Alterations in leukocyte telomere length and mitochondrial DNA copy number in benzene poisoning patients.

OBJECTIVE: The aim of this study is to examine and evaluate the impact of benzene poisoning on the relative content of the mitochondrial MT-ND1 gene and telomere length in individuals with occupational chronic benzene poisoning (CBP) compared to a control group. The study will analyze and gather data on the mitochondrial gene content and telomere length in cases of benzene poisoning, and investigate the relationship with blood routine parameters in order to contribute scientific experimental data for the prevention and treatment of CBP. METHOD: The case group comprised 30 individuals diagnosed with occupational chronic benzene poisoning, whereas the control group consisted of 60 healthy individuals who underwent physical examinations at our hospital concurrently. Blood routine indicators were detected and analyzed, and the PCR method was employed to measure changes in mitochondrial MT-ND1 content and telomere length. Subsequently, a comparison and analysis of the aforementioned indicators was conducted. RESULT: The case group exhibited a higher mitochondrial gene content (median 366.2, IQR 90.0 rate) compared to the control group (median 101.5, IQR 12.0 rate), with a statistically significant difference between the two groups (P < 0.05). Additionally, the case group demonstrated lower white blood cell levels (3.78 ± 1.387 × 109/L) compared to the control group (5.74 ± 1.41 × 109/L), with a significant difference between the two groups (P < 0.05). Furthermore, the case group displayed lower red blood cell levels (3.86 ± 0.65 × 1012/L) compared to the control group (4.89 ± 0.65 × 1012/L), with a significant difference between the two groups (P < 0.05). The hemoglobin level in the case group (113.33 ± 16.34 g/L) was lower than that in the control group (138.22 ± 13.22 g/L). There was a significant difference between the two groups (P < 0.05). Platelet levels in the case group (153.80 ± 58.31 × 109/L) is smaller than the control group (244.92 ± 51.99 × 109/L), there was a significant difference between the two groups (P < 0.05). The average telomere length of the normal control group was 1.451 ± 0.475 (rate); The mean telomere length of individuals in the case group diagnosed with benzene poisoning was determined to be 1.237 ± 0.457 (rate). No significant correlation was observed between telomere length and three blood routine parameters, namely white blood cells (WBC), hemoglobin (HB), and platelets (PLT). However, a significant correlation was found between telomere length and red blood cell count (RBC). Additionally, a negative correlation was observed between mitochondrial gene content and white blood cell count (r = - 0.314, P = 0.026), as well as between mitochondrial gene content and red blood cell count (r = - 0.226, P = 0.032). Furthermore, a negative correlation was identified between mitochondrial gene content and hemoglobin (r = - 0.314, P = 0.028), and platelets (r = - 0.445, P = 0.001). CONCLUSION: Individuals diagnosed with occupational chronic benzene poisoning exhibit a reduction in telomere length and an elevation in the relative content of the mitochondrial MT-ND1 gene. Moreover, a negative correlation is observed between the content of the mitochondrial MT-ND1 gene and four blood routine parameters, namely white blood cells (WBC), red blood cells (RBC), hemoglobin (HB), and platelets (PLT). Consequently, benzene exposure may potentially contribute to the onset of premature aging.

Phylogenomic Analysis of Cytochrome P450 Gene Superfamily and Their Association with Flavonoids Biosynthesis in Peanut (Arachis hypogaea L.).

