Publications by authors named "Joanna Stachura"

14 Publications

  • Page 1 of 1

Shape of the anterior surface of the cornea after extended wear of silicone hydrogel soft contact lenses.

Ophthalmic Physiol Opt 2021 May 4. Epub 2021 May 4.

Division of Ophthalmology and Optometry, Department of Ophthalmology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

Purpose: To measure geometrical changes in the anterior surface of the cornea after wearing silicon hydrogel (SiH) soft contact lenses continuously for 1 week.

Methods: Forty-three eyes with 3.0D of myopia and 22 eyes with 3.0D of hyperopia were enrolled in the prospective, interventional study. All subjects underwent a general eye examination, corneal tomography with wavefront aberration analysis, corneal thickness measurements and epithelial thickness mapping before and after wearing SiH lenses (Acuvue Oasys) for 7 days.

Results: No significant changes in average keratometry were observed in either refractive group. In the myopic group, keratometry findings for the flat meridian (K1) and central corneal thickness decreased significantly. After +3.0 D lens wear in the hyperopic group, a significant decrease in epithelial thickness up to 3.19 µm was observed in the central and paracentral cornea, (p < 0.001). In both refractive groups, the largest epithelial thickness increase was seen in the periphery. A decrease in spherical aberration was noted in myopic eyes, while an increase of both higher order corneal aberrations and coma was found in hyperopic subjects.

Conclusion: Extended wear of SiH lenses results in a significant change in epithelial thickness leading to alteration in the geometry of the anterior surface of the cornea, particularly in hyperopic patients. These epithelial thickness variations lead to changes in the higher order aberrations of the cornea.
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http://dx.doi.org/10.1111/opo.12830DOI Listing
May 2021

Three-year outcomes of mixed astigmatism correction with single-step transepithelial photorefractive keratectomy with a large ablation zone.

J Cataract Refract Surg 2021 Apr;47(4):450-458

From the Division of Ophthalmology and Optometry, Department of Ophthalmology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland (Kaluzny, Piotrowiak-Słupska, Kaszuba-Modrzejewska, Rzeszewska-Zamiara, Stachura); Oftalmika Eye Hospital, Bydgoszcz, Poland (Kaluzny, Piotrowiak-Słupska); SCHWIND eye-tech-solutions, Kleinostheim, Germany (Verma, Arba-Mosquera).

Purpose: To evaluate refractive and visual outcomes of single-step transepithelial photorefractive keratectomy (transPRK) in the treatment of mixed astigmatism with the use of an aberration-neutral profile and large ablation zone.

Setting: Nicolaus Copernicus University and Oftalmika Eye Hospital, Bydgoszcz, Poland.

Design: Retrospective, observational case series.

Methods: This study included patients who underwent transPRK to correct mixed astigmatism and completed the 3-year follow-up. Procedures were performed with an Amaris 750S excimer laser using an aberration-neutral profile and optical zone of 7.2 mm or more.

Results: A total 48 eyes of 39 patients were included. Preoperatively, mean spherical manifest refraction was +1.37 ± 0.98 diopter (D) (0.25 to 4.00 D), and astigmatism was -4.00 ± 0.76 D (-2.25 to -6.00 D). Three years postsurgery, it was -0.17 ± 0.26 D and -0.41 ± 0.44 D, respectively. Attempted spherical equivalent correction within ±0.50 D was achieved in 45 eyes (94%) and cylindrical correction in 34 (71%). Preoperative corrected distance visual acuity (CDVA) was 20/20 or better in 38 eyes (79%), and postoperative uncorrected was 20/20 or better in 29 eyes (60.0%). No eye had lost 2 or more Snellen lines of CDVA, whereas 3 eyes (6%) gained 2 or more lines. In 4 eyes (8%), haze of low intensity was observed at the periphery, with scores between 0.5 and 1.0, and only 1 eye getting a score of 2 in 0- to 4-degree scale.

Conclusions: Mixed astigmatism correction with large-ablation-zone transPRK provided good results for efficacy, safety, predictability, and visual outcomes in a 3-year follow-up.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000476DOI Listing
April 2021

Change in the geometry of positive- and negative-powered soft contact lenses during wear.

PLoS One 2020 9;15(11):e0242095. Epub 2020 Nov 9.

Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Toruń, Poland.

