.2024; Views: 673; Downloads: 505
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6. Morphological characteristics of young and old murine hematopoietic stem cell niches, as modeled in vitroMojca Justin, Ema Rogac Randl, Veno Kononenko, Matej Hočevar, Damjana Drobne, Primož Rožman, 2023, original scientific article Abstract: The hematopoietic stem cell (HSC) niche undergoes detrimental changes with age. The molecular differences between young and
old niches are well studied and understood; however, young and old niches have not yet been extensively characterized in terms of
morphology. In the present work, a 2D stromal model of young and old HSC niches isolated from bone marrow was investigated
using light and scanning electron microscopy (SEM) to characterize cell density after one, two, or three weeks of culturing, cell
shape, and cell surface morphological features. Our work is aimed at identifying morphological differences between young and
old niche cells that could be used to discriminate between their respective murine HSC niches. The results show several age-
specific morphological characteristics. The old niches differ from the young ones in terms of lower cell proliferating capacity,
increased cell size with a flattened appearance, increased number of adipocytes, and the presence of tunneling nanotubes. In
addition, proliferating cell clusters are present in the young niches but not in the old niches. Together, these characteristics
could be used as a relatively simple and reliable tool to discriminate between young and old murine HSC niches and as a
complementary approach to imaging with specific cellular markers.
Keywords: bone marrow, hematoopetic stem cell niche, aging, adipocytes, scanning electron microscopy
Published in DiRROS: 26.01.2024; Views: 427; Downloads: 202
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7. Engineered combinatorial cell device for wound healing and bone regenerationLucija Kadunc, Duško Lainšček, Rok Gašperšič, Petra Sušjan, Uroš Kovačič, Miha Butinar, Boris Turk, Roman Jerala, Iva Hafner Bratkovič, 2023, original scientific article Abstract: Growth factors are the key regulators that promote tissue regeneration and healing processes. While the effects of individual growth factors are well documented, a combination of multiple secreted growth factors underlies stem cell–mediated regeneration. To avoid the potential dangers and laborintensive individual approach of stem cell therapy while maintaining their regeneration-promoting effects based on multiple secreted growth factors, we engineered a “mix-and-match” combinatorial platform based on a library of cell lines producing growth factors. Treatment with a combination of growth factors secreted by engineered mammalian cells was more efficient than with individual growth factors or even stem cell–conditioned medium in a gap closure assay. Furthermore, we implemented in a mouse model a device for allogenic cell therapy for an in situ production of growth factors, where it improved cutaneous wound healing. Augmented bone regeneration was achieved on calvarial bone defects in rats treated with a cell device secreting IGF, FGF, PDGF, TGF-β, and VEGF. In both in vivo models, the systemic concentration of secreted factors was negligible, demonstrating the local effect of the regeneration device. Finally, we introduced a genetic switch that enables temporal control over combinations of trophic factors released at different stages of regeneration mimicking the maturation of natural wound healing to improve therapy and prevent scar formation.
Keywords: wound healing, bone regeneration, growth factors
Published in DiRROS: 01.06.2023; Views: 718; Downloads: 290
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8. Multiscale femoral neck imaging and multimodal trabeculae quality characterization in an osteoporotic bone sampleEnrico Soldati, Flavy Roseren, Daphne Guenoun, Lucia Mancini, Emilio Catelli, Silvia Prati, Giorgia Sciutto, Jerome Vicente, Stefano Iotti, David Bendahan, Emil Malucelli, Martine Pithioux, 2022, original scientific article Abstract: Although multiple structural, mechanical, and molecular factors are definitely involved in osteoporosis, the assessment of subregional bone mineral density remains the most commonly used diagnostic index. In this study, we characterized bone quality in the femoral neck of one osteoporotic patients as compared to an age-matched control subject, and so used a multiscale and multimodal approach including X-ray computed microtomography at different spatial resolutions (pixel size: 51.0, 4.95 and 0.9 µm), microindentation and Fourier transform infrared spectroscopy. Our results showed abnormalities in the osteocytes lacunae volume (358.08 ± 165.00 for the osteoporotic sample vs. 287.10 ± 160.00 for the control), whereas a statistical difference was found neither for shape nor for density. The osteoporotic femoral head and great trochanter reported reduced elastic modulus (Es) and hardness (H) compared to the control reference (−48% (p < 0.0001) and −34% (p < 0.0001), respectively for Es and H in the femoral head and −29% (p < 0.01) and −22% (p < 0.05), respectively for Es and H in the great trochanter), whereas the corresponding values in the femoral neck were in the same range. The spectral analysis could distinguish neither subregional differences in the osteoporotic sample nor between the osteoporotic and healthy samples. Although, infrared spectroscopic measurements were comparable among subregions, and so regardless of the bone osteoporotic status, the trabecular mechanical properties were comparable only in the femoral neck. These results illustrate that bone remodeling in osteoporosis is a non-uniform process with different rates in different bone anatomical regions, hence showing the interest of a clear analysis of the bone microarchitecture in the case of patients’ osteoporotic evaluation
Keywords: synchrotron X-ray microtomography, bone, trabecular struicture, osteons, osteoporosis, phase-contrast imaging, open access
Published in DiRROS: 28.04.2023; Views: 512; Downloads: 267
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