However, the prognostic value of TRIM59 in the survival of tumor patients remains controversial. We therefore conducted a meta-analysis to assess the prognostic significance of TRIM59 in cancer patients.The family of tripartite motif (TRIM) proteins, which includes 80 known TRIM protein genes in humans, play a key role in cellular processes.PubMed, Embase, VIP, CNKI and Wanfang Data were searched for eligible reports published before September 30, 2018. The hazard ratio (HR) and 95% confidence intervals (CIs) were adopted to estimate the association between TRIM59 and overall survival (OS).P < .001), indicating that higher TRIM59 expression could be an independent prognostic factor for poor survival in cancer patients.Six studies with 1584 patients were included to assess the effect. The results showed that high levels of TRIM59 were significantly associated with poor OS in cancer patients (HR = 1.43, 95%CI: 1.24–1.66, Our meta-analysis suggests that higher TRIM59 expression predicts poor prognosis in cancer patients, and it may therefore serve as a promising prognostic factor. TRIM family members are through recognition, combined with specific target proteins, play the role of RING finger domain dependent ubiquitin ligase, the important regulatory proteins and ubiquitin binding for ubiquitin modification, induce the target proteins into proteasome dependent ubiquitin degradation process, so as to further regulate the target protein involved in many biological processes.TRIM (Tripartite motif) family proteins harbor an RBCC (RING B-box coiled coil) motif, and contain a common N-terminal RING  finger domain, one or two B-box motifs, and a coiled-coil region. Humans possess 70 TRIM protein-coding genes. TRIM59 is located on endoplasmic reticulum in cells and is mainly composed of 403 amino acid residues. It was first cloned by Chang in 2002. It is speculated by work energy analysis that TRIM59 may promote the stability of ubiquitin regulatory proteins by mediating the interaction between proteins. TRIM59 was initially described as a potential oncoprotein in 2011, and since then an increasing number of studies have supported the role of TRIM59 as an oncoprotein. TRIM59 has also been reported to be involved in certain types of human cancer, The expression level of TRIM59 has been shown to be upregulated in many cancers including lung cancer, gastric cancer, breast cancer, hepatocellular carcinoma, colorectal cancer, and others.TRIM59 (Tripartite motif 59), is a cell-surface molecule. It is located on human chromosome 3, and is a member of the C-XI subfamily of TRIM family proteins. In addition to an RBCC motif, there is also a TM (transmembrane) domain in the C-terminal region of TRIM59, involved in the regulation of intracellular localization of TRIM59.Based on bioinformatics analysis, Hao found that the expression level of TRIM59 in NSCLC  was significantly increased. Further study showed that the patients with high expression of TRIM59 had high mortality and high recurrence rate, shown that the overexpression of TRIM59 suggested poor prognosis. Cox regression analysis showed that TRIM59 was an independent prognostic factor in tumor tissues. Zhan suggested that TRIM59 may promote the proliferation of NSCLC by up-regulating cell cycle associated proteins. Zhang shown that the expression of trim59 in breast cancer cells is up-regulated. In addition, they also found that TRIM59 can activate TGF-β (transforming growth factor β) signaling pathway to promote the proliferation, migration and invasion of breast cancer cells by decreasing the protein expression level of p-smad2. Zhou found that TRIM59 was highly expressed in gastric cancer and was significantly related to the prognosis of the patients base on bioinformatics retrieval and analysis of multiple databases. Furthermore, the expression levels of TRIM59 mRNA and protein in clinical samples, tissue chips and gastric cancer cell lines were detected. It was found that the expression level of trim59 in gastric cancer tissues was higher than that in paracancerous tissues, and the expression level of TRIM59 in gastric cancer cell lines was also significantly higher than that in normal gastric epithelial cells. At the same time, Luo screened out the single nucleotides polymorphism of three TRIM59 in Chinese Han population. The risk of gastric cancer in the subjects with variant (GA-AA) with rs1141023 was higher than that in the subjects with common genotypes. Further analysis showed that the polymorphism of rs1141023 was significantly correlated with tumor stage and lymph node metastasis. Xue detected the high expression of TRIM59 protein in liver cancer tissues of patients with liver cancer, the difference was statistically significant. Further studies showed that the positive expression of TRIM59 protein was closely related to pathological grade, tumor differentiation, vascular invasion and clinical TNM stage, suggesting that trim59 may play an important role in the differentiation, invasion and metastasis of HCC cells. Sun detected TRIM59 in 90 cases of colorectal cancer by qRT-PCR. It was found that the expression of TRIM59 in colorectal cancer tissue was significantly higher than that in non-cancer tissue, and the high expression of TRIM59 was significantly correlated with TNM stage, lymph node metastasis, depth of invasion and distant metastasis. Kaplan-Meier curve showed that the overall survival time of patients with high expression of TRIM59 was significantly lower than that of patients with low expression of TRIM59. In addition, TRIM59 was also studied for high expression in osteosarcoma, prostate cancer, bladder cancer, cervical cancer, and renal cell carcinoma.The relationship between TRIM59 and carcinogenesis has been described in several in vitro studies, and some studies have clarified the relationship between TRIM59 and the prognosis of one tumor, but not systematically. The aim of our meta-analysis was therefore to provide a quantitative assessment of the prognostic value of TRIM59 in various types of cancer.22.1PubMed, Embase, VIP, CNKI  and Wanfang Data were searched for relevant studies that evaluated the prognostic value of TRIM59 in cancer patients. We evaluated studies published up until September 30, 2018. Our search strategy used the text “TRIM59” or “Tripartite motif 59”. Additionally, the referenced articles in relevant literature were also manually reviewed for suitable studies. This study is a meta-analysis, so there is unnecessary to provide an Ethical Approval.2.2Studies were independently screened by 2 authors (Chao and Wang) according to the title, abstract, and type of article. There were no language restrictions added to the literature search. Articles were selected if they satisfied all of the following criteria:1)patients were pathologically diagnosed with cancer;2)sufficient information was provided to estimate the relation between TRIM59 expression and the hazard ratios (HRs) of tumor patients;3)when generating HRs from published Kaplan–Meier curves, the reported minimum and maximum follow-up times and number of subjects in each arm were reported.2.3 The final score was the minimum grade.Two investigators (Chao and Wang) independently assessed the eligible studies in accordance with the Newcastle-Ottawa Quality Assessment Scale (NOS).2.4Two authors (Chao and Wang) independently extracted the following data:1)first author, publication year, country, sample size, methods, duration of follow-up, and other relevant data;2)HRs and their 95% confidence intervals (CIs) for overall survival (OS) were extracted from the studies if the data were explicitly supplied in the published results – if the survival data were not provided, we extracted them from Kaplan–Meier curves for further processing;3)the detection biomarker was TRIM59.2.5 were used for HR estimation. The inconsistency index I2 was utilized to assess the heterogeneity of included studies. If P > .10 and I2 < 50%, we considered the heterogeneity non-significant, and a fixed-effect model was adopted; otherwise, a random-effects model was adopted. To estimate the reliability of the pooled results, a sensitivity analysis was performed by omitting single studies. In order to assess the publication bias, Begg and Egger funnel plots were drawn. Data management and analysis were performed with STATA 12.0 software .We used the HRs with their 95% CIs to estimate the effect of TRIM59 expression on survival rates. We directly extracted HRs with corresponding 95% CIs if they were provided in the original articles. Otherwise, the methods described by Parmar et al33.1–15As shown in the Flow Diagram, 229 studies were identified according to the search strategy from PubMed, Embase, VIP, CNKI and Wanfang Data. Of these, 73 studies were removed due to duplication. By screening the abstracts, 147 studies were excluded as they were laboratory research reports, contained irrelevant content, or were reviews. After reading through the full text, three additional studies were excluded due to a lack of sufficient data. Finally, 6 studies were included for further analysis.3.2,12–15 and one study reported the HR data directly. The quality scores ranged from 7 to 8.The detailed information of each study is summarized in Table 3.32 = 0, P = .744). A forest plot revealed that high expression levels of TRIM59 correlate with poor OS in tumor patients . Meanwhile, Heterogeneity analysis revealed that there was no between-study heterogeneity in the eight studies .A fixed- effect model was adopted due to the low level of heterogeneity among studies  signaling pathway to induce migration and invasion in medulloblastoma. In support of this, silencing TRIM59 inhibits the TGF-β/Smad2/3 signaling pathway, leading to inhibited invasion and migration in bladder cancer cells. A series of studies have indicated that many TRIM proteins are linked to autophagy.