Cytochrome P450s (CYPs) constitute extensive enzyme superfamilies in the plants, playing pivotal roles in a multitude of biosynthetic and detoxification pathways essential for growth and development, such as the flavonoid biosynthesis pathway. However, CYPs have not yet been systematically studied in the cultivated peanuts (Arachis hypogaea L.), a globally significant cash crop. This study addresses this knowledge deficit through a comprehensive genome-wide analysis, leading to the identification of 589 AhCYP genes in peanuts. Through phylogenetic analysis, all AhCYPs were systematically classified into 9 clans, 43 gene families. The variability in the number of gene family members suggests specialization in biological functions. Intriguingly, both tandem duplication and fragment duplication events have emerged as pivotal drivers in the evolutionary expansion of the AhCYP superfamily. Ka/Ks analysis underscored the substantial influence of strong purifying selection on the evolution of AhCYPs. Furthermore, we selected 21 genes encoding 8 enzymes associated with the flavonoid pathway. The results of quantitative real-time PCR (qRT-PCR) experiments unveiled stage-specific expression patterns during the development of peanut testa, with discernible variations between pink and red testa. Importantly, we identified a direct correlation between gene expression levels and the accumulation of metabolites. These findings offer valuable insights into elucidating the comprehensive functions of AhCYPs and the underlying mechanisms governing the divergent accumulation of flavonoids in testa of different colors.

Impact of chronic benzene poisoning on aberrant mitochondrial DNA methylation: A prospective observational study.

Benzene is used as an industrial solvent, which may result in chronic benzene poisoning (CBP). Several studies suggested that CBP was associated with mitochondrial epigenetic regulation. This study aimed to explore the potential relation between CBP and mitochondrial DNA (mtDNA) methylation. This prospective observational study enrolled CBP patients admitted to Shenzhen Prevention and Treatment Center for Occupational Diseases hospital and healthy individuals between 2018 and 2021. The white blood cell (WBC), red blood cell (RBC), hemoglobin (HB), and platelet (PLT) counts and mtDNA methylation levels were measured using blood flow cytometry and targeted bisulfite sequencing, respectively. A total of 90 participants were recruited, including 30 cases of CBP (20 females, mean age 43.0 ± 8.0 years) and 60 healthy individuals (42 females, mean age 43.5 ± 11.5 years). This study detected 168 mitochondrial methylation sites >0 in all study subjects. The mtDNA methylation levels in the CBP cases were lower than the healthy individuals [median ± interquartile-range (IQR), 25th percentile, 75th percentile: (1.140 ± 0.570, 0.965, 1.535)% vs. median ± IQR, 25th percentile, 75th percentile: (1.705 ± 0.205,1.240,2.445)%, P < 0.05]. Additionally, the spearman correlation analysis showed that the mtDNA methylation levels were positively correlated with the counts of circulating leukocytes [WBC (r = 0.048, P = 0.036)] and platelets [PLT (r = 0.129, P < 0.01)]. We provided solid evidence of association between CBP and aberrant mtDNA methylation.

Graph-Based Semi-Supervised Learning: A Comprehensive Review.

Semi-supervised learning (SSL) has tremendous value in practice due to the utilization of both labeled and unlabelled data. An essential class of SSL methods, referred to as graph-based semi-supervised learning (GSSL) methods in the literature, is to first represent each sample as a node in an affinity graph, and then, the label information of unlabeled samples can be inferred based on the structure of the constructed graph. GSSL methods have demonstrated their advantages in various domains due to their uniqueness of structure, the universality of applications, and their scalability to large-scale data. Focusing on GSSL methods only, this work aims to provide both researchers and practitioners with a solid and systematic understanding of relevant advances as well as the underlying connections among them. The concentration on one class of SSL makes this article distinct from recent surveys that cover a more general and broader picture of SSL methods yet often neglect the fundamental understanding of GSSL methods. In particular, a significant contribution of this article lies in a newly generalized taxonomy for GSSL under the unified framework, with the most up-to-date references and valuable resources such as codes, datasets, and applications. Furthermore, we present several potential research directions as future work with our insights into this rapidly growing field.

AID-induced CXCL12 upregulation enhances castration-resistant prostate cancer cell metastasis by stabilizing ß-catenin expression.

