BioScience Trends
Online ISSN : 1881-7823
Print ISSN : 1881-7815
Volume 11 , Issue 4
Showing 1-15 articles out of 15 articles from the selected issue
Policy Forum
  • Peipei Song, Chunlin Jin, Wei Tang
    2017 Volume 11 Issue 4 Pages 366-369
    Published: August 31, 2017
    Released: September 12, 2017
    JOURNALS FREE ACCESS

    On July 11, 2017, the State Council of China issued a bold plan to revolutionize medical education and promote collaboration between medical education and practice. The cornerstone of the plan is training more qualified medical professionals to improve public healthcare on the path to Healthy China 2030. According to this plan, a "5+3" training system will be instituted to train medical professionals in China, and top medical colleges will be encouraged to recruit more students. However, given the less-than-ideal professional status of Chinese doctors, the frequent incidents of violence against them, long working hours and a heavy workload, and an unsatisfactory income, attracting personnel to work in medicine and health care has become a challenge. Prior to the end of 2016, there were 3.19 million practicing (assistant) physicians in China, amount to 2.31 per thousand population. The average workload of physicians was 7.3 outpatient visits per day and 2.6 beds per day, and these figures are much higher for physicians working in tertiary hospitals. Studies have found that 78% of physicians work more than 8 hours a day and 7% of physicians work more than 12 hours a day, but the average annual income of physicians in 2015 was 77,000 yuan (about $12,360), in contrast to an average annual income of $294,000 for physicians in the United States. Medical humanities education is also emphasized by the new medical education reform to foster the humanistic spirts of medical students in order to improve public healthcare in China. In the face of a mindset that "medical technology comes first" and growing expectations among the public, public education is needed to provide the public with a more comprehensive view by explaining the limitations of modern medicine since "medicine is not a panacea". Additional efforts should be undertaken by the Government, organizations, physicians, patients, and the public to create a virtuous cycle of healthcare in China.

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Reviews
  • Yun Yu, Aihua Fei, Zengbin Wu, Chengjin Gao, Shuming Pan
    2017 Volume 11 Issue 4 Pages 370-382
    Published: August 31, 2017
    Released: September 12, 2017
    JOURNALS FREE ACCESS

    With the increasing incidence of multi-drug resistant strains, especially carbapenem resistant strains, polymyxsins (mainly colistin and polymyxin B) based regimens seem to be a revival as an effective treatment of last resort in these infections. Evidence from 47 clinical trials or case series we reviewed showed that polymyxins based regimens are effective and have less toxicity compared with previous trials. When used alone, the mortality of intravenous polymyxsins ranged from 0% to 74.3%, clinical response (cure and improvement) rate was 7-82.1%, and microbiological eradication was 27.3-73.9%. The main reasons for the combination therapy are to get potential synergistic effects and to prevent the selection of heteroresistant strains. Several studies showed combination therapy seemed to be more effective than monotherapy, though a few doubts remain. Clinically, polymyxsins can be used in combination with several antibiotics, such as carberpenem, sulbactam, tigecycline, fosfomycin, glycopeptide, rifampicin and so on, but the optimal combination regimen is yet to be confirmed. The optimal dose of polymyxins is also controversial. With the limited clinical evidence, it's suggested loading dose regimens may be more effective, but more attention should be paid to adverse effects. Although recommended in some studies, high dose polymxins regimens with inconsistent clinical evidence need more trials to confirm. It is important to note that concerning dosing regimens, colistin and polymyxin B are not quite the same. In renal impaired patients polymyxin B should be prescribed without dosing adjustment. Risk of renal failure may increase in the following situations, such as the combination of intravenous colistin plus intravenous vancomycin, higher doses-colistin, and intravenous colistin combined with inhalational colistin. In conclusion, there're still controversies in combination regimens, dosing strategies and so on. Prospective trials of lager sample size are needed.