–21 TRIM59 regulates autophagy by modulating both the transcription and the ubiquitination of BECN1 (Beclin 1). An increasing number of studies have reported that TRIM59 is closely related to carcinogenesis and tumor prognosis. In 2011, TRIM59 was initially found to act as a potential oncoprotein in a mouse model of cancer. In basic laboratory research, TRIM59 has been shown to promote the migration and invasion of cancer cells, and knockdown of TRIM59 inhibits malignancy processes in human cancer cells. Moreover, TRIM59 has been shown to be involved in the cytotoxicity of BCG -activated macrophages. In human clinical studies, overexpression of TRIM59 has been found in colorectal cancer, breast cancer, hepatocellular carcinoma, lung cancer, gastric cancer, glioblastoma and others. Additionally, many studies have investigated the specific association of TRIM59 with tumorigenesis in each respective cancer field. We therefore conducted this meta-analysis to obtain a more definitive conclusion on the relationship between TRIM59 and cancer-related survival.Tripartite motif (TRIM) family proteins have various functions in cellular processes, including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, carcinogenesis, and angiogenesis. Research surrounding the TRIM59 protein has primarily focused on intracellular signaling, autophagy, and carcinogenesis. In dsDNA receptor-mediated signaling, TRIM59 binds to ECSIT , leading to the inhibition of NFkB (nuclear factor-kappa B) and IRF3 (Interferon regulatory factor 3) signaling.With the advances in the study of TRIM59, researchers have found that TRIM59 is involved in a variety of malignant biological behaviors in tumors, which suggests that TRIM59 has the potential to be a target for future cancer therapies. As far as we know, this is the first meta-analysis to investigate the prognostic role of TRIM59 in tumor patients. Our analysis revealed that high expression of TRIM59 is associated with poor prognoses in cancer patients. The six articles included in this study indicated that TRIM59 was related to TNM (Tumor Node Metastasis) in hepatocellular carcinoma, lung cancer, colorectal cancer, and breast cancer. Because of data limitations, we could not further analyze the association between TRIM59 and TNM. We look forward to future studies and original data concerning the relationship between TRIM59 and tumor biology.P < .001), which did not change when single studies were omitted, which demonstrates the consistency of the results. Additionally, we found no heterogeneity between studies.Although the number of studies included was only six, the number of patients included was 1584, which does not influence the reliability of results. The pooled HR value was 1.43 the number of included studies and the total sample size were limited. Only 6 types of tumor were included, thus we were unable to conduct a subgroup analysis.2)The articles included were only from China, therefore results may only be applicable to Asian populations. An increasing number of studies, especially including European and American patient populations should be included.3)There was insufficient data to investigate the association between clinico-pathological characteristics and the level of TRIM59.4)A lack of unified cut-off criteria for TRIM59 levels made it difficult to distinguish between patients with high vs. low TRIM59 expression.5)The HR was obtained using the Engauge Digitizer 10.0 software from the Kaplan–Meier curve, which may be a source of error.6)The search model might have excluded potentially eligible studies that were written in other languages.6This meta-analysis revealed that high TRIM59 expression is a predictor of poor OS in cancer patients. TRIM59 may therefore serve as a promising prognostic biomarker that can be utilized to improve future cancer therapies.Conceptualization: Min Wang, Bin Wang.Data curation: Min Wang, Ce Chao.Formal analysis: Min Wang, Ce Chao.Funding acquisition: Min Wang, Ce Chao, Guanghua Luo, Xianghong Zhan, Dongmei Di.Investigation: Min Wang, Yongxiang Qian.Methodology: Min Wang, Guanghua Luo, Bin Wang.Project administration: Bin Wang, Xiaoying Zhang.Resources: Min Wang.Software: Ce Chao, Bin Wang.Supervision: Bin Wang, Xianghong Zhan, Dongmei Di, Yongxiang Qian.Validation: Xiaoying Zhang.Writing – original draft: Ce Chao.Writing – review & editing: Guanghua Luo, Bin Wang, Yongxiang Qian, Xiaoying Zhang.


Allergic rhinitis is a major chronic inflammatory disease of the respiratory tract. A large number of epidemiological investigations have shown that the prevalence of allergic rhinitis (AR) is increasing, resulting in a large burden of disease. Desensitizing drugs such as nasal glucocorticoids and antihistamines are commonly used to treat allergic rhinitis, but this method has a long treatment period and is prone to repeated attacks, and there are certain adverse reactions. Acupuncture can be used to treat a wide variety of diseases including allergic rhinitis without the occurrence of drug damage. We aim to evaluate the efficacy and safety of acupuncture in the treatment of allergic rhinitis.Relevant databases include the English databases incorporating Web of science, PubMed, Springer, Medline, Cochrane Library, EBASE, WHO International Clinical Trials Registry Platform (ICTRP), as well as the Chinese databases like the China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journal Database (VIP), Wanfang Database, and Chinese Biomedical Literature Database will be searched normatively according to the rule of each database from the inception to September 1, 2018. Reference list of identified studies, potential gray literatures, relevant conference abstracts, and clinical trial registrations will also be searched. The literature screening, data extraction, and quality assessment will be conducted by 2 researchers independently. Data will be synthesized by either the fixed-effects or random-effects model according to a heterogeneity test. Symptom score will be assessed as the primary outcome. Rhinoconjunctivitis quality of life questionnaire (RQLQ), participants with asthma can use asthma control test (ACT), medicine usage and scoring, laboratory examination, and side effects or adverse events will be evaluated as the secondary outcome. Meta-analysis will be performed using RevMan5.3.5 software provided by the Cochrane Collaboration.This study will provide high-quality synthesis based on current evidence of acupuncture treatment for allergic rhinitis in several aspects, including symptom score, drug score, quality of life score, asthma control score, side effects and laboratory examination such as nasal function test, serum total immunoglobulin (IgE), nasal secretion smear, etc.The results of this study will provide updated evidence for weather acupuncture is an effective and safe intervention for allergic rhinitis.It is not necessary for this systematic review to acquire an ethical approval. This review will be disseminated in a peer-reviewed journal or conference presentation.PROSPERO CRD42018109105. It is reported that 40% of AR patients complicated with bronchial asthma, in addition to nasal symptoms, they may also have pulmonary symptoms such as wheezing, coughing, shortness of breath, and chest tightness. Clinical attention should be paid to the interaction and influence of AR and asthma. It is one of the most common diseases in otolaryngology, head and neck surgery (RL-HNS) and is conservatively estimated that more than 500 million AR patients worldwide, the prevalence of AR in the population of mainland China is 4 to 38%.Allergic rhinitis (AR) is a non-infectious inflammatory disease of the nasal mucosa, which is mainly released by immunoglobulin (IgE)-mediated mediators (mainly histamine) after contact with allergens, and involves a variety of immune-active cells and cytokines. Typical symptoms of AR are paroxysmal sneezing, watery nasal discharge, nasal itching, and nasal congestion, Pollen blockers cream and cellulose powder can significantly reduce nasal symptoms and quality of life in patients with AR.–7 Nasal glucocorticoids is currently the most effective drugs for the treatment of AR, for patients with bronchial asthma, can be conducive to asthma control and improve lung function.,9 Other drugs, including antihistamines, antileukotrienes, mast cell membrane stabilizers, decongestants, and anticholinergics, are also commonly used. Allergen-specific immunotherapy has short-term and long-term effects on AR, preventing the development of asthma and reducing new sensitization. Some Chinese herbal medicines have anti-allergic, anti-inflammatory, and immunomodulatory effects, are effective and safe in improving the nasal symptoms of perennial and persistent AR.Although rhinitis can’t be completely cured at present, through the standardized comprehensive prevention and treatment, the symptoms of patients can be well controlled and the quality of life is significantly improved. The treatment of AR includes environmental control, drug therapy, immunotherapy, and health education.,18 Both animal experiments and clinical trials show a certain therapeutic effect of acupuncture. Studies indicated that Warm acupuncture can improve the symptoms of AR rats, which may be associated to its effect in inhibiting the expression of serum IgE, interleukin-1β (IL-1 β), and tumor necrosis factor-α (TNF-α). Randomized controlled trial found that acupuncture was safe and effective in the treatment of medium to severe persistent AR. Compared with the western medicine group, the acupuncture group had more advantages in the persistence of efficacy. Research on acupuncture for rhinitis has been increasing in recent years, and a meta-analysis on AR treated by acupuncture is necessary to conduct. In this review, we aim to systematically assess the efficacy and safety of acupuncture for AR.The development of acupuncture therapy has a history of thousands of years. Guided by the theory of traditional Chinese medicine, special needles are used to penetrate the patient's body according to certain acupuncture points. A certain operation method can be used to achieve the treatment through the conduction of meridians and acupoints. Acupuncture has the advantages of wide indication, obvious curative effect, convenient operation, economical and safety, etc. It can be used to treat various diseases including allergic rhinitis.22.1http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018109105. The protocol follows the Cochrane Handbook for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) statement guidelines. We will describe the changes in our full review if needed.This systematic review protocol has been registered on PROSPERO as CRD42018109105. Available from: 2.22.2.1In order to evaluate the efficacy and safety of acupuncture in the treatment of AR, all relevant randomized controlled trials (RCTs) published in English and Chinese on acupuncture for AR can be included. Non-RCTs, reviews, case report, experimental studies, expert experience, and duplicated publications will be excluded.2.2.2Study participants in different age ranges with AR can be included in the study without restricting nationality, sex, race, occupation or education. Patients with vasomotor rhinitis, non-allergic rhinitis with eosinophilia syndrome, infectious rhinitis, hormonal rhinitis, drug-induced rhinitis, aspirin intolerance triad, cerebrospinal rhinorrhea were excluded.2.2.3The study focus on clinical trials of AR with the therapy of acupuncture, and the results will provide clinicians with consultation and advice. Thus, the experimental group treated only with acupuncture and without any combination of other drugs and treatment will be included, regardless of the number of acupoints, the method of needle insertion, duration and frequency. Combination therapy can’t evaluate the effect of acupuncture will be excluded. Studies of control groups will be treated with no treatment or sham acupuncture, placebo, and other interventions .2.2.42.2.4.1Symptom score will be assessed as the primary outcome. The main evaluation indicators of symptom score included nasal symptoms  and ocular symptoms . If asthma is combined, additional asthma symptoms such as wheezing, cough, shortness of breath, and chest tightness should be recorded.2.2.4.2The secondary outcomes of this review mainly includes the following aspects:1.Rhinoconjunctivitis quality of life questionnaire (RQLQ), participants with asthma can use asthma control test (ACT)2.Medicine usage and scoring3.Nasal function examination and nasal provocation test4.Allergen detection , total serum IgE detection, serum specific IgE detection will be included)5.Supplementary examination 6.Side effects and adverse events2.32.3.1Relevant databases include the English databases incorporating Web of science, PubMed, Springer, Medline, Cochrane