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Effect of ?2?macroglobulin in the early stage of jaw osteoradionecrosis.

ABSTRACT: Advanced osteoradionecrosis (ORN) is one of the most serious complications in patients with head and neck cancer, resulting in poor prognosis. Numerous studies have therefore focused on the pathogenesis and interventions of ORN early stage. The present study aimed to investigate whether ?2?macroglobulin (?2M) could prevent early?stage jaw osteoradionecrosis caused by radiotherapy (RT). Following local injection of ?2M, a single dose of 30 Gy was delivered to rats for pathological exploration. For 28 days, the irradiated mandible and soft tissues were examined for potential changes. Furthermore, primary human bone marrow mesenchymal stem cells pretreated with ?2M followed by 8 Gy irradiation (IR) were also used. Tartrate?resistant acid phosphatase assay, terminal uridine deoxynucleotidyl nick end labeling assay and immunohistochemical staining were performed on irradiated mandibular bone, tongue or buccal mucosa tissues from rats. Cell proliferation was assessed by evaluating the cell morphology by microscopy and by using the cell counting kit?8. Fluorescence staining, flow cytometry and western blotting were conducted to detect the reactive oxygen species level, cell apoptosis and protein expression of superoxide dismutase 2 (SOD2), heme oxygenase?1 (HO?1) and phosphorylated Akt following irradiation. The results demonstrated that ?2M attenuated physical inflammation, osteoclasts number and fat vacuole accumulation in mandibular bone marrow and bone marrow cell apoptosis following IR in vivo. Furthermore, ?2M pretreatment suppressed the expression of 8?hydroxy?2'?deoxyguanosine in mandibular bone and tongue paraffin embedded sections, which is a marker of oxidative damage, and increased SOD2 expression in mucosa and tongue paraffin embedded sections. The present study demonstrated the efficient regulation of antioxidative enzymes, including SOD2 and heme oxygenase?1, and reduction in oxidative damage by ?2M. In addition, in vitro results confirmed that ?2M may protect cells from apoptosis and suppress reactive oxygen species accumulation. Overall, the present study demonstrated that ?2M treatment may exert some radioprotective effects in early?stage ORN via antioxidant mechanisms, and may therefore be considered as a potential alternative molecule in clinical prophylactic treatments.

SUBMITTER: Li J

PROVIDER: S-EPMC7252453 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Effect of α2‑macroglobulin in the early stage of jaw osteoradionecrosis.

Li Jie J Yin Ping P Chen Xueying X Kong Xiangbo X Zhong Wanzhen W Ge Yaping Y She Yangyang Y Xian Xuehong X Qi Lei L Lin Zhi Z Moe Justine J Fang Silian S

International journal of oncology 20200423 1

Advanced osteoradionecrosis (ORN) is one of the most serious complications in patients with head and neck cancer, resulting in poor prognosis. Numerous studies have therefore focused on the pathogenesis and interventions of ORN early stage. The present study aimed to investigate whether α2‑macroglobulin (α2M) could prevent early‑stage jaw osteoradionecrosis caused by radiotherapy (RT). Following local injection of α2M, a single dose of 30 Gy was delivered to rats for pathological exploration. Fo ...[more]