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  • Lanting Chen, Xuemin Qiu, Na Zhang, Yan Wang, Mingyan Wang, Dajin Li, ...
    2017 Volume 11 Issue 4 Pages 383-388
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: July 17, 2017
    JOURNALS FREE ACCESS

    Cervical cancer is one of the most frequently diagnosed cancers and is a major cause of death from gynecologic cancers worldwide; the cancer burden from cervical cancer is especially heavy in less developed countries. Most cases of cervical cancer are caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes 16 and 18. Non-resolving inflammation caused by HPV infection provides a microenvironment that facilitates cancer development. Molecular alterations during the process of HPV-induced carcinogenesis are characterized by DNA methylation within the HPV genome, promoter hypermethylation of tumor suppressor genes in the host genome, as well as genomic instability caused by viral DNA integrating into the host genome. Catalytic polypeptide-like apolipoprotein B mRNA editing enzymes (APOBECs) normally function as part of the innate immune system. APOBEC expression is stimulated upon viral infection and plays an important role in HPV-induced cervical cancer. APOBECs catalyze the deamination of cytosine bases in nucleic acids, which leads to a conversion of target cytosine (C) to uracil (U) and consequently a change in the single-stranded DNA/RNA sequence. APOBEC proteins mediate the complex interactions between HPV and the host genome and link immunity and viral infection during HPV-driven carcinogenesis. Understanding the effects of APOBECs in HPV-induced cervical carcinogenesis will enable the development of better tools for HPV infection control and personalized prevention and treatment strategies.

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  • Peipei Song, Yulong Cai, Haowen Tang, Chuan Li, Jiwei Huang
    2017 Volume 11 Issue 4 Pages 389-398
    Published: August 31, 2017
    Released: September 12, 2017
    JOURNALS FREE ACCESS

    Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. In this review, we made a review on current guidelines published from January 2001 to June 2017 worldwide with a focus on the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and the Japanese CiNii were systematically searched. A total of 18 characteristic guidelines for HCC management were finally included, including 8 guidelines from Asia, 5 from Europe, and 5 from the United States of America (USA). If guidelines were published in multiple versions, the most recent update was included, and surveillance, diagnosis, and treatment were compared. The composition of and recommendations in current guidelines on HCC varied, so these guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories of a "Size-based pathway" and a "Non-size-based pathway." The treatment criteria were divided into 4 categories: i) Criteria based on the Barcelona Clinic Liver Cancer staging system; ii) Criteria based on the modified Union of International Cancer Control staging system; iii) Criteria based on the Child-Pugh class of liver function; and iv) Criteria based on tumor resectability. Findings from comparison of current guidelines might help target and concentrate efforts to improve the clinical management of HCC. However, further studies are needed to improve the management and outcomes of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions in the treatment of HCC in the future.

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  • Xiaobin Feng, Jiahong Dong
    2017 Volume 11 Issue 4 Pages 399-405
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: August 19, 2017
    JOURNALS FREE ACCESS

    The management of bile duct injury (BDI) remains a considerable challenge in hepatobiliary surgery. BDI is mainly iatrogenic, and mostly occurs in cholecystectomy. Laparoscopic cholecystectomy (LC) has been performed widely, however, the incidence of BDI associated with LC increases 2-3 times compared to that in open cholecystectomy (OC). BDI also occurs in robotic cholecystectomy. In China, the evidence-based Practice Guideline for Diagnosis and Treatment of BDI was published by the Biliary Surgery Group of Surgery Branch of Chinese Medical Association, with the purpose of reducing the incidence of BDI as well as promoting its optimal diagnosis and treatment. Surgery remains the mainstay of treatment for BDI and traumatic bile duct stricture. The definitive repair involves a series of procedures including exposing the proximal and distal bile duct, anastomotic bile duct tissue preparation, minimally invasive tissue anastomoses, and so on. Successful management is a surgical challenge requiring great specialized experience and precise surgical skill. The application of precision biliary surgery is recommended for promoting standardized management of BDI.