Library, EBASE, WHO International Clinical Trials Registry Platform (ICTRP), as well as the Chinese databases like the China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journal Database (VIP), Wanfang Database, and Chinese Biomedical Literature Database will be searched normatively according to the rule of each database from the inception to September 1, 2018.2.3.2The reference list of studies and relevant systematic reviews will be retrieved and examined for additional trials. Relevant conference abstracts will also be searched for eligible trials. In addition, we will search OpenGrey.eu as potential gray literature. ClinicalTrial.gov for ongoing and recently completed studies related to this topic will also be searched.2.3.3The search strategy for Web of science is listed in Table This search strategy will be modified as required for other electronic databases.2.42.4.1 of the Cochrane Collaboration System Evaluator's Manual:The basic process for incorporation into the literature is determined by reference to the 5.1.0 version1.Obtain relevant literature by searching the specified databases, import them into the document management software Endnote X7 and screen out the duplicate documents in each database.2.Eliminated documents that are obviously unrelated to this study by reading the titles and abstracts of the literature.3.Download and screen the full text of the selected clinical studies related to the study4.If there is missing or incomplete data in the study, it can be obtained through contact the study author.5.Screening the literature included in the study according to the inclusion criteria in the literature and identified the number of papers included.All the procedures will be carried out by 2 independent reviewers and completed cross check. If there is any disagreement, the 3rd author will be invited to assist in the discussion and make a decision. The study of screening flow diagram is summarized in Figure 2.4.2Two independent reviewers will extract data from eligible studies and enter the following information in the data extraction sheet: The basic characteristics of the study ; participant characteristics ; Interventions ; Outcomes ; If there is fund support, it will also be recorded. When a consensus on the data extraction can’t be obtained through discussion, the 3rd author will make a decision.2.4.3 When a consensus on risk assessment can’t be reached by consultations, the 3rd author will make a decision.A rigorous quality assessment of the literature included in the study was conducted using the bias risk assessment tool of the Cochrane Collaborative Network System Evaluator’ Manual. For the methodological characteristics of the 7 items extracted in each study, High, Low, Unclear evaluations were performed for each item. Meanwhile, the STRICTA checklist will be completed.2.4.4A risk ratio (RR) with 95% confidence intervals (CIs) will be used to estimate the dichotomous outcomes, and the continuous data will be analyzed by mean difference (MD) or standard MD (SMD) with 95% CIs.2.4.5We will only extract the 1st experimental period data of crossover trials to avoid carryover effects. With multiple intervention groups, we will combine all relevant experimental groups and control intervention groups into a single respectively group to prevent a unit of analysis issue.2.4.6If there are missing or incomplete data, we will attempt to contact the original authors to obtain information by email or phone. If missing data are not available, the analysis will rely on available data.2.4.7I2 value,25 will be applied to calculate and present the heterogeneity degree. When P > .1, I2 < 50%, it is considered that there is no heterogeneity between the experiment, and the fixed effect model will be used for statistics, otherwise, the random effect model is adopt to analyze. When the number of merged articles is greater than 10, the potential publishing bias will be tested using an inverted funnel chart developed by Egger.Data analysis was performed using RevMan5.3.5 software provided by the Cochrane Collaboration. Using the software to obtain forest plots and test the heterogeneity between the included studies, Chi-square test, and 2.4.8Funnel plot will be used to assess the reporting biases when the trials included in a meta-analysis over 10.2.4.9I2 < 50%) or random-effects model (I2 ≥50%) will be selected. The dichotomous data will be analyzed by RR with 95% CIs, while the continuous data will be analyzed by MD/SMD with 95% CIs. The meaningful heterogeneity will be explained by any additional assessment included sensitivity analysis or subgroup analysis depended on the data.RevMan5.3.5 will be used for all statistical analyses. Based on the heterogeneity levels of the included studies, the fixed-effects model , acupuncture has been used in China for thousands of years. Acupuncture may modulate the immune system, it has been proposed as a useful treatment for patients with allergic rhinitis.It should be noted that there might be limitations in this review. First, the use of language including English and Chinese may induce the bias of the study. Second, different types of acupuncture, acupoints, duration, frequency, the age of patients, and degree of AR may cause high heterogeneity. Third, it is difficult to undertake single or double-blind experiment measures during acupuncture therapy.HPB, DXS and YLL contributed to conceive the idea of research, develop the search strategy, and draft the manuscript. QS and YY critically revised the manuscript and provided valuable advice on the protocol. LXG and MXY is in charge of coordination and direct implementation. HZS and DD will screen the titles, abstracts, full text and extract data independently. When HZS and DD had any disagreements about the results, CLL would act the 3rd person to coordinate. DXS and CLL will conduct statistical analysis. All review authors approved the publication of the protocol. All authors participated in the protocol design, commented on drafts of this paper, read and approved the publication of the final manuscript.Conceptualization: Haipeng Bao, Dongxu Si, Youlin Li.Data curation: Longxia Gao, Huizhuo Sun, Dashzeveg Damchaaperenlei, Chunlei Li.Formal analysis: Dongxu Si.Project administration: Haipeng Bao, Dongxu Si, Youlin Li.Supervision: Qi Shi, Yue Yan, MingXia Yu.Writing – original draft: Haipeng Bao, Dongxu Si.Writing – review & editing: Haipeng Bao, Youlin Li.


LIPC C-514T and APOA5 C56G are Ser19Trp carriers and greatly benefit from sterol intake in the diet. LIPC C-514T TT homozygous carriers had lower low-density lipoprotein cholesterol (LDL-c) levels than CC homozygote and CT heterozygote carriers after the ingestion of plant sterols (p = 0.001). These two genes also showed statistically significant changes in total cholesterol levels , and no significant changes in high-density lipoprotein (HDL) cholesterol levels , respectively. No statistically significant differences were observed for other genes. Further studies are needed to establish which genotype combinations would be the most protective against hypercholesterolemia.Raised serum cholesterol concentration is a well-established risk factor in cardiovascular disease. In addition, genetic load may have an indirect influence on cardiovascular risk. Plant-based sterol-supplemented foods are recommended to help reduce the serum low-density lipoprotein cholesterol level. The objective was to analyse the influence of different polymorphisms in hypercholesterolemia patients following a dietary treatment with plant sterols. A randomised double-blind cross-over controlled clinical trial was carried out in 45 people (25 women). Commercial milk, containing 2.24 g of sterols, was ingested daily during a 3-week period, and then the same amount of skim milk, without sterols, was consumed daily during the 3-week placebo phase. Both phases were separated by a washout period of 2 weeks. At the beginning and end of each phase, blood draws were performed. Genes  Human health is a result of complex interactions between genetic predisposition and the environment in which genes manifest. It has long been recognised that individual differences in genetic variation influence the association between dietary recommendations and health, which is yet to be reflected in the dietary guidelines. Identifying the interplay between genes and dietary patterns holds promise for a new era of personalised medicine, whereby the recommended diet for best health is tailored towards how an individual’s metabolism is genetically predisposed to respond to dietary intake .The understanding of genetic approaches in the nutritional sciences is referred to as nutrigenomics. Nutrigenomics explores the interaction between genetic factors and dietary nutrient intake regarding various disease phenotypes and general health , with thThrough the use of genome-wide association studies, genetic variations (single nucleotide polymorphisms) have been identified as genetic factors, making it more likely to determine individual disease predisposition .MTHFR gene polymorphisms are also associated with an increased risk of congenital heart failure [Naturally occurring variants of the apolipoprotein A5 gene have been associated with increased triglyceride levels, and have been found to confer risk for cardiovascular diseases. Some of the  failure , especia failure . The hep failure . Genetic failure , as it i failure . In addi failure .Cholesterol metabolism is a well-defined responder to dietary intake, and a classic biomarker of cardiovascular health. For this reason, circulating cholesterol levels have become essential in shaping the nutritional recommendations of health authorities worldwide for better management of cardiovascular disease, a leading cause of mortality and one of the most costly health problems globally .A number of cholesterol-related gene–diet interactions have been confirmed, some of which may have clinical importance, supporting a deeper insight into the rapidly emerging field of nutrigenetics for meaningful conclusions that may eventually lead to genetically-targeted dietary recommendations, in the era of personalised nutrition .On the other hand, nutrition and dietary treatments are important in managing cardiovascular disease. Plant sterols have been postulated as beneficial regulatory agents for the control of the disease ,14,15. TExperts from the European Food Safety Authority confirmed that blood cholesterol can be reduced by an average of 7–10.5% if a person consumes 1.5–2.4 g of plant sterols a day. This effect is generally observed within the first 2–3 weeks. Mid- and long-term studies, of up to 85 weeks, show that the blood cholesterol reducing effect could be sustained throughout that period .Future studies should be carried out, with the aim of learning about the increasing difference and soundness of dietary treatment data available in concordance with individual genomic profiles.The aim of this study was to analyse the influence of different polymorphisms in hypercholesterolemia patients following dietary treatment with plant sterols.A randomised double-blind cross-over controlled clinical trial was designed. Participants were recruited at the San Carlos Clinical University Hospital in Madrid (SCCUHM) and the El Escorial Hospital in Madrid. Volunteers throughout the hospital