PMID: 32377713

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Project description:ImportanceProton radiation therapy (PRT) has reduced radiation-induced toxic effects, such as mucositis and xerostomia, over conventional photon radiation therapy, leading to significantly improved quality of life in patients with head and neck cancers. However, the prevalence of osteoradionecrosis (ORN) of the jaw following PRT in these patients is less clear.ObjectiveTo report the prevalence and clinical characteristics of ORN in patients with oral and oropharyngeal cancer (OOPC) treated with PRT.Design, setting, and participantsThis case series reports a single-institution experience (Memorial Sloan Kettering Cancer Center, New York, New York) between November 2013 and September 2019 and included 122 radiation therapy-naive patients with OOPC treated with PRT. Data were analyzed from 2013 to 2019.Main outcomes and measuresClinical parameters, including sex, age, comorbidities, tumor histology, concurrent chemotherapy, smoking, comorbidities, and preradiation dental evaluation, were obtained from the medical record. Patients with clinical or radiographic signs of ORN were identified and graded using the adopted modified Glanzmann and Grätz grading system. Characteristics of ORN, such as location, clinical presentation, initial stage at diagnosis, etiology, time to diagnosis, management, and clinical outcome at the last follow-up, were also collected.ResultsOf the 122 patients (mean [SD] age, 63 [13] years; 45 [36.9%] women and 77 [63.1%] men) included in this study, 13 (10.6%) developed ORN following PRT during a median (range) follow-up time of 40.6 (<1-101) months. All patients had spontaneous development of ORN. At the time of initial diagnosis, grade 0, grade 1, grade 2, and grade 3 ORN were seen in 2, 1, 9, and 1 patient, respectively. The posterior ipsilateral mandible within the radiation field that received the full planned PRT dose was the most involved ORN site. At a median (range) follow-up of 13.5 (0.2-58.0) months from the time of ORN diagnosis, complete resolution, stable condition, and progression of ORN were seen in 3, 6, and 4 patients, respectively. The 3-year rates of ORN and death in the total cohort were 5.2% and 21.5%, while the 5-year rates of ORN and death were 11.5% and 34.4%, respectively.Conclusions and relevanceIn this case series, the prevalence of ORN following PRT was found to be 10.6%, indicating that ORN remains a clinical challenge even in the era of highly conformal PRT. Clinicians treating patients with OOPC with PRT should be mindful of this complication.

Project description:BackgroundTo evaluate factors associated with osteoradionecrosis of the jaw (ORNJ) in patients with head and neck squamous cell carcinoma (HNSCC), focusing on jaw-related dose-volume histogram (DVH) parameters.MethodsWe retrospectively reviewed the medical records of 616 patients with HNSCC treated with curative-intent or postoperative radiation therapy (RT) during 2008-2018. Patient-related (age, sex, history of smoking or alcohol use, diabetes mellitus, performance status, pre-RT dental evaluation, pre- or post-RT tooth extraction), tumor-related (primary tumor site, T-stage, nodal status), and treatment-related (pre-RT surgery, pre-RT mandible surgery, induction or concurrent chemotherapy, RT technique) variables and DVH parameters (relative volumes of the jaw exposed to doses of 10 Gy-70 Gy [V10-70]) were investigated and compared between patients with and without ORNJ. The Mann-Whitney U test was used to compare RT dose parameters. Univariate and multivariate Cox regression analyses were used to assess factors associated with ORNJ development. Kaplan-Meier analyses were performed for cumulative ORNJ incidence estimation.ResultsForty-six patients (7.5%) developed ORNJ. The median follow-up duration was 40 (range 3-145) months. The median time to ORNJ development was 27 (range 2-127) months. DVH analysis revealed that V30-V70 values were significantly higher in patients with than in those without ORNJ. In univariate analyses, primary tumor site, pre-RT mandible surgery, post-RT tooth extraction, and V60 > 14% were identified as important factors. In multivariate analyses, V60 > 14% (p = 0.0065) and primary tumor site (p = 0.0059) remained significant. The 3-year cumulative ORNJ incidence rates were 2.5% and 8.6% in patients with V60 ≤ 14% and > 14%, respectively (p < 0.0001), and 9.3% and 1.4% in patients with oropharyngeal or oral cancer and other cancers, respectively (p < 0.0001).ConclusionsV60 > 14% and oropharyngeal or oral cancer were found to be independent risk factors for ORNJ. These findings might be useful to minimize ORNJ incidence in HNSCC treated with curative RT.