Prostate cancer (PCa) is one of the most common malignant diseases of urinary system and has poor prognosis after progression to castration-resistant prostate cancer (CRPC), and increased cytosine methylation heterogeneity is associated with the more aggressive phenotype of PCa cell line. Activation-induced cytidine deaminase (AID) is a multifunctional enzyme and contributes to antibody diversification. However, the dysregulation of AID participates in the progression of multiple diseases and related with certain oncogenes through demethylation. Nevertheless, the role of AID in PCa remains elusive. We observed a significant upregulation of AID expression in PCa samples, which exhibited a negative correlation with E-cadherin expression. Furthermore, AID expression is remarkably higher in CRPC cells than that in HSPC cells, and AID induced the demethylation of CXCL12, which is required to stabilize the Wnt signaling pathway executor ß-catenin and EMT procedure. Our study suggests that AID drives CRPC metastasis by demethylation and can be a potential therapeutic target for CRPC.

Hop2 interacts with the transcription factor CEBPα and suppresses adipocyte differentiation.

CCAAT enhancer binding protein (CEBP) transcription factors (TFs) are known to promote adipocyte differentiation; however, suppressors of CEBP TFs have not been reported thus far. Here, we find that homologous chromosome pairing protein 2 (Hop2) functions as an inhibitor for the TF CEBPα. We found that Hop2 mRNA is highly and specifically expressed in adipose tissue, and that ectopic Hop2 expression suppresses reporter activity induced by CEBP as revealed by DNA transfection. Recombinant and ectopically expressed Hop2 was shown to interact with CEBPα in pull-down and coimmunoprecipitation assays, and interaction between endogenous Hop2 and CEBPα was observed in the nuclei of 3T3 preadipocytes and adipocytes by immunofluorescence and coimmunoprecipitation of nuclear extracts. In addition, Hop2 stable overexpression in 3T3 preadipocytes inhibited adipocyte differentiation and adipocyte marker gene expression. These in vitro data suggest that Hop2 inhibits adipogenesis by suppressing CEBP-mediated transactivation. Consistent with a negative role for Hop2 in adipogenesis, ablation of Hop2 (Hop2-/-) in mice led to increased body weight, adipose volume, adipocyte size, and adipogenic marker gene expression. Adipogenic differentiation of isolated adipose-derived mesenchymal stem cells showed a greater number of lipid droplet-containing colonies formed in Hop2-/- adipose-derived mesenchymal stem cell cultures than in wt controls, which is associated with the increased expression of adipogenic marker genes. Finally, chromatin immunoprecipitation revealed a higher binding activity of endogenous CEBPα to peroxisome proliferator-activated receptor γ, a master adipogenic TF, and a known CEBPα target gene. Therefore, our study identifies for the first time that Hop2 is an intrinsic suppressor of CEBPα and thus adipogenesis in adipocytes.

Dynamic analysis of peripheral blood TCR ß-chain CDR3 repertoire in occupational medicamentosa-like dermatitis due to trichloroethylene.

Previously, we had cross-sectionally explored the characteristics of T cell receptor (TCR) repertoires from occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT) patients, now we further analyzed the dynamic features of OMDT TCR repertoires. Peripheral blood TCR ß-chain complementarity-determining region 3 (CDR3) genes were detected with the high throughput sequencing in 24 OMDT cases in their acute, chronic and recovery stages, respectively, and in 24 trichloroethylene-exposed healthy controls. The TCR repertoire diversity, TRBV/TRBD/TRBJ gene usage and combination, frequencies of CDR3 nucleotide (nt) and amino acid (aa) sequences in the cases in different stages and in the controls were analyzed. TRBV6-4 and TRBV7-9 frequencies significantly differed between the cases and controls (both P < 6.1 × 10-4). TRBV6-4 combination with TRBJ2-1, TRBJ2-2, TRBJ2-3, and TRBJ2-6, and TRBV7-9 combination with TRBJ2-1 were associated with the stage by OMDT severity (all P < 0.001). Ten CDR3-nt and 7 CDR3-aa sequences in TRBV7-9-TRBJ2-1 combination and 1 CDR3-nt and 1 CDR3-aa sequences in TRBV6-4-TRBJ2-1 combination were identified as associated with the severity of OMDT (all P < 0.001). We revealed further how TCR repertoires vary with the severity in the development of OMDT, and severity-related TCRs may provide important therapeutic targets for OMDT in clinical practice.