were invited to participate. Patients from primary care and endocrinology departments were specifically invited to participate. Prior to the trial, the participants received instructions on the purpose of the study and signed an informed consent form.Corporación Alimentaria Peñasanta, S.A., Asturias, Spain), available on the market throughout the whole study. Treatment and placebo skim milk were identical in sensorial and nutrient composition.The plant sterols were ingested using Naturcol milk , the same quantity of skim milk without plant sterol was used for the placebo. An 80% target was set as the minimum threshold for consumption. Milk was packaged without labelling to ensure neither the subjects nor the researchers were aware of the type of milk, and were only differentiated by the lid’s colour. Groups were randomly assigned, using random number tables.Of the 54 initial participants, 45 completed the genetic study: 25 women and 20 men with a mean age of 37.9 ± 7.5 years. The sample was recruited based on total cholesterol as the primary biomarker, according to the standard formulas for that purpose. The formula was calculated for a difference of ±15% of total cholesterol (200 mg/dL), taking into account a standard deviation of 35 mg/dL for a confidence interval of 95%, a statistical power of 85%, and a loss rate of 10%, using the formula for sample size. Inclusion criteria: men and women, aged 18–50 years, with total cholesterol (TC) > 200 mg/dL.Exclusion criteria: TC < 200 mg/dL, cardiac pathology ; lactose intolerance, allergy to cow’s milk proteins or plant sterols; obesity (body mass index –BMI– >30) or pharmacological treatment . Subjects that already supplemented with plant sterols. None of the participants presented active thyroid disease, liver disease, alcoholism, or any other such condition that dynamically altered lipid levels and/or diets. The samples for the analytical tests were extracted by medical staff after a 12-h fast at the Clinical Analysis Unit in the SCCUHM and El Escorial Hospital, and in the San Carlos Specialty Unit in San Lorenzo de El Escorial.The blood extraction protocol of the laboratory was as follows: blood extraction was performed with a gel serum tube, using the technique ‘Blood collection’ with an s-Monovette in aspiration ,20,21. AThe laboratory that performed the tests is located in the same city of the study, and has the required legal accreditations, certificates, and standards, ISO 9001:2008, and accreditation 511/LE2114 according to criteria included in the UNE-EN ISO 15189 Standard.A variation in the effect of dietary treatment with plant sterols in milk on lipoprotein metabolism (reduction of LDL-c) was observed; therefore, a genomic analysis was performed.With this analysis, we sought to understand the following hypothesis: (1) that genetic polymorphisms could be associated with a higher or lower response effect to the plant sterol treatment for hypercholesterolemia. Polymorphisms APOA5 C56G Ser19Trp, Prothrombin G20210A, F5 Arg506Gln, MTHFR C677T, LIPC C-514T, LPA I4300M, PPAR_ALPHA L162V, APOA5 1131T>C, APOE APOE2/3/4 and APOE APOE2,3,4 were studied.Genomic DNA, for genotyping the SNP, was extracted from saliva samples. The analyses were run by Vitagenes Lab . The genotyping was conducted using the Biobank Axiom1 96-Array from Affymetrix. Genotype calling was performed with respect to Affymetrix’s best practice guidelines, including analysis with SNPolisher, assuming a quality control rate of >0.97 ,23.The extraction and purification of DNA from saliva samples was carried out as follows: each DNA extraction was run on an agarose gel to ensure high quality and high molecular weight. To ensure maximum purity of the extracted DNA (ratio > 1.7), the OD260/280 ratio was analysed, that is, the optical density of the extracted DNA at 260 nm and 280 nm wavelengths. All analyses were performed in duplicate to ensure maximum precision and reliability in their results.All Vitagenes analytical processes were carried out in laboratories that had CLIA certification, thus attaining the optimal level of technical quality and precision proposed by the FDA in the United States .An ad hoc questionnaire was designed for the study. The questionnaire and anthropometric study were performed by a single trained researcher, ensuring the homogeneity and standardisation of the uniformity criteria and methodology to follow. The study variables were established in terms of the proposed objectives: sex, age, clinical and pharmacological history, sleep quality, health habits, use of tobacco and alcohol, intestinal transit, food consumption frequency, and physical activity. In addition, each participant’s weight, height, waist perimeter, BMI, fat percentage, subcutaneous fat percentage, and lean body mass (kg) were measured. Weight, BMI and body composition were determined by means of tetrapolar multi-frequency (20 and 100 kHz) electrical bioimpedance, InBody Model 230, following the usual standard protocol and the manufacturer’s recommendations . Waist pT-test, for related samples, or the Wilcoxon rank sum test according to the compliance with the assumption of normality of the dependent variables. The efficacy of the intervention was verified by comparing the differences  in the ingestion of milk with sterols and the placebo, by applying the Student’s T-test for related samples, or the Wilcoxon rank sum test depending on the compliance with the assumption of normality of the lipid increase. The effect size and the proportion of the mean differences were calculated with regard to the standard deviation of the baseline, or milk with sterols as the case may be. The level of significance applied was 5%.The data were analysed using the SPSS 21.0 statistical package. A descriptive analysis was first made of the sociodemographic and anthropometric data, the baseline, and the final lipid values under the ingestion of Naturcol and the placebo. The normality of the lipid values was determined using the Shapiro–Wilk test. To analyse the efficacy of the ingestion of Naturcol and the placebo, the difference in lipid values was calculated before and after ingestion, also applying the Student’s The study was approved by the respective bioethics committees of the San Carlos Clinical University Hospital in Madrid (SCCUHM) and the El Escorial Hospital in Madrid. This study followed the ethical principles enshrined in the Helsinki Declaration, the recommendations for good clinical practice, current Spanish legislation regulating clinical research in humans, and the protection of personal and bioethical data .2)  completed the trial. Nine subjects failed to complete the trial because of different genotyping, and failure to complete the plant sterols treatment (ingested less than 80% of the consumption protocol). They had an average age of 37.9 ± 7.5 years and weighed 69 kg (BMI 23.7 kg/m2) . Baselinp > 0.05) were found between the decreased percentage of lipid parameters  cholesterol, and Non-HDL cholesterol), and the genotypes observed for the following genes (p = 0.416) and APOE APOE2,3,4.No statistically significant differences , but not HDL cholesterol , respectively, after the treatment with sterols . APOA5 1131T>C and APOE APOE2/3/4 did not show statistically significant differences .LIPC C-514T, APOA5 1131T>C and APOE APOE2/3/4 greatly benefit from sterol intake in the diet . In LIPCp = 0.121; p = 0.180).A large difference was also observed in the case of LPA I4300M and PPAR_alpha L162V genes, between the carriers of the homozygous  and heterozygous  variants, although the difference is not statistically significant .Polymorphisms APOA5 C56G Ser19Trp, MTHFR C677T and APOE APOE2,3,4 exert a favourable effect in the treatment, but no statistically significant differences in the reduction of LDL-c can be seen  was associated with different rates of baseline cholesterol, according to their single nucleotide polymorphism (SNP).After checking whether any genotype was directly related to baseline LDL-c, it was found that only one of the analysed genes  could not establish by genotype. The obtained results for each gene were as follows: MTHFR C677T (p = 0.184), LIPC C-514T (p = 0.522), LPA I4300M (p = 0.158), PPAR_ALPHA L162V (p = 0.936), APOA5 1131T>C (p = 0.484), APOE APOE2/3/4 (p = 0.604), and APOE APOE2,3,4 (p = 0.233).Other genes and their haplotypes could not be linked to a higher or lower level of basal cholesterol, as measured by the parametric test, Phytosterols are known to reduce serum LDL-c level without changing HDL-c levels. Daily consumption of phytosterol-enriched foods is widely used as a therapeutic option to lower plasma cholesterol and the risk of atherosclerotic disease . CliftonWhen the recent scientific literature is reviewed, important studies  evaluatiLike other authors ,30, thisp = 0.01).Maasz et al. (2008)  suggesteRegarding the ApoE, it has been observed that the ε4 allele of the ApoE4 is a major risk factor for coronary heart disease. However, the same results were not observed in the case of ApoE2, whose polymorphisms did not seem significantly related to coronary risk .p = 0.046). On the other hand, the same genotype was associated with the presence of small LDLs (p = 0.003). The risk analysis showed that under a dominant model, the LIPCC-514T polymorphism was associated with increased hypertriglyceridemia  and coronary artery calcification . The T allele carriers had higher levels of low-density lipoprotein cholesterol (LDL-C) in obese boys, and TC and LDL-C in non-obese girls  [The relationship between the hepatic lipase gene and the influence on HDL-c has not been clearly established, although it seems to be an inverse relationship . The inf < 0.05) .p = 0.003), and the homozygous mutant genotype TT was significantly associated with the risk of congenital heart disease .Li et al. (2015)  exposed The results suggested that genetic and metabolic biomarkers when used together may predict inter-individual lipid level responsiveness to the plant-sterol-intervention, and thus could be useful in devising individualised cholesterol-lowering strategies. We cannot find an accurate and concise explanation, beyond the observation of these differences in the results, which should undoubtedly be refuted until more research can corroborate our findings, and with samples of the wider population. However, nutrigenomics has already observed these differences for years, as mutations in some genes are known to hinder gene function, for example, in the classic studies of PUFAS and Framingham ,41,42. IHaving analysed the influence of different polymorphisms in hypercholesterolemia patients following a dietary treatment with plant sterols, we can conclude that gene LIPC C-514T carriers, especially TT homozygous carriers, lowered LDL-c more than CC homozygote and CT heterozygote carriers, after ingestion of plant sterols. LIPC C-514T and APOA5 C56G Ser19Trp carriers greatly improve their lipid profile from sterol intake in the diet. No statistically significant differences were observed for other genes.Human genome discoveries need to be moved into health practice in a way that maximises health benefits and minimises harm to individuals and populations.These results provide the basis for further studies to establish which genotype combinations would be the most protective against hypercholesterolemia.