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  • Bo Zhang, Haidong Xu, Juntao Wang, Bin Liu, Guodong Sun
    2017 Volume 11 Issue 4 Pages 406-417
    Published: August 31, 2017
    Released: September 12, 2017
    JOURNALS FREE ACCESS

    Lumbar intervertebral disc herniation (LIDH), as the main contributor to low back pain and sciatica, imposes a heavy burden on both the individual and society. Non-operative treatment or conservative treatment has proven effective in alleviation of the symptoms of LIDH and are considered to be a first-line choice for most cases. Active lifestyle, physical therapy, complementary and alternative medicine therapy or Traditional Chinese medicine (TCM) therapy, and pharmacotherapy are routinely used as effective non-operative treatment for LIDH patients. However, how to choose one or several conservative treatments with higher efficacy, less side effects, minimal injury, and low cost is still a challenge for doctors and LIDH patients. Furthermore, there are some national characteristics for some conservative treatments in different countries, which bring difficulties for the widespread use of these methods. Here we initiated a search on the non-operative treatment especially TCM therapy for LIDH mainly using PubMed, Web of Science, China National Knowledge Internet (CNKI), and Chinese biomedicine database since the 1980s with no restriction of language. According to these related references, we gave a narrative review which emphasizes up-to-date knowledge regarding the effectiveness and safety of various conservative methods with special consideration for TCM therapy including acupuncture, autonomy, Chinese massage, and Chinese herbal medicines, for LIDH treatment. We hope this review will further contribute to an understanding of conservative treatment as an important choice for LIDH patients and provide useful information for the development of more effective conservative methods for LIDH treatment.

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Original Articles
  • Yan Zhang, Jing Fu, Shuwen Yang, Ming Yang, Annan Liu, Leilei Wang, Su ...
    2017 Volume 11 Issue 4 Pages 418-426
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: July 24, 2017
    JOURNALS FREE ACCESS

    The aim of this study was to assess the prevalence of metabolic syndrome (MetS) in non-obese adults (body mass index (BMI) < 25 kg/m2) and the prevalence of obese adults (body mass index (BMI) ≥ 25 kg/m2) without MetS in Chinese Beijing urban subjects. A cross-sectional study was conducted and the subjects who came to the hospital to receive a health examination were enrolled randomly. Regardless of age stratification, men have a higher prevalence of MetS than women. Among the urban Beijing population, prevalence of metabolically obese but normal weight (MONW) is lower than metabolically healthy but obese (MHO) regardless of gender. Except for the underweight group, participants exhibit significant differences between MetS and non-MetS subgroups in all tested variables in normal weight and overweight groups, whereas MONW and MHO participants exhibit significant differences in all variables except for creatinine (CR), aspartate aminotransferase (AST), uric acid (UAC) and high-density lipoprotein cholesterol (HDL-C). Women tend to have a higher MONW prevalence but lower MHO prevalence than men. Accordingly, MetS happens more frequently among those 40-59 yr. Besides, sex, age, WC, SBP, DBP, ALT, FG, UAC, TG, HDL-C and LDL-C are risk factors for MetS after multivariate adjustment. In conclusion, the prevalence of MONW is lower than MHO regardless of gender. Women tend to have a higher MONW prevalence but lower MHO prevalence than men.

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  • Nan Chu, Yuyan Gui, Xuemin Qiu, Na Zhang, Lisha Li, Dajin Li, Wei Tang ...
    2017 Volume 11 Issue 4 Pages 427-438
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: July 17, 2017
    JOURNALS FREE ACCESS