Genomic analysis of mutations in platelet mitochondria in a case of benzene-induced leukaemia: A case report.

INTRODUCTION: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia. PATIENT CONCERNS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis. DIAGNOSIS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method. INTERVENTIONS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments. OUTCOMES: After 3 months treatment her blood routine test indicators were restored to normal. CONCLUSION: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.

Satisfaction and needs of pharmacists in prescription-checking training: a cross-sectional survey.

OBJECTIVE: Prescription checking is becoming increasingly prevalent in medical institutions. However, the prescription-checking ability of pharmacists requires improvement. The study aim was to explore the main aspects of prescription-checking training and provide an empirical reference for the training of pharmacists in medical institutions. METHODS: Participants were pharmacists willing to complete a Likert questionnaire. Descriptive statistics were used to examine percentages and composition ratios. The chi-square test and exploratory factor analysis were used for inferential analysis. RESULTS: The questionnaire showed good internal consistency reliability and validity. A total of 90% of participants were satisfied with the training. Exploratory factor analysis extracted three satisfaction dimensions: training organization, teaching method, and knowledge consolidation and assessment. The average examination score for the 20 courses was 89.21/100. Regarding trainee needs, 94.66% preferred face-to-face lectures, 89.33% expected high professional skills of the lecturers and 62.67% believed that clinical expertise was highly desirable. CONCLUSIONS: There was a high demand for prescription-checking training among pharmacists. Trainees in this study showed high satisfaction. The most important aspects of prescription-checking training were training organization and knowledge consolidation and assessment. It is recommended that training should be stratified. Pharmacists preferred face-to-face and interactive lectures as a supplement to clinical knowledge.

Hop2 Interacts with ATF4 to Promote Osteoblast Differentiation.

Activating transcription factor 4 (ATF4) is a member of the basic leucine zipper (bZip) transcription factor family required for the terminal differentiation of osteoblasts. Despite its critical importance as one of the three main osteoblast differentiation transcription factors, regulators of osteoblast terminal maturation remain poorly defined. Here we report the identification of homologous pairing protein 2 (Hop2) as a dimerization partner of ATF4 in osteoblasts via the yeast two-hybrid system. Deletional mapping revealed that the Zip domain of Hop2 is necessary and sufficient to bind ATF4 and to enhance ATF4-dependent transcription. Ectopic Hop2 expression in preosteoblasts increased endogenous ATF4 protein content and accelerated osteoblast differentiation. Mice lacking Hop2 (Hop2-/- ) have a normal stature but exhibit an osteopenic phenotype similar to the one observed in Atf4-/- mice, albeit milder, which is associated with decreased Osteocalcin mRNA expression and reduced type I collagen synthesis. Compound heterozygous mice (Atf4+/- :Hop2+/- ) display identical skeletal defects to those found in Hop2-/- mice. These results indicate that Hop2 plays a previous unknown role as a determinant of osteoblast maturation via its regulation of ATF4 transcriptional activity. Our work for the first time reveals a function of Hop2 beyond its role in guiding the alignment of homologous chromosomes. © 2019 American Society for Bone and Mineral Research.