In addition, measurement of bioaerosols was conducted at an urban area as reference data. Significantly higher concentrations of bioaerosols were found at the mountain site. However, several fold smaller levels of bioaerosols were detected at the seashore site . Concentrations of atmospheric culturable bioaerosols at mountain and seashore sites were measured in field investigations by using a bio-culture sampler. The eastern Korean peninsula was selected for the measurements because of the short distance between the mountain site and the seashore site. Detectable concentrations of culturable fungal and bacterial bioaerosols (maximum 1065 CFU/m The air in the mountains and at the seashore is generally believed to be clean because of the lack of hazardous pollutants. Residents of urban areas frequently visit the mountains and the seashore to breathe clean air in natural environments. However, we hypothesized that significant amounts of airborne microorganisms may be present in these areas. In the mountains many living organisms may release airborne microorganisms into the surrounding environments and the air at the seashore may contain many airborne microorganisms because of humid air conditions. We tried to check our hypothesis by field experiments, providing practical bioaerosol information of mountains and seashore. Atmospheric airborne microorganisms, known as bioaerosols, have been found to be associated with many diseases, such as pneumonia, tuberculosis, allergic rhinitis, asthma, and brucellosis ,4,5,6,7.Measurement of bioaerosols was conducted at a mountain site, a seashore site, and an urban area . All of 3 with positive-hole corrections [We measured outdoor fungal and bacterial bioaerosols from February to April, during mid spring on the Korean peninsula. The sampler , which has been used in previous bioaerosol monitoring studies ,11,12, wrections ,11,13,14In addition to measurement of bioaerosols, we measured concentrations of aerosol particles by using an optical particle counter  to investigate any relevance of aerosol particles to culturable bioaerosol concentrations . At leas3. However, the concentration was 10.7-fold lower at the seashore site (75 ± 13 CFU/m3) on the same day . For bacterial bioaerosols, the concentrations were 775 ± 361 and 150 ± 40 CFU/m3 at the mountain and seashore sites , respectively. The concentrations at the bus terminal (urban site) were between those of the mountain and seashore sites. Differences in temperature and relative humidity among the sites was not significant enough to produce large differences in these concentrations [We conducted measurements of fungal and bacterial bioaerosols for three months. trations . t-test p-value > 0.05) and 7-fold  smaller, respectively, than those at the mountain site. 3 to 1065 CFU/m3, while those at the seashore site ranged from 0 CFU/m3 to 270 CFU/m3. The concentrations of bacterial bioaerosols at the mountain site ranged from 4 CFU/m3 to 1064 CFU/m3, while those at the seashore site ranged from 0 CFU/m3 to 195 CFU/m3. t-test p-value < 0.05). However, for culturable fungal bioaerosols, the concentration at the mountain site was 411 ± 36 CFU/m3 and the concentration was 9-fold lower (46 ± 10 CFU/m3) at the seashore site on the same day , as shown in 3 at the mountain and seashore sites , respectively. Therefore, the overall aerosol particle concentration was not main reason for the difference of bioaerosol concentrations between the mountain site and the seashore site. There could be several explanations for these findings of bioaerosol concentrations at the mountain and seashore sites. Trees and other living organisms in the mountains could produce fungal and bacterial bioaerosols ; therefoCulturable bioaerosol concentrations were measured in mountain, seashore, and urban areas on the Korean peninsula. Significantly higher levels of bioaerosols were found in the air at the mountain site, while several fold smaller amounts of bioaerosols were detected at the seashore site in the field experiments. Further mechanism studies are necessary to investigate the reasons for this phenomenon.


Objective: Selective serotonin reuptake inhibitors (SSRIs) have been the most widely used psychopharmacological agents prescribed for depression worldwide. Some adverse effects of SSRI drugs on central nervous system are insomnia and bruxism. These drugs also affect sleep. Quetiapine is used as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD). It is a low- dose dibenzothiazepine with more potent 5-HT2 than D2 receptor-blocking properties that can be used to manage bruxism because of its antagonist effect on the 5-HT2 receptor.Cases: The cases were 5 patients who have recently been treated with SSRIs and presented with bruxism. Low- dose quetiapine (between 25 and 50 mg daily) was prescribed for the patients, and after a few days, they reported no bruxism and continued taking the medication. Conclusion: We found that quetiapine can improve bruxism and mandibular dystonia, which are side effects of SSRIs. SSRIs are the most widely prescribed psychopharmacological agents for depression worldwide. They are approved by the FDA for the following indications: major depressive disorder (MDD), obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), panic disorder, and social phobia. SSRIs are clearly superior to older antidepressant medications in safety . ConsideMany clinical trials have been conducted to reduce these side effects. In particular, many studies aimed at determining the effects of some drugs such as buspirone -13 , ari Moreover, 5-HT2 blockade would theoretically result in less inhibition of the dopaminergic neurons and, hence, less interference with mesocortical tract dopamine release.Quetiapine is a dibenzothiazepine with more potent 5-HT2 than D2 receptor-blocking properties . Low incidence of EPS in quetiapine (for example akathisia) may be explained by its relatively high 5-HT2A binding compared to its activity at D2 receptors .Quetiapine is used to treat schizophrenia, is indicated as monotherapy for the acute treatment of depressive episode associated with bipolar disorder, and it is also used as adjunctive therapy to antidepressants for the treatment of MDD.The clinical effects of quetiapine and also its effects on the mentioned receptors encouraged us to provide a report on a number of our patients who were suffering from side effects of bruxism due to the use of SSRIs. However, their condition improved after using low- dose quetiapine.CASE 1: the first case was a 28- year-old female with MDD . She was started on 75mg sertraline daily but started to suffer from bruxism and jaw spasm in the second week of receiving the medication. She stopped taking sertraline because of its side effects and immediately visited a psychiatrist because of her depression and bruxism. Again, she was prescribed 75mg sertraline and 25mg quetiapine. Her bruxism improved after 5 days, and she remained symptom- free throughout the following month.CASE 2: the second case was a 35- year-old male with episodes of MDD during last 5 years and suffered some side effects, such as akathisia, restlessness, bruxism and mandibular dystonia, after taking sertraline. He discontinued the medication due to the side effects. Then, he was prescribed sertraline 12.5 mg daily and the dose was increased to 50 mg daily. However, after a week, he began to suffer from bruxism and mandibular dystonia. Thus, he started taking quetiapine (25 mg one time at night) and his condition improved after 5 days and continued taking SSRI drug for his major depressive disorder.CASE 3: the third case was an 18-year-old female with MDD during last 2 months, with depressed mood, restlessness, diminished ability to concentrate, fatigue, and insomnia. She was prescribed with fluoxetine (20 mg daily), but shortly after the onset of drug treatment, she developed bruxism. She improved significantly after one week by taking quetiapine 12.5 mg in the morning and 25 mg at night, and she completely improved after 3 weeks.CASE 4: Our fourth case was a 45-year-old female with MDD . She started sertraline 12.5 mg daily and had good drug compliance. Three weeks after sertraline dose was increased to 50 mg daily, she developed bruxism, lip movements, and jaw dystonia. She received quetiapine (12.5 mg in the morning and 25 mg at night) and, as a result, her condition improved after 5 days, and she remained symptom-free throughout the following month. CASE 5: Our fifth case was a 32-year-old female with postpartum depression 5 years ago. She had been admitted to the hospital due to suicidal ideas at that time. She received ECT and citalopram, clonazepam, and quetiapine, and her condition improved completely. She had no psychiatric problems for the last 5 years up to 2 months ago when she showed restlessness, sleep problems, depressed mood, decreased social function, and suicidal ideas. We recommended hospitalization because of her MDD diagnosis, but she disagreed, so we started her on citalopram (10 mg daily) and clonazepam (1 mg daily) in an outpatient setting. Two weeks after starting the medication, she showed partial improvement. The patient suffered from bruxism and, thus, was prescribed quetiapine (25 mg daily); and 10 days after taking quetiapine, she reported no bruxism and continued taking citalopram.In these case series, we reported 5 patients with MDD who received SSRIs medication. They suffered from some side effects including bruxism, jaw dystonia, restlessness, akathisia, and insomnia due to taking antidepressant medication. Some of the patients stopped taking their medication and suffered relapse or continuance of symptoms and some others returned to their psychiatrics because of side effects. To treat bruxism and mandibular dystonia due to SSRIs medication, we used low- dose quetiapine (between 25 and 50 mg daily) and observed improvement in these side effects, which permitted the continuance of SSRIs medication to treat psychiatric diseases. The effectiveness of low- dose quetiapine in managing bruxism, as the beneficial effect of trazodone on bruxism , may be Thus, low- dose quetiapine should be used to improve bruxism and mandibular dystonia as side effects of medications with SSRIs due to their high affinity to 5-HT2 receptor and their usefulness as an adjunctive therapy to antidepressants to treat MDD, 20 (We Future studies should be conducted to examine the effect of quetiapine on improving the mentioned complications in larger groups of patients with SSRIs side effects.Based on the results of the present study, low- dose quetiapine can improve bruxism and mandibular dystonia, which are side effects of SSRIs. This led to possibility of continuing treatment with SSRIs to control patients’ disorders.