Contact lens wear causes mutual interactions between the ocular surface and the lens, which may affect comfort as well as vision. The aim of this study was to examine deformations in modern positive- and negative-powered silicone hydrogel soft contact lenses (SiH SCLs) after 7 days of continuous wear. This pre-post interventional study included 64 eyes: 42 eyes with myopia of -3.00 D and 22 eyes with hyperopia of +3.00 D. All patients underwent general ophthalmic examination, corneal topography/tomography, total corneal and epithelial thickness mapping, and specular microscopy before and after the wearing period. SiH SCLs made of senofilcon A were worn continuously for 7 days on all eligible eyes. The geometry of the new and used lenses was measured 3 to 6 minutes after removal in two perpendicular planes using a custom-made swept source optical coherence tomography (SS-OCT) system for in vitro measurements. The anterior and posterior radii of curvature decreased in -3.00 D lenses in two perpendicular planes. This effect correlated significantly with average keratometry of the cornea. Sagittal lens height was lower in +3.00 D lens after wear, which correlated moderately with the corneal sagittal height. A significant decrease in central corneal epithelial thickness was observed after wearing +3.0 D lenses. In conclusion, SiH SCLs made of senofilcon A undergo minor deformations after 7-day continuous wear. Geometry modifications are different for -3.00 D and +3.00 D lenses, and they imitate the shape of the anterior eye surface. These geometric changes are accompanied by a decrease in the central thickness of corneal epithelium after +3.00 D lens wear.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242095PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652269PMC
December 2020

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy.

Cancer Immunol Immunother 2020 Jun 28;69(6):1101-1112. Epub 2020 Feb 28.

Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Str., F Building, 02-097, Warsaw, Poland.

It was previously reported that the activation of antitumor immune response by photodynamic therapy (PDT) is crucial for its therapeutic outcome. Excessive PDT-mediated inflammation is accompanied by immunosuppressive mechanisms that protect tissues from destruction. Thus, the final effect of PDT strongly depends on the balance between the activation of an adoptive arm of immune response and a range of activated immunosuppressive mechanisms. Here, with flow cytometry and functional tests, we evaluate the immunosuppressive activity of tumor-associated myeloid cells after PDT. We investigate the antitumor potential of PDT combined with indoleamine 2,3-dioxygenase 1 (IDO) inhibitor in the murine 4T1 and E0771 orthotopic breast cancer models. We found that the expression of IDO, elevated after PDT, affects the polarization of T regulatory cells and influences the innate immune response. Our results indicate that, depending on a therapeutic scheme, overcoming IDO-induced immunosuppressive mechanisms after PDT can be beneficial or can lead to a systemic toxic reaction. The inhibition of IDO, shortly after PDT, activates IL-6-dependent toxic reactions that can be diminished by the use of anti-IL-6 antibodies. Our results emphasize that deeper investigation of the physiological role of IDO, an attractive target for immunotherapies of cancer, is of great importance.
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http://dx.doi.org/10.1007/s00262-020-02528-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230067PMC
June 2020

Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma.

Leukemia 2019 10 14;33(10):2416-2428. Epub 2019 Mar 14.

Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

The BCL-2 inhibitor venetoclax has only limited activity in DLBCL despite frequent BCL-2 overexpression. Since constitutive activation of the B cell receptor (BCR) pathway has been reported in both ABC and GCB DLBCL, we investigated whether targeting SYK or BTK will increase sensitivity of DLBCL cells to venetoclax. We report that pharmacological inhibition of SYK or BTK synergistically enhances venetoclax sensitivity in BCL-2-positive DLBCL cell lines with an activated BCR pathway in vitro and in a xenograft model in vivo, despite the only modest direct cytotoxic effect. We further show that these sensitizing effects are associated with inhibition of the downstream PI3K/AKT pathway and changes in the expression of MCL-1, BIM, and HRK. In addition, we show that BCR-dependent GCB DLBCL cells are characterized by deficiency of the phosphatase SHP1, a key negative regulator of the BCR pathway. Re-expression of SHP1 in GCB DBLCL cells reduces SYK, BLNK, and GSK3 phosphorylation and induces corresponding changes in MCL1, BIM, and HRK expression. Together, these findings suggest that SHP1 deficiency is responsible for the constitutive activation of the BCR pathway in GCB DLBCL and identify SHP1 and BCL-2 as potential predictive markers for response to treatment with a venetoclax/BCR inhibitor combination.
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http://dx.doi.org/10.1038/s41375-019-0442-8DOI Listing
October 2019

Long-Term Anatomic and Functional Outcomes after Macular Hole Surgery.

J Ophthalmol 2018 26;2018:3082194. Epub 2018 Nov 26.

Department of Ophthalmology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum, Bydgoszcz, Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland.

Aim: To evaluate the structural and functional outcomes in patients who underwent macular hole (MH) surgery in the long-term follow-up.

Materials And Methods: Forty-four eyes of 40 patients (28 females and 12 males) were examined. The examination included visual acuity, optical coherence tomography, and colour vision testing. The same evaluation was performed in 30 fellow eyes.