Clinical features of laryngeal myasthenia gravis: A case series.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease. Dysarthria, dysphagia, and difficulty swallowing as exclusive initial and primary complaints in MG (laryngeal MG) are rare and seldom reported. METHODS: Here we review and analyze the largest series of laryngeal MG patients. RESULTS: A total of 30 patients with laryngeal MG as primary manifestation were found in 20 case reports/series. Dysarthria was the most frequent primary symptom (14/30), followed by dysphagia (11/30), slurred speech (4/30) and dysphonia (1/30). Sixty-three percent visited the otolaryngology department first. Only 23.33% of patients were diagnosed with MG at the first clinic visit. Forty-five percent laryngeal MG patients were acetylcholine receptor (AChR) antibody positive, 52.9% showed decremental response in the repetitive nerve stimulation (RNS) test, and 92.6% were positive in the neostigmine/edrophonium test. Fluctuating weakness was examined in 16 of 30 patients and observed in 14/16 patients. CONCLUSION: Laryngeal MG is a rare and possibly under-diagnosed condition. The patients can present with dysarthria, dysphagia, or difficulty swallowing. Fluctuation in severity of disease by neostigmine/edrophonium test is a typical feature for MG patients. AChR antibody and RNS tests should be included to evaluate the pathologic changes in the neuromuscular junction.

Identification of gene expression models for laryngeal squamous cell carcinoma using co-expression network analysis.

One of the most common head and neck cancers is laryngeal squamous cell carcinoma (LSCC). LSCC exhibits high mortality rates and has a poor prognosis. The molecular mechanisms leading to the development and progression of LSCC are not entirely clear despite genetic and therapeutic advances and increased survival rates. In this study, a total of 116 differentially expressed genes (DEGs), including 11 upregulated genes and 105 downregulated genes, were screened from LSCC samples and compared with adjacent noncancerous. Statistically significant differences (log 2-fold difference > 0.5 and adjusted P-value < .05) were found in this study in the expression between tumor and nontumor larynx tissue samples. Nine cancer hub genes were found to have a high predictive power to distinguish between tumor and nontumor larynx tissue samples. Interestingly, they also appear to contribute to the progression of LSCC and malignancy via the Jak-STAT signaling pathway and focal adhesion. The model could separate patients into high-risk and low-risk groups successfully when only using the expression level of mRNA signatures. A total of 4 modules (blue, gray, turquoise, and yellow) were screened for the DEGs in the weighted co-expression network. The blue model includes cancer-specific pathways such as pancreatic cancer, bladder cancer, nonsmall cell lung cancer, colorectal cancer, glioma, Hippo signaling pathway, melanoma, chronic myeloid leukemia, prostate cancer, and proteoglycans in cancer. Endocrine resistance (CCND1, RAF1, RB1, and SMAD2) and Hippo signaling pathway (CCND1, LATS1, SMAD2, and TP53BP2) could be of importance in LSCC, because they had high connectivity degrees in the blue module. Results from this study provide a powerful biomarker discovery platform to increase understanding of the progression of LSCC and to reveal potential therapeutic targets in the treatment of LSCC. Improved monitoring of LSCC and resulting improvement of treatment of LSCC might result from this information.

Platelet mitochondrial cytochrome c oxidase subunit I variants with benzene poisoning.

BACKGROUND: Chronic benzene poisoning (CBP) is one of the most common chronic occupational poisoning which is associated with mitochondrial oxidative damage, and lead to increasing risk of respiratory diseases such as lung cancer. Cytochrome c oxidase subunit I (COI) is one of the key enzymes that plays an important role in oxidative damage regulation by eliminating reactive oxygen species (ROS). This study investigated the relationship between COI gene variants and the risk of CBP. METHODS: We investigated 44 non-smoking patients who were diagnosed with CBP and 57 unexposed non-smoking controls between the ages of 23 and 60 with their background including work experience, lifestyle and medical records. Peripheral blood (2 mL) was collected in EDTA tube and the platelet was purified from the collected blood. Variants of COI were analyzed by PCR and sequencing. Multivariable linear regression analysis was used to assess the association between CBP exposure and variants. RESULTS: The frequency of the mitochondrial DNA (mtDNA) T6392C, G6962 variants were 10, 7 out of 44 CBP group patients, which was higher when compared to that of 4, 2 out of 57 in the control group, suggesting these variants could be the risk factor for CBP [odds ratio (OR) 3.897, 95% CI: 1.131-13.425, P=0.023; OR 5.203, 95% CI: 1.024-26.442, P=0.034]. There was a significant difference (P<0.05) of COI variants, including T6392C and G6962A, in platelet mtDNA between patients and control samples. Meanwhile, the frequency of the mtDNA C7196A variant were 13 out of 44 control group, which was higher when compared to that of 2 of 57 in the CBP group patients, suggesting this variant could be the protective factor for CBP (OR 6.205, 95% CI: 1.320-29.162, P=0.010). CONCLUSIONS: Our study suggests that T6392C, G6962A and C7196A from platelet mtDNA variants play a significant role in the etiology of CBP and facilitate the development of molecular biomarker on CBP diagnosis.