The pulmonary ciliated muconodular papillary tumor (CMPT) is a very rare tumor with only several case reports in published literatures, and its clinicopathological features, standard treatment methods and prognosis has not been well defined.Two cases of CMPT diagnosed and treated in our hospital and 39 cases reported in the published literature were analyzed retrospectively.EGFR, KRAS, and BRAF and ALK rearrangements in CMPT. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. The follow-up duration was 0–120 months, and no case of tumor recurrence was found until the final follow-up.The cohort of 41 CMPT patients comprised of 20 males and 21 females, aged 9–84 years. The diameter of the primary tumor was 0.3–4.5 cm. Most of these lesions were subsolid nodules, as observed on computed tomography and easily misdiagnosed as early lung adenocarcinoma. Tumors of 26 patients were stained by immunohistochemistry method, which revealed that CK7, CEA, and TTF-1 were positive and CK20 was negative in most patients. The results of gene alternation demonstrated mutations in The incidence of CMPT was low and rate of image misdiagnosis high. Immunohistochemistry is helpful for accurate diagnosis of CMPT. Sub-lobectomy may be proper and adjuvant treatment should be avoided since the disease is now prone to benign lesions. Furthermore, since the biological behavior of this tumor is not yet fully elucidated, additional case data are essential for accurate conclusions. Ishikawa , for theTwo cases of CMPT were treated in our hospital during September 2017 and March, 2018. The tumor specimens of both patients were obtained with informed consent, and underwent immunohistochemistry staining, and the pathological sections were reviewed by two chief pathologists. Both cases were eventually diagnosed as CMPT. We performed a comprehensive literature search for published articles using the WANGFANG DATA in Chinese, PubMed and Clinicalkey in English. A total of 13 articles  were eventually included, and the data from 39 cases, reported in the literature, were analyzed statistically. This study was approved by the medical ethics committee of our hospital.Clinical data of two patients in our center were obtained from the medical record database center, while the data of other 39 patients were collected according to the description of relevant literatures. Clinical data included nationality, age, sex, smoking history, location of the lesion, diameter of the tumor, follow-up time and survival. Two patients in our hospital were followed up on the telephone until May 26, 2018. The follow-up duration of the other 39 patients was described in the relevant literature.The clinical data of 2 patients in our hospital and 39 cases reported in the literature are summarized in Tables 3. A grey, solid, and hard nodule (0.8 cm) was observed in the section of the lung. The tumor had a clear boundary and was not involved in visceral pleura. At high magnification, the tumor was not enveloped, and a relatively clear boundary between the tumor and the surrounding tissue was evident. No obvious necrosis was detected in the tumor. At low magnification, the tumor cells arrayed irregularly along the alveolar wall and were tubular. The alveolar septum was broadened, and papillary protuberances were visible. The tumor cells lacked atypia and showed intensely stained nuclei rarely comprising of mitotic structures. Also, the tumor comprised of different cell types including mucous cells, ciliated cells, and basal cells. Immunohistochemistry analysis showed AE1/AE3 (3+), CEA (+), TTF-1 (3+), CK7 (3+), C-MET (2+), MUC5AC (+), P63 , P53 , BRAF-V600E (−), EGFR (2+), HER2 (−), ROS1 (−), Ki-67   was observed in the section of the lung. The tumor had a clear boundary and was not involved in visceral pleura. At high magnification, the tumor was not enveloped and a relatively clear boundary was detected between the tumor and the surrounding tissue. No obvious necrosis was seen in the tumor. At low magnification, the tumor arrayed tubular structures, the mucus was visible in the lumen, and micropapillary tumor cells were found in the mucus. In addition, the tumor cells lacked atypia and showed intensely stained nuclei with rare mitosis. The tumor comprised of various cell types including mucous cells, ciliated cells, and basal cells. Immunohistochemistry showed TTF-1 (3+), CK7 (3+), P63 , CK5/6 , MUC5AC (1+), CK20 (−), and Ki-67 (2%)  mutation.Grossly, the size of the wedge-shaped lung was 1.5 × 2.0 × 3.0 cmTumors of 26 patients were stained by immunohistochemistry method, the results showed that CK7 was expressed in all cases, while CEA and TTF-1 were expressed in most cases. P63, CK5/6, and P40 were expressed in the basal cells, while MUC5AC was expressed in ciliated columnar cells. The Ki-67 index of most CMPT was low and usually < 3%.BRAF-V600E (COSM476) mutation was detected in 6 cases; BRAF-G606R (COSM27640) was positive in 1 case and negative in 10; EGFR exon 19 deletion was positive in 3 cases and EGFR mutation was negative in 15; KRAS-G12D was positive in 1 case, KRAS-G12D and KRAS-G12A was positive at the same time in 1 case, and KRAS G12C was positive in another case while KRAS was negative in 15; ALK rearrangement was positive in 2 cases and negative in 15 cases  months and no recurrence was observed.CMPT was first reported in 2002 and termed as an independent tumor. Since then, a few CMPT cases have been reported. A malignant pulmonary tumor containing cilium is yet a rarity. Hitherto, only a few studies have reported that the well-differentiated papillary lung adenocarcinoma contains cilia –17. AlthCMPT is often observed in middle-aged and elderly individuals; however, a case of a 19-year-old girl was reported in the literature . CMPT caBRAF gene mutation in CMPT was higher than that of EGFR and KRAS mutations and ALK rearrangement. In the pathological diagnosis, CMPT should be differentiated from isolated peripheral ciliated papilloma, mucinous adenocarcinoma, mucoepidermoid carcinoma, and bronchiolobronchial squamous metaplasia.Macroscopically, CMPT is a tan-white nodule located in the peripheral lung. The section of the CMPT tumor is soft and the lesion filled with mucus . MicroscPresently, a standard procedure for the treatment of CMPT is absent. Based on the current evidence, wedge resection of the lung with negative pulmonary margin can be used as a primary recommendation. Systematic lymph node dissection or sampling is of little significance. However, in clinical practice, the intraoperative pathological diagnosis of the frozen tumor sample is often difficult for accurate identification of the nature of the lesion, and the CMPT is often misdiagnosed as adenocarcinoma; occasionally, CMPT was found to exist with other lung adenocarcinomas (as in our second patient). Therefore, in this case, it is appropriate for surgeons to treat patients with surgery according to the principles of adenocarcinoma treatment..Previously, CMPT was considered as a low-grade malignancy; however, all the reported cases including 2 patients at our hospital have not yet been found to recur or metastasize. Therefore, CMPT can be speculated as a benign lesion. Owing to a limited number of cases and short follow-up duration, the long-term physiological behavior of CMPT remains to be observed. Furthermore, as CMPT is very rare and due to the limited knowledge of the pathologist about the disease, CMPT could have been misdiagnosed in the past. Thus, we reviewing the previous pathological sections by the pathologist for a rediagnosis and analyzing these patients for conclusive evidence is imperative.CMPT is a nodular tumor commonly seen in the peripheral lung of middle-aged and elderly individuals. The current evidence states that CMPT is a benign tumor; however, some pathological characteristics of CMPT suggested its low-grade malignant potential. Based on the existing evidence, we speculated that sub-lobectomy might be the preferred choice for the treatment of CMPT. Thus, collecting additional clinical data is essential for accurate conclusions.


