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Immunotherapy of peritoneal carcinomatosis
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Michael A. Ströhlein, Markus M. Heiss
Despite the variety of immunocompetent cells obviously included in the peritoneal cavity, the anti-inflammatory Th2 phenotype was found to be predominant in physiological conditions. Therefore, polarization to a more cellular phenotype by unspecific immunomodulation was tried. The streptococcal preparation OK-432 was tested in a rat model to have immunostimulatory activity on natural killer cells, lymphokine-activated killer (LAK) cells, and T-lymphocytes. Locoregional administration of OK-432 was found to be effective in single patients with malignant ascites from gastric cancer, which was associated with an upregulation of Th1 responses [3]. Induction of predominant Th1 type T-helper cells was further increased by combining OK-432 with interleukin-2. Another concept was the intraperitoneal (i.p.) application of fms-like tyrosine kinase-3-ligand (Flt3-L), a truncated glycoprotein that increases DCs and monocytes. Increased interleukin-12 as a sign of enhanced cellular immunity together with a maturational shift toward the monocyte-derived DC phenotype was observed [4]. Clinical efficacy against peritoneal carcinomatosis was only limited to a special group of immunoreactive patients, which were able to overcome factors like tumor-related immunosuppression within OK-432 or Flt3-L treatment. Nevertheless, these attempts demonstrated the potential of induction of a more predominant Th1 phenotype together with stimulation of innate components of the immune system like natural killer cells and macrophages.
Combined radiation injury and its impacts on radiation countermeasures and biodosimetry
Published in International Journal of Radiation Biology, 2023
Juliann G. Kiang, William F. Blakely
CI with hemorrhage following high-dose radiation exacerbates CI-induced EPO and HIF-1α due to increased NF-κB in the kidney. The inflammation-associated microRNA (miR) expression in the kidney was also altered. Among 29 miRs on day 1 after RCI (Figure 1), 14 were significantly increased and 15 were significantly decreased. Let-7e, miR-29b, miR-30e, miR-27a, miR-32 and miR-135 were associated with NF-κB, HIF-1α, and EPO (Kiang et al. 2017a). However, CI with skin wound following high-dose radiation increased miR-34a to a similar magnitude as RI at early times but not on day 30 (Figure 2). MiR-34a was inhibited by G-CSF. MiR-34a decreased Bcl-2 and increased Bax, whereas G-CSF increased Bcl-2. Therefore, the balance between G-CSF and miR-34a should be critical for cell survival or death (Kiang et al. 2022). It should be kept in mind that FMS-like tyrosine kinase 3 ligand (flt-3L, a bone marrow dysplasia marker) was increased by RI and CI, but the RI-induced increases and CI-induced increases were similar (Jiao et al. 2010; Kiang et al. 2017a). In contrast, citrulline (produced by intestinal epithelial cells) was increased by RI and CI, but the CI-induced decreases were more than RI-induced decreases, confirming the CI-induced GI damage was more than the RI-induced GI damage (Kiang et al. 2020).
Increased synthesis of pro-inflammatory cytokines in C9ORF72 patients
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Gabriel Pinilla, Anupama Kumar, Mary Kay Floaters, Carlos A. Pardo, Jeffrey Rothstein, Hristelina Ilieva
Fms-like tyrosine kinase 3 ligand is a cytokine and growth factor that increases the number of T and B lymphocytes by activating the hematopoietic progenitors. It binds to CD135 on hematopoietic progenitors and is considered crucial for plasmocytoid and classical dendritic cell development (31). CSF levels of Fms-like tyrosine kinase 3 ligand levels have been reported elevated in ALS patients (32). GM-CSF is produced by macrophages, T cells, fibroblasts, endothelial cells and stimulates stem cells to produce granulocytes, monocytes, and macrophages. GM-CSF levels were found decreased with longer duration of ALS disease (33). CCL5 or RANTES (regulated on activation, normal T cell expressed and secreted) has T-cell chemotactic properties and was also found different between the two ALS groups. While CCL5 levels increase with age (34), there is no statistically difference between the ages of the two ALS groups (58.2 IQR 10.8 vs. 62.0 IQR 8.0), thus the effect of age is an unlikely explanation. It is quite possible that the detected changes in growth factor levels specific for the C9+ group are a compensatory type of change. In the future, it will be interesting to obtain a detailed analysis of lymphocyte counts and subtypes in this patient group in parallel with the growth factor analysis.
Identification of the differentially expressed protein biomarkers in rat blood plasma in response to gamma irradiation
Published in International Journal of Radiation Biology, 2020
Jia-Li Sun, Shuang Li, Xue Lu, Jiang-Bin Feng, Tian-Jing Cai, Mei Tian, Qing-Jie Liu
Over the past decade, proteomics based on mass spectrometry technology can provide fast, high-quality and more valuable information for screening more sensitive and reliable candidate molecular biomarkers in response to ionizing radiation. A few studies have reported that some proteins were altered in a dose-dependent manner following ionizing radiation exposure, such as C-reactive protein (CRP), serum amyloid A (SAA), growth arrest and DNA damage-inducible 45 (GADD45) proteins, FMS-like tyrosine kinase 3 ligand (Flt-3L), and so on (Sproull and Camphausen 2016; Sproull et al. 2017). Recently, using high-resolution proteomic analysis of both plasma and urine from non-human primates following whole body irradiation, a panel of overlapping proteins with characteristic time- and dose-dependent changes was identified (Byrum et al. 2017; Balog et al. 2018). Ferredoxin reductase (FDXR), Bcl-2 associated X protein (BAX), DNA-bindinig protein 2 (DDB2) and alpha-actinin-1 (ACTN1) proteins were observed to have significant changes with received doses in the hematopoietically humanized mouse model following X-irradiation. The combination of radiation-responsive proteins has the potential for assessment of radiation dose (Lee et al. 2018). However, these studies were carried on different models, platforms and experimental conditions, there is still no unanimous protein expression alterations that was considered as a good radiation biodosimeter. Therefore, systematically identifying and validating new protein biomarkers of radiation exposure are essential.