Results: MH closure was obtained in 42 eyes (95.45%). There was no reopening of the initially closed MHs. In long-term postoperative examination, we observed IS/OS junction defects in 28 (63.6%) eyes and ELM defects in 19 (43.2%) eyes. We found that the IS/OS junction defects correlated with the diameter of the MH (=0.016), whereas ELM defects correlated with both the diameter of the MH (=0.001) and duration time of the MH (=0.008). The presence of ELM defects in OCT was the cause of inferior BCVA in long-term observation time (=0.004). The mean BCVA before the MH surgery was 0.15. It improved significantly both in early ( < 0.001) and long-term postoperative observation ( < 0.005). Generally, the functional outcomes were better in eyes with short-time duration of the MH, when a smaller diameter (<400 m) of the hole was measured and a V-shaped closure of the MH and the restoration of the ELM line on OCT were present. Pseudoprotanomaly was noted in 13 (35.1%) eyes. In the fellow eye group, mean BCVA was 0.95 (range, 0.6-1.0). In 3 eyes, we detected vitreomacular traction, and in 4 eyes, initial cataract. These conditions, as well as probably early stage of diabetes mellitus, influenced functional outcomes of studied eyes.

Conclusions: The anatomic and functional outcomes after macular surgery are satisfactory and improve with time. After a successful closing of the MH, the restoration of the retina progresses at a slower pace than improvement in visual acuity.
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http://dx.doi.org/10.1155/2018/3082194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287145PMC
November 2018

Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.

Blood 2019 01 15;133(1):70-80. Epub 2018 Oct 15.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.
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http://dx.doi.org/10.1182/blood-2018-08-872465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318426PMC
January 2019

Three-year outcomes after high hyperopia correction using photorefractive keratectomy with a large ablation zone.

Br J Ophthalmol 2019 06 9;103(6):849-854. Epub 2018 Aug 9.

SCHWIND Eye-Tech-Solutions, Kleinostheim, Germany.

Aim: To evaluate refractive and visual outcomes of photorefractive keratectomy (PRK) to treat high hyperopia using an aberration-neutral profile and large ablation zone.

Methods: This was a retrospective, consecutive observational case series at the Oftalmika Eye Hospital, Bydgoszcz, Poland. We included 51 consecutive eyes of 34 patients who underwent alcohol-assisted PRK to correct hyperopia within the range of +3.6 to +6.15 D (mean+4.61±0.67 D). Procedures were performed with an Amaris 750S excimer laser (Schwind eye-tech-solutions GmbH, Kleinostheim, Germany) using an aberration-neutral profile and a 10 mm total ablation zone. Refractive results, predictability, safety and efficacy were evaluated 3 years postoperatively.

Results: At 1-year postsurgery, the mean manifest refraction spherical equivalent (MRSE) was -0.002±0.43 D and mean cylinder was -0.181±0.31 D, while the values were +0.09±0.46 D and -0.15±0.26 D, respectively, at 2 years (MRSE p<0.001) and +0.15±0.44 D and -0.15±0.26 D, respectively, at 3 years (MRSE p<0.001). 78% of eyes were within ±0.50 D of the attempted spherical equivalent correction. Three years postoperatively, 22% of eyes lost one line of corrected distance visual acuity and 27% gained a line or two. The change in the mean corneal spherical aberrations for the 6 mm zone was from 0.27±0.07 to 0.08±0.13 µm.

Conclusions: High hyperopia correction with PRK using an aberration-neutral profile and large ablation zone provides good efficacy, safety, predictability and visual outcomes. Relatively low change of corneal spherical aberrations and low increase of hyperopia in the first three postoperative years were observed.
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http://dx.doi.org/10.1136/bjophthalmol-2017-311694DOI Listing
June 2019

Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy.

Int J Mol Sci 2018 Aug 1;19(8). Epub 2018 Aug 1.

Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland.

Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy.
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http://dx.doi.org/10.3390/ijms19082256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121368PMC
August 2018

Inhibition of autophagy sensitizes cancer cells to Photofrin-based photodynamic therapy.

BMC Cancer 2018 02 20;18(1):210. Epub 2018 Feb 20.

Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.

Background: Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or pro-survival mechanism in a context-dependent manner. Therefore, we aimed to determine the role of autophagy in Photofrin-based PDT.

Methods: In vitro cytotoxic/cytostatic effects of PDT were evaluated with crystal violet cell viability assay. Autophagy induction was analyzed by immunoblotting and immunofluorescence using anti-LC3 antibody. Autophagy was inhibited by shRNA-mediated ATG5 knockdown or CRISPR/Cas9-mediated ATG5 knockout. Apoptosis was assessed by flow cytometry analysis of propidium iodide and anexin V-positive cells as well as by detection of cleaved PARP and caspase 3 proteins using immunoblotting. Protein carbonylation was evaluated by the 2,4-dinitrophenylhydrazine (DNPH) method.