However, each leads to different consequences in opioid related Central Sleep Apnea (CSA) patients. Given the high prevalence of CSA and frequently use of opioids worldwide, it seems that evaluation of the condition in these patients is required to determine their responsiveness to the above mentioned treatments and to choose the most appropriate therapy.Nowadays, the most practical approaches used to treat sleep apnea, are Continuous Positive Airway Pressure (CPAP), Bi-level Positive Airway Pressure therapy (BPAP), supplemental O2 and BPAP) in which if the patient was nonresponsive to a treatment, the next therapy was applied. If the patient was nonresponsive to all of these approaches, only oxygen was administered. Finally, the collected data were analyzed with SPSS software (ver. 22).This longitudinal cross-sectional study included 41 opioid related CSA patients who underwent a step-by-step protocol  was observed to BPAP, whereas better response in patients with lower AHI was to CPAP+O2Among 41 participants, the responsiveness to CPAP, CPAP+OAccordingly, CPAP and BPAP are successful approaches to treat opioid related CSA patients in various medical conditions including long-run addiction course, concurrent smoking and addiction but it appears that further studies are essential. The Sleep-Disordered Breathing (SDB) which is generally classified into Obstructive Sleep Apnea (OSA) and Central Sleep Apnea (CSA), has been reported in 6.5 to 9 percent of adults .Despite the lower prevalence of CSA rather than OSA , CSA synTo verify this categorization, some studies indicated increased risk of OSA due to opioids , 6. For Given chronic opioid users response to hypercapnia through a depressed ventilation versus their augmented response to hypoxia, the lack of regulation about respiratory chemical reactions may lead to an instable breathing ,7, 10. H2 or CPAP+O2, as a single therapy or step-by-step were used to achieve the desired response  and/or during two-sectional diagnostic PSG for hours, these patients were diagnosed when five or more central apneas and/or central hypopneas are present per hour.The demographic and clinical characteristics in CSA and hypoxia including age, sex, weight, height, Body Mass Index (BMI), blood pressure, neck circumference, course of using opium, apnea-hypopnea index, Central Apnea Index (CAI), use of opioid and smoking were recorded in an encoded form to keep the privacy .2O. If the patient was nonresponsive to CPAP, Bi-level Positive Airway Pressure (BPAP) was used. It should be noted that CPAP and BPAP titrations were performed based on the American Academy of Sleep Medicine (AASM 2008) guideline for adults . The qualitative data were reported by frequencies (percentage) and the quantitative data were expressed as Mean ± SD. Also, to compare quantitative data of each therapeutic approach with others and the response to treatment two by two, the exact Fisher test was applied and to compare all four therapeutic approaches existing in the study protocol, the Chi-square test was used. Given that the Kolmogorov–Smirnov test indicated the normality of data distribution, for quantitative data and in order to compare the mean variables between responsive and nonresponsive patients to the treatment, we used Independent samples t-test. To compare mean variables of four therapeutic approaches, one-way ANOVA was used and the two by two comparison of therapeutic approaches was made by the post hoc Tukey test. In all analyses, we used a significance level of < 0.05.This study included 41 male addicted patients with CSA . Among these patients, those with diabetes mellitus, hypertension and hyperlipidemia (HLP) were 48.8, 36.6 and 17.1%, respectively of which 50% were not only opioid addicts but also smokers .As shown, 17 patients were responsive to CPAP versus 24 nonresponsive patients. There were significant difference between these patients in mean AHI and smoking . The majority of nonsmoking addicts with rather high degree of AHI were more responsive to CPAP. Moreover, the addiction course among these CPAP responders (mean addiction course=9.71±2.64y) was significantly shorter than nonresponsive patients to CPAP (mean addiction course=11.50±2.62y)  .2, versus 18 nonresponsive patients. A lower mean AHI was reported for CPAP+O2 responders   .2, 16 patients were responsive to BPAP versus 2 nonresponsive patients. There was no difference between responsive and nonresponsive patients to treatment in terms of basic and clinical factors   .2 and BPAP responders. Also, a lower mean BMI was reported for these nonresponsive patients, although the difference was not statistically significant . On the other hand, mean age of CPAP responders was significantly higher than CPAP+O2 responders . In addition, CPAP and BPAP responders showed the severest CSAs  compared to CAPAP+O2 responders with mildest CSA (mean AHI=21.67±15.87 no. /h) . Also, a considerable percentage of smoking opioid addicts had shown a desirable response to BPAP with the longest course of using opioids (mean=11.69±2.77y) versus CPAP responders with the shortest course of using opioids (9.71±2.64y)   .According to the results, all patients with CSA were males with the mean age of 63.78±11.95 years. Moreover, more than 50 percent of these patients were smokers with the addiction course of 10.76±2.74 years.In this regard, the prevalence of CSA is considerably higher in men and it increases with age. For example a community cohort of 741 men showed that the CSA prevalence was estimated to be 0.4% overall among those aged 65 and older . Also, a2 and BPAP were 41.5%, 14.6% and 39%, respectively. At the end, 4.9% of patients remained nonresponsive to these three approaches and thus, this group of patients underwent oxygen administration and was discharged.The findings of therapeutic approaches indicated that among 41 patients, responsive patients to CPAP, CPAP + O2 and BPAP + O2 based on a step-by-step protocol were 54%, 27% and 10%, respectively; thus, using CPAP as the primary choice and CPAP+O2 as the second choice for treatment of this group of patients were recognized  suggested a more desirable responsiveness to both approaches of CPAP and BPAP in addicted CSA patients (with AHI>25 no. /h) compared to CPAP+O2 (with AHI>15).On the other hand, the assessment of patients' condition impact on responsiveness to therapeutic approaches in the current study showed that the majority of CPAP responders were not smokers but with a rather high AHI. Also, this therapy for patients with longer addiction course was unsuccessful. Then, using CPAP+OIn this regard, many studies have supported the effect of CPAP on CSA ,24,27,282 and fewer obstructive episodes were reported in nonresponsive patients to CPAP than CPAP responders  showed a significant improved AHI, while only a slightly improved AHI was reported in 9 patients with high AHI (AHI≥15). In the latter group, a significant improved AHI was reported using BPAP titration. Also, longer mean duration of Cheyne-Stokes respiration (CSR) and higher plasma Brain Natriuretic Peptide (BNP) as well as significantly lower PaCOsponders .Also, another study reported an improved AHI (AHI<10) in 28 patients (59.6%) using ASV for opioid-related CSA treatment. Using the criteria of AHI<5 under optimal ASV end-expiratory pressure, a similar result was reported in 29 patients (61.7%) .Actually the CPAP therapy could result in restoration of upper airway patency as well as stabilization of the respiratory control system. CSA is defined as cycles of apnea and hyperpnea, which induces hypocapnea. CPAP dampens hyperventilation and stabilizes respiration .In the past, few studies with contradictory results were done with the aim of comparing the efficacies of various treatments in addicts with CSA. The different results could be achieved due to different definitions of CSA, therapeutic approaches and medical conditions as well as the type of opioids and the course of opioid use . The CSAA 12-months follow-up to assess the adherence rate, could be considerable although a long-run follow-up was not performed in the current study.Perhaps the reduction in CAI and arousal index with PAPs was associated with a reduction in loop gain, hyperventilation and finally cyclic periodic breathing pattern .One group of the potent respiratory depressants are opioids which may lead to hypoxia and hypercapnia in some opioid related CSA patients. It appears that to improve oxygenation and to reduce CSA events in the majority of the opioid-related CSA patients, using PAP titration can be beneficial. However, dealing with low PAP adherence is challenging .Finally, according to the results, the concurrence of addiction and smoking and/or longer course of addiction resulted in significant increased success rate of BPAP versus CPAP.Some studies investigating the relationship between opioids use and CSA, displayed that there is a dependent correlation between opioid dosage and CSA and opioids use can reduce slow wave as well as REM sleep stages ,32.In the literature it has been reported that CPAP without oxygen supplement was ineffective in three patients with a long-run use of opioids and only it can slightly prevent hypoxemia .Also, some studies have pointed out that ASV and BPAP are more expensive than CPAP and in some cases without desired response. Thus, the practical approach can be still using CPAP as the primary therapy, although ASV and BPAP can be applied as alternatives if CPAP failed ,25, 26. Therefore, further RTC studies with larger sample size are recommended to compare basic and clinical outcomes of CPAP and other therapies. Furthermore, lack of long-run patients' follow-up after treatment is one of the limitations of this study. Thus, it is suggested to follow-up patients for a longer period of time in further studies with a similar staged protocol and conduct independent studies to evaluate two-by-two these approaches to provide more appropriate documented results using larger sample size.


Cervical cancer is the second most common malignancy worldwide in women and the third most common cause of cancer death in developing countries. This type of cancer spreads mainly to the lung, the bone, and the brain; however, the pericardium is an unusual site of invasion, which is associated with a poor prognosis. We present a case of a 35-year-old woman with six months of leg edema and abnormal uterine bleeding. During the initial evaluation, cardiac tamponade and a bilateral pleural effusion were found. A left supraclavicular lymphadenopathy was identified on physical examination, while gynecological examination and MRI were irrelevant. Initial cytology of the pericardial fluid showed a poorly differentiated carcinoma, and a cervical biopsy revealed a squamous cell invasive carcinoma. Chemotherapy was started with carboplatin and paclitaxel, but no clinical improvement was noted and the patient died 46 days after arrival. Cardiac tamponade in a young female patient is a harbinger to widen the differential diagnosis to include not only infectious, cardiac, or metabolic etiology but also oncological causes since this will allow appropriate treatment. Pericardial metastasis is an unusual manifestation of cervical cancer, generally identified at autopsy . SymptomA 35-year-old woman arrived at the emergency department because of rest dyspnea and a 6-month history of lower extremity edema. She had a 3-month history of intermittent abnormal vaginal bleeding. On initial evaluation, the patient was hypoxemic with an oxygen saturation of 80% with room air. Relevant clinical signs were tachycardia and hypotension, decreased heart sounds, and a left supraclavicular lymphadenopathy. A chest X-ray showed a widening of the cardiac silhouette with a bilateral pleural effusion .Pericardiocentesis was performed and a total of 500 mL of bloody secretion was drained with symptomatic improvement. Pleural fluid was obtained by thoracocentesis, and cytology was positive for a poorly differentiated carcinoma .An excisional biopsy of the left supraclavicular lymphadenopathy was positive for metastatic squamous cell carcinoma. The cervical biopsy reported a squamous cell carcinoma associated with an intraepithelial high-grade lesion Figures  and 4. CChemotherapy was begun with carboplatin and paclitaxel. Despite the treatment received during her hospitalization, she again presented a pericardial and pleural effusion with subsequent hemodynamic instability and respiratory failure. Due to the fact that in our center there is no experience in applying intrapericardial sclerotherapy, it was offered to repeat pericardiocentesis; however, this intervention was refused. The patient died 46 days after the initial presentation.Cervical cancer is the second most common cancer diagnosed in women worldwide and the third cause of cancer death in developing countries , 3, 4. TCoxsackievirus, VEB, CMV, and M. tuberculosis); autoimmune diseases; cancer from lymphatic or hematogenous dissemination (metastasis: melanoma (50%), lung (30%), breast (12%), and lymphoma (12%)) [The most common causes of pericardial effusion with or without tamponade are infections ) , 11, 12;%) , 11, a (12%)) .Maisch et al. analyzed 357 pericardial effusion samples from 1988 to 2008 and identified 68 patients with cancer-associated pericardial effusion. In 42 patients, a malignant pericardial effusion was noted; in 15 patients, it was induced by radiation; in 11, by viral disease; and in 6, with an autoimmune process. From the cancer-associated pericardial effusion, it was found that 52.4% was from lung cancer, 19% breast cancer, 4.8% Hodgkin's lymphoma, 4.8% colon cancer, 2.4% mesothelioma and esophageal cancer, and 14.2% was of unknown origin undifferentiated cancer [Pericardial effusion as a clinical presentation can be acute , subacute (uremia or idiopathic), or chronic (constrictive or adhesive). The clinical features are dyspnea, pleuritic pain, cough, fatigue, and syncope. Cardiac tamponade causes hypotension, tachycardia, and decreased heart sounds (Beck triad). The paradoxical pulse is reported as the most sensitive sign (82%) to diagnose cardiac tamponade, followed by tachycardia and elevated jugular venous pressure with a sensitivity of 77% and 76%, respectively , 5, 13. Pericardiocentesis is a diagnostic and therapeutic procedure. The drainage of the pericardial fluid is assessed daily. The inserted catheter is removed when drainage is less than 30 mL/day. Such a procedure has a greater risk of major complication 1.2%) such as ventricle laceration, pneumothorax, ventricular tachycardia, and bacteremia. In patients with cancer, the risk of recurrence is about 90% .2% such . There aWithin the initial approach of a young woman presenting with cardiac tamponade, an etiology must be identified and cancer should be considered as a possible cause. A correct workup is required to achieve a timely diagnosis, in order to grant the patient the best possible outcome.


