| 1. |
- Bahnan, Wael, et al.
(author)
-
Spike-Dependent Opsonization Indicates Both Dose-Dependent Inhibition of Phagocytosis and That Non-Neutralizing Antibodies Can Confer Protection to SARS-CoV-2
- 2022
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
-
Journal article (peer-reviewed)abstract
- Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization correlate with the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phagocytosis.
|
|
| 2. |
- Eriksson, Anna, et al.
(author)
-
Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia
- 2010
-
In: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 80:10, s. 1507-1516
-
Journal article (peer-reviewed)abstract
- Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC50 of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC50 = 0.4 mu M) and Kasumi-1 (IC50 = 2.3 mu M). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion. AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML.
|
|
| 3. |
- Gad, Helge, et al.
(author)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Journal article (peer-reviewed)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 4. |
- Glimelius, Bengt, et al.
(author)
-
U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
-
In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
-
Journal article (peer-reviewed)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
|
|
| 5. |
- Groß, Rüdiger, et al.
(author)
-
Macromolecular Viral Entry Inhibitors as Broad-Spectrum First-Line Antivirals with Activity against SARS-CoV-2
- 2022
-
In: Advanced Science. - : Wiley. - 2198-3844. ; 9:20
-
Journal article (peer-reviewed)abstract
- Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS-CoV-2. Macromolecular inhibitors are shown to exhibit the highly sought-after broad-spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS-CoV-2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS-CoV-2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.
|
|
| 6. |
- Harbst, Katja, et al.
(author)
-
Molecular profiling reveals low- and high-grade forms of primary melanoma.
- 2012
-
In: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 18:15, s. 4026-4036
-
Journal article (peer-reviewed)abstract
- For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Höglund, Anna T., 1960-, et al.
(author)
-
Knowledge of human papillomavirus and attitudes to vaccination among Swedish high school students
- 2009
-
In: International Journal of STD and AIDS (London). - : SAGE Publications. - 0956-4624 .- 1758-1052. ; 20:2, s. 102-107
-
Journal article (peer-reviewed)abstract
- The aim of the study was to investigate knowledge of and attitudes to sexually transmitted infection (STI) and STI prevention with special focus on human papillomavirus (HPV) and the new vaccine against HPV, among 16-year-old high school students in a Swedish context. A study-specific questionnaire was distributed to 572 first year high school students from five different high schools in a medium-sized town in Sweden. The students lacked knowledge of HPV and its association with cervical cancer. Similarly, their knowledge of the new vaccine was limited. Their attitude to condom use when having sex with a new partner was positive, but decreased if oral contraceptives were used and if they were vaccinated against an STI. The main source of information was the school, followed by youth clinics and the media. The results highlight the clinical importance for school nurses and personnel at youth clinics to inform adolescents about HPV and its association with cancer.
|
|
| 10. |
- Höglund, Katja, et al.
(author)
-
The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease
- 2020
-
In: Acta Veterinaria Scandinavica. - : BMC. - 0044-605X .- 1751-0147. ; 62:1
-
Journal article (peer-reviewed)abstract
- Background The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay. Results Catestatin concentration decreased with increasing left atrial and ventricular size (R-2 <= 0.09, P <= 0.019), and increased with increasing systolic and diastolic blood pressures (R-2 <= 0.08, P <= 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study. Conclusions In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.
|
|