Results: Photofrin-PDT leads to robust autophagy induction in two cancer cell lines, Hela and MCF-7. shRNA-mediated knockdown of ATG5 only partially blocks autophagic response and only marginally affects the sensitivity of Hela and MCF-7 cells to PDT. ATG5 knockout in HeLa cell line utilizing CRISPR/Cas9 genome editing results in increased PDT-mediated cytotoxicity, which is accompanied by an enhanced apoptotic response and increased accumulation of carbonylated proteins.

Conclusions: Altogether, these observations imply that autophagy contributes to Photofrin-PDT resistance by enabling clearance of carbonylated and other damaged proteins. Therefore, autophagy inhibition may serve as a strategy to improve PDT efficacy.
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http://dx.doi.org/10.1186/s12885-018-4126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819678PMC
February 2018

HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies.

Blood 2017 10 22;130(14):1628-1638. Epub 2017 Aug 22.

Molecular Therapy in Hematology and Oncology & Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene () has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.
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http://dx.doi.org/10.1182/blood-2016-08-736066DOI Listing
October 2017

Inhibition of lymphangiogenesis impairs antitumour effects of photodynamic therapy and checkpoint inhibitors in mice.

Eur J Cancer 2017 09 11;83:19-27. Epub 2017 Jul 11.

Department of Immunology, Medical University of Warsaw, Warsaw, Poland; Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland. Electronic address:

Photodynamic therapy (PDT) has been shown to destroy tumour-associated lymphatic vessels. Therefore, we sought to investigate the functional outcomes of PDT-mediated damage to the lymphatic vessels. We observed that PDT with verteporfin, completely but transiently, blocks the functional lymphatic drainage in the orthotopic mammary tumour models. Sustained inhibition of lymphatic vessels regeneration induced by lenalidomide or the soluble form of vascular endothelial growth factor receptor 3 (sVEGFR3) that neutralises lymphangiogenic vascular endothelial growth factor C (VEGF-C), significantly impaired antitumour efficacy of PDT. Antilymphangiogenic compounds also significantly inhibited the ability of intratumourally inoculated dendritic cells (DCs) to translocate to local lymph nodes and diminished the number of tumour-infiltrating interferon-γ-secreting or tumour antigen-specific CD8 T cells. Lenalidomide also abrogated antitumour effects of the combination immunotherapy with PDT and anti-programmed death-ligand 1 (PD-L1) antibodies. Altogether, these findings indicate that PDT-mediated damage to the lymphatic vessels negatively affects development of antitumour immunity, and that drugs that impair lymphatic vessel regeneration might not be suitable for the use in combination with PDT.
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http://dx.doi.org/10.1016/j.ejca.2017.06.004DOI Listing
September 2017

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development.

Oncoimmunology 2016 Jul 13;5(7):e1182278. Epub 2016 May 13.

Department of Immunology, Medical University of Warsaw , Warsaw, Poland.

Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).
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http://dx.doi.org/10.1080/2162402X.2016.1182278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006909PMC
July 2016

Adenanthin targets proteins involved in the regulation of disulphide bonds.

Biochem Pharmacol 2014 May 11;89(2):210-6. Epub 2014 Mar 11.

Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; Institute of Physical Chemistry, Polish Academy of Sciences, Department 3, Warsaw, Poland. Electronic address:

Adenanthin has been recently shown to inhibit the enzymatic activities of peroxiredoxins (Prdx) I and II through its functional α,β-unsaturated ketone group serving as a Michael acceptor. A similar group is found in SK053, a compound recently developed by our group to target the thioredoxin-thioredoxin reductase (Trx-TrxR) system. This work provides evidence that next to Prdx I and II adenanthin targets additional proteins including thioredoxin-thioredoxin reductase system as well as protein disulfide isomerase (PDI) that contain a characteristic structural motif, referred to as a thioredoxin fold. Adenanthin inhibits the activity of Trx-TR system and PDI in vitro in the insulin reduction assay and decreases the activity of Trx in cultured cells. Moreover, we identified Trx-1 as an adenanthin binding protein in cells incubated with biotinylated adenanthin as an affinity probe. The results of our studies indicate that adenanthin is a mechanism-selective, rather than an enzyme-specific inhibitor of enzymes containing readily accessible, nucleophilic cysteines. This observation might be of importance in considering potential therapeutic applications of adenanthin to include a range of diseases, where aberrant activity of Prdx, Trx-TrxR and PDI is involved in their pathogenesis.
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http://dx.doi.org/10.1016/j.bcp.2014.02.022DOI Listing
May 2014