P < 0.0001) and one day  after initiation of treatment compared to baseline (before the insertion of appliance). Salivary chromium level was higher in periods of one day  and one week  after the initiation of treatment compared to baseline. Corrosion of fixed orthodontic appliances leads to elevated salivary nickel and chromium concentrations early after initiation of orthodontic treatment. Randomized clinical trials controlling for factors affecting the saliva composition are recommended on a higher number of patients and among different ethnicities.Nickel and chromium ions released from fixed orthodontic appliances may act as allergens. This study aimed to systematically review the effect of fixed orthodontic treatment on salivary levels of these ions by doing a meta-analysis on cross-sectional and cohort studies. The Web of Science, Scopus, Cochrane Library, and PubMed databases were searched for articles on salivary profile of nickel or chromium in patients under fixed orthodontic treatment published from January 1983 to October 2017. A random-effect meta-analysis was done using Review Manager 5.3 to calculate mean difference (MD) and 95% confidence interval (CI), and the quality of questionnaire was evaluated by the Newcastle–Ottawa scale. Fourteen studies were included and analyzed in this meta-analysis. Salivary nickel level was higher in periods of 10 min or less (MD = −11.5 µg/L, 95% CI = −16.92 to −6.07;  Orthodontic appliances are highly biocompatible, although some side effects associated with the release of nickel ions have been documented . Fixed oControversy exists regarding the reported values of nickel and chromium ions released during fixed orthodontic treatment in previous studies; therefore, we decided to systematically review the previous studies on the effect of fixed orthodontic treatment on salivary levels of nickel and chromium ions in a meta-analysis of observational studies. This meta-analysis was done according to the guidelines for the preferred reporting items for systematic review and meta-analysis (PRISMA) .We searched the Web of Science, Scopus, Cochrane Library, and PubMed databases for articles on assessment of salivary profiles of nickel or chromium in patients under orthodontic treatment using the search terms "nickel or chromium", "orthodontic", and "saliva or salivary". The search was limited to human studies accessible in PubMed, Web of Science, and Scopus published from January 1983 to October 2017.Articles on evaluation of salivary profile of nickel or chromium in patients under fixed orthodontic treatment  were selOne author (M.S.) reviewed the articles, screened the titles and abstracts based on the aforementioned criteria, and extracted the required data. Two authors (M.R. & M.S.) independently rechecked the full text of the screened studies. Data collected from each study included the name of the first author, year of publication, country, number of patients evaluated, percentage of male patients, mean age of patients, and salivary nickel or chromium levels. These data were rechecked by another author (M.M.I.). The quality of the questionnaire was evaluated using the Newcastle–Ottawa scale , in whicP < 0.1, and P-value (2-sided) <0.05 was considered statistically significant in this meta-analysis. The heterogeneity (I2) statistic yields results ranging from zero to 100%; 0 to 25% indicates lack of heterogeneity, 25% to 50% indicates moderate heterogeneity, 50% to 75% indicates large heterogeneity, and 75% to 100% indicates extreme heterogeneity [A random-effect meta-analysis was done by the Review Manager 5.3  using the mean difference (MD) and 95% confidence interval (CI). Heterogeneity between the estimates was evaluated by the Q and I2 statistic. For the Q statistic, heterogeneity was considered if ogeneity . In addiogeneity , or mediogeneity . The uniThe search of the four databases yielded 451 studies . After eP < 0.0001), 1 day , 1 week , 3 weeks , 1 month , 2 months , 3 months , 6 months , 12 months , and 24 months  after fixed orthodontic treatment compared to baseline (before fixed orthodontic treatment). There was no heterogeneity in 10 min or less, 1 day, 3 weeks, 2 months, and si6x months, whereas extreme heterogeneity was found in 1 week and 1 month, and a large heterogeneity was observed in 12 months. There were significant differences in time periods of 10 min or less, 1 day, 2 months, and 3 months. In time periods of 10 min or less and 1 day, salivary nickel level was higher after treatment compared to before treatment, but in periods of 2 months and 3 months, salivary nickel level after treatment was less than that before treatment. P = 0.42), 1 day , 1 week , 3 weeks , 1 month , 2 months , 3 months , 6 months , 12 months , and 24 months  after insertion compared to baseline (before fixed orthodontic treatment). There was no heterogeneity in 3 weeks and 6 months after treatment, whereas an extreme heterogeneity was found in 1 day, 1 week, and 12 months and a large heterogeneity in 10 min or less and 1 month after treatment. There were significant differences in time periods of 1 day and 1 week; salivary chromium level was found to be higher after treatment than before treatment in both periods.P = 0.0002), after two weeks , before placement of archwires , immediately after placement of archwires , four weeks after placement of wires , and eight weeks after placement of wires compared to baseline (before fixed orthodontic treatment). There was a large heterogeneity in the first and third periods, whereas there was no heterogeneity in the second, fourth, and fifth periods. There were significant differences in all periods such that the salivary nickel level was higher after placement of the bands and brackets and immediately after placement of archwires compared to baseline (before treatment), but this value was lower after two weeks, before placing the archwires, four weeks after placement of wires, and four weeks after placement of wires compared to before treatment.P = 0.13) in patients compared to controls. There was a moderate heterogeneity.Three studies showed MD of the salivary nickel in patients under fixed orthodontic treatment compared to controls . The pooP = 0.82) in patients compared to controls. There was a large heterogeneity.This meta-analysis evaluated the salivary nickel and chromium levels in patients under fixed orthodontic treatment for different periods of time compared to controls. The salivary nickel level was higher in periods of 10 min or less and 1 day from the insertion of appliance as well as after placement of the bands and brackets and immediately after placement of archwires compared to baseline, while the salivary nickel level was lower than the baseline (pretreatment) value in periods of after two months and three months from the insertion of appliance as well as two weeks after the insertion of appliance except for wires, and four weeks after the placement of wires. The salivary chromium level was higher than the baseline pretreatment value in periods of one day and one week after the insertion of appliance. In this meta-analysis, the mean concentration of chromium in the reviewed studies ranged from 0.68 to 142.16 µg/L and the mean concentration of nickel ranged from 0.52 to 102.68 µg/L.It has been shown that nickel and chromium ions can cause hypersensitivity reactions, dermatitis, and asthma; thus, nickel and chromium ions released from stainless-steel orthodontic bands, brackets, and wires are likely to cause allergic reactions ,27. The P > 0.05). Also, evaluation of chromium level in five studies revealed that three studies [P > 0.05) while two other studies [An in vitro study demonstrated the corrosion potential of orthodontic appliances . Some st studies ,34,44 re studies ,15 repor studies  showed aLimitations of this meta-analysis included different protocols of saliva sampling in different studies, different analyses of the saliva samples in different studies, different percentages of males and females in the studies, different age range of patients, different time periods of evaluation, and small number of participants in the majority of studies.Overall, within the limitations of this meta-analysis, it can be concluded that corrosion of fixed orthodontic appliances leads to elevated salivary nickel and chromium levels early after the initiation of orthodontic treatment. The small amount of nickel released from orthodontic appliances in cross-sectional/cohort and case-control studies may support the opinion of an orally-induced tolerance level against nickel early after the initiation of orthodontic treatment. Randomized clinical trials controlling for the factors affecting the composition of saliva are recommended with a larger sample size and among different ethnic groups.