Oxidative and anti-oxidative status in muscle of young rats in response to six protein diets.

We investigated the impact of six protein diets on oxidation and anti-oxidation status in the muscle of young rats. Rats were fed six protein diets for 14 days, including casein (control), and proteins isolated from soy, fish, chicken, pork and beef. Grx1, Trx1 and other oxidative metabolic indices in muscle were quantified. Compared with the casein diet, the soy protein diet had a similar oxidation level, but higher GSH and lower SOD activities. The chicken and fish protein groups had lower GSH and higher SOD activities, the pork protein group showed lower Grx1 levels than the casein group and the beef protein group showed the highest GSH, Grx1 and Trx1 levels as reflected by RT-PCR, Western blotting and immunohistochemistry analyses. Intake of meat proteins showed higher ROS and T-AOC but lower MDA levels than non-meat proteins, which may be due to the increase in Grx1 and Trx1 expression and other antioxidants. Meat proteins are more conducive to muscle of growing rats.

MicroRNA­195 inhibits cell proliferation, migration and invasion in laryngeal squamous cell carcinoma by targeting ROCK1.

Laryngeal carcinoma is the second most common malignancy of the head and neck cancers. The most common type of laryngeal carcinoma comprises laryngeal squamous cell carcinoma (LSCC), which accounts for ~95% of laryngeal carcinoma cases. Despite great progress in diagnostic and therapeutic techniques over the last few decades, the prognosis for patients with LSCC remains poor. A number of studies reported that various miRNAs are dysregulated in LSCC and serve critical roles in LSCC tumorigenesis and tumor development. The present study aimed to evaluate the expression level of microRNA (miR)­195 and its possible roles in LSCC. Briefly, miR­195 was downregulated in LSCC tissues and cell lines. In addition, low miR­195 expression was significantly correlated with lymph node metastasis and TNM stage of LSCC patients. Further study has demonstrated that miR­195 overexpression suppressed cell proliferation, migration and invasion of LSCC. Moreover, rho­associated kinase 1 (ROCK1) was identified as a direct target gene of miR­195. Downregulation of ROCK1 exerted similar roles to that of miR­195 overexpression in LSCC, suggesting ROCK1 was a direct downstream target of miR­195. These findings elucidated a novel molecular mechanism for the pathogenic mechanism in LSCC carcinogenesis and progression, and may have a potential role in the treatment of patients with LSCC.

[Effects of indium exposure on relative content of mitochondrial ND1 gene in human peripheral blood lymphocytes in vitro].

OBJECTIVE: To study the effects of indium exposure on the relative content of mitochondrial ND1 gene in lymphocytes. METHODS: Venous blood was obtained from 14 healthy workers and anticoagulated with heparin. Blood lymphocytes were separated and divided into three tube cultures. For two tubes in the exposed group, indium chloride was added to final concentrations of 0.2 mmol/L and 0.8 mmol/L, respectively. For one tube in the control group, an equal volume of normal saline solution was added. After incubation for 72 h, the relative content of mitochondrial gene in each group was determined using quantitative real-time PCR. RESULTS: Lymphocytes exposed to 0.8 mmol/L indium chloride had a significantly higher relative content of mitochondrial gene than those exposed to 0.2 mmol/L indium chloride and those in the control group (P < 0.05, P < 0.05). CONCLUSION: Lymphocytes exposed to a high concentration of indium and its compounds have an elevated relative content of mitochondrial ND1 gene, indicating increased oxidative DNA damage induced by exposure to a high concentration of indium and its compounds.