Project description:Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, involves clonal variants of the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) and soluble serum factors. While rosetting is a well-known phenotypic marker of parasites associated with severe malaria, the reason for this association remains unclear, as do the molecular details of the interaction between the infected erythrocyte (IE) and the adhering erythrocytes. Here, we identify for the first time a single serum factor, the abundant serum protease inhibitor α2-macroglobulin (α2M), which is both required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06 and some other rosette-mediating PfEMP1 proteins. We map the α2M binding site to the C terminal end of HB3VAR06, and demonstrate that α2M can bind at least four HB3VAR06 proteins, plausibly augmenting their combined avidity for host receptors. IgM has previously been identified as a rosette-facilitating soluble factor that acts in a similar way, but it cannot induce rosetting on its own. This is in contrast to α2M and probably due to the more limited cross-linking potential of IgM. Nevertheless, we show that IgM works synergistically with α2M and markedly lowers the concentration of α2M required for rosetting. Finally, HB3VAR06+ IEs share the capacity to bind α2M with subsets of genotypically distinct P. falciparum isolates forming rosettes in vitro and of patient parasite isolates ex vivo. Together, our results are evidence that P. falciparum parasites exploit α2M (and IgM) to expand the repertoire of host receptors available for PfEMP1-mediated IE adhesion, such as the erythrocyte carbohydrate moieties that lead to formation of rosettes. It is likely that this mechanism also affects IE adhesion to receptors on vascular endothelium. The study opens opportunities for broad-ranging immunological interventions targeting the α2M--(and IgM-) binding domains of PfEMP1, which would be independent of the host receptor specificity of clinically important PfEMP1 antigens.

Project description:BACKGROUND:With an increasing indication spectrum of antiresorptive drugs, the medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is continuously gaining clinical relevance. Impaired osteoclast function, accompanied by altered cell morphology and expression of osteoclastic effector proteins, contributes to the pathogenesis of MRONJ (BP). However, the underlying regulatory mechanisms at a transcriptional level are unaddressed so far. These mechanisms are crucial to the development of disease-characteristic osteoclastic anomalies, that contribute to the pathogenesis of MRONJ (BP). NFATc1 is considered a master upstream osteoclastic activator, whereas BCL6 acts as osteoclastic suppressor. The present study aimed to elucidate the NFATc1 and BCL6 mediated osteoclastic regulation and activity in MRONJ (BP) compared to osteoradionecrosis (ORN) and osteomyelitis (OM) and normal jaw bone. METHODS:Formalin-fixed jaw bone specimens from 70 patients [MRONJ (BP) n?=?30; OM: n?=?15, ORN: n?=?15, control: n?=?10] were analyzed retrospectively for osteoclast expression of NFATc1 and BCL6. The specimens were processed for H&E staining and immunohistochemistry. The histological sections were digitalized and analyzed by virtual microscopy. RESULTS:Osteoclastic expression of NFATc1 and BCL6 was significantly higher in MRONJ (BP) specimens compared to OM and control specimens. NFATc1 and BCL6 labeling indices revealed no significant differences between MRONJ (BP) and ORN. The ratio of nuclear BCL6+ osteoclasts to cytoplasmic BCL6+ osteoclasts revealed significantly higher values for MRONJ (BP) specimens compared to OM and controls. CONCLUSION:This study displays that osteoclasts in MRONJ (BP) tissues feature increased expression of the higher-level regulators, paradoxically of both NFATc1 and BCL6. These observations can help to explain the genesis of morphologically altered and resorptive inactive osteoclasts in MRONJ (BP) tissues by outlining the transcriptional regulation of the pathomechanically relevant osteoclastic effector proteins. Furthermore, they strengthen the etiological delineation of MRONJ (BP) from OM and extend the osteoclast profiles of MRONJ (BP), OM and ORN and thus could lead to a better histopathological differentiation that can improve treatment decision and motivate new therapeutic concepts.

Dataset Information

Effect of ?2?macroglobulin in the early stage of jaw osteoradionecrosis.

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Effect of α2‑macroglobulin in the early stage of jaw osteoradionecrosis.

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