Metronidazole amino acidum natrium combined with radiation in the treatment of nasopharyngeal carcinoma: A meta-analysis based on randomized controlled trials.

OBJECTIVE: We performed this meta-analysis to assess the metronidazole amino acidum natrium combined with radiation in the treatment of nasopharyngeal carcinoma. MATERIALS AND METHODS: Two reviewers independently reviewed the databases of PubMed and CNKI. The prospective, randomized, controlled trials of metronidazole amino acidum natrium combined with radiation versus radiotherapy alone in the treatment of nasopharyngeal carcinoma were included in this meta-analysis. The objective response rate (RR) of 1-, 3-, and 5-year survival rates were pooled by statistical software. The publication bias was evaluated by Begg's funnel plot. RESULTS: Sixteen prospective, randomized, controlled trials were finally included in this meta-analysis. The quality assessment showed that the method's quality was relatively poor. The pooled results showed that the metronidazole amino acidum natrium combined with radiation can significantly improve the objective RR for the primary lesion (RR = 1.37, 95% confidence interval [CI]: 1.23-1.53, P < 0.05) and neck metastasis lesion (RR = 1.36, 95% CI: 1.25-1.49, P < 0.05). For survival analysis, the combined treatment can significantly improve the 1-year survival (RR = 1.57, 95% CI: 1.28-1.93, P < 0.05), 3-year survival (RR = 1.23, 95% CI: 1.06-1.41, P < 0.05), and 5-year survival rates (RR = 1.27, 95% CI: 1.05-1.53, P < 0.05). CONCLUSION: Metronidazole amino acidum natrium combined with radiation can improve the objective RR and long-term survival compared to radiation therapy alone in the treatment of nasopharyngeal carcinoma.

FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation.

Aberrant fibroblast growth factor receptor 3 (FGFR3) signaling disrupts chondrocyte proliferation and growth plate size and architecture, leading to various chondrodysplasias or bone overgrowth. These observations suggest that the duration, intensity and cellular context of FGFR signaling during growth plate chondrocyte maturation require tight, regulated control for proper bone elongation. However, the machinery fine-tuning FGFR signaling in chondrocytes is incompletely defined. We report here that neurofibromin, a Ras-GAP encoded by Nf1, has an overlapping expression pattern with FGFR1 and FGFR3 in prehypertrophic chondrocytes, and with FGFR1 in hypertrophic chondrocytes during endochondral ossification. Based on previous evidence that neurofibromin inhibits Ras-ERK signaling in chondrocytes and phenotypic analogies between mice with constitutive FGFR1 activation and Nf1 deficiency in Col2a1-positive chondrocytes, we asked whether neurofibromin is required to control FGFR1-Ras-ERK signaling in maturing chondrocytes in vivo. Genetic Nf1 ablation in Fgfr1-deficient chondrocytes reactivated Ras-ERK1/2 signaling in hypertrophic chondrocytes and reversed the expansion of the hypertrophic zone observed in mice lacking Fgfr1 in Col2a1-positive chondrocytes. Histomorphometric and gene expression analyses suggested that neurofibromin, by inhibiting Rankl expression, attenuates pro-osteoclastogenic FGFR1 signaling in hypertrophic chondrocytes. We also provide evidence suggesting that neurofibromin in prehypertrophic chondrocytes, downstream of FGFRs and via an indirect mechanism, is required for normal extension and organization of proliferative columns. Collectively, this study indicates that FGFR signaling provides an important input into the Ras-Raf-MEK-ERK1/2 signaling axis in chondrocytes, and that this input is differentially regulated during chondrocyte maturation by a complex intracellular machinery, of which neurofibromin is a critical component.

Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.

Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFß. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1(flox/flox) bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx (-/-) mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.