    Female fertility declines with age as the number of ovarian follicles decreases and aneuploidy increases. Degradation of the cohesin complex might be responsible for age-related aneuploidy. Dehydroepiandrosterone (DHEA) can improve the ovarian reserve and reduce the rate of aneuploidy, but the relationship between DHEA and cohesin levels in oocytes is still unknown. The aim of the current study was to evaluate the effect of the supplement DHEA on ovarian function, including the number of follicles and cohesin levels in oocytes. C57BL/6J mice at 3 weeks, 6 weeks, 12 weeks, 6 months, and 10 months of age were used to obtain a systematic view into follicle apoptosis and cohesin levels in oocytes. Nine-month-old C57BL/6J mice were administered saline (n = 5), 17β-estradiol (100 µg/kg per day, n = 5), or DHEA (5mg/Kg per day, n = 5). After 4 weeks, aged mice were weighed and sacrificed, and ovarian tissue samples were prepared. Anti-VASA staining and HE staining were used to count the number of follicles. Anti-γH2AX staining and TUNEL were used to measure follicle apoptosis and immunofluorescent staining was used to detect the levels of three oocyte cohesin subunits: REC8, SMC1β, and SMC3. Administration of the supplements 17β-estradiol and DHEA to aged mice increased the number of primordial and primary follicles and decreased the age-related apoptosis of follicles. Levels of the cohesin subunits REC8 and SMC1β declined with age, but DHEA and 17β-estradiol tended to delay that decline. The supplement DHEA increased the number of primordial and primary follicles in aged mice by inhibiting follicle apoptosis and tended to delay the decrease in cohesin levels in oocytes.

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  • Hui Liu, Fengtong Zuo, Huijun Wu
    2017 Volume 11 Issue 4 Pages 439-449
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: August 19, 2017
    JOURNALS FREE ACCESS

    The purposes of the current study were to investigate the effects of a monoclonal antibody (mAb) on cytosolic phospholipase A2 alpha (cPLA2α) in mice with cerebral ischemia-reperfusion (IR) injury and to ascertain the potential mechanisms of those effects. This study evaluated whether the use of anti-cPLA2α mAb could reduce stroke injury in a mouse model of cerebral IR injury. The expression/activity of cPLA2α and cPLA2α- derived proinflammatory lipid mediators such as prostaglandin E2 (PGE2), leukotriene B4 (LTB4), lysophosphatidylcholine (LPC), and free fatty acids (FFA) was assessed. This study also evaluated neurological deficits, motor function, pathological changes, apoptosis, and the area of infarction in the injured mice. Mice treated with anti-cPLA2α mAb recovered neurological function and their condition improved, apoptosis in the brain decreased and infarct volume decreased, and expression of cPLA2α, 5-LOX, COX-2, FFA, LPC, PGE2, and LTB4 was attenuated. Our findings indicate that cPLA2α plays a key role in cerebral IR injury and that treatment with anti-cPLA2α mAb after cerebral IR injury helps to reduce levels of proinflammatory cytokines, alleviate tissue damage, and reduce levels of deleterious lipid mediators. Thus, anti-cPLA2α mAb treatment has the potential to treat ischemic brain damage.

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  • Ran Jia, Lu Lu, Xiaozhen Liang, Zhiwu Sun, Lingbing Tan, Menghua Xu, L ...
    2017 Volume 11 Issue 4 Pages 450-459
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: June 26, 2017
    JOURNALS FREE ACCESS

    Respiratory Syncycial Virus (RSV) is the most important pathogen responsible for children's severe lower respiratory tract infection. So far no RSV vaccine has yet been authorized for clinical use. The main impediment that blocked development of RSV vaccine is that inactivated RSV vaccine could cause RSV vaccine-enhanced disease (RVED). The mechanism of RVED remains unclear. Recently some researchers found that insufficient activation of innate immunity, including Toll-like receptors (TLRs), might be associated with the onset of RVED. Based on the above findings, this research was conducted to further study the mechanism of RVED. We first vaccinated mice with formalin-inactivated RSV vaccine (FIRSV) and then exposed them to RSV to establish a RVED mouse model. Consequently, we found that mice previously inoculated with FIRSV showed obvious weight loss and extensive pneumonia, as well as T helper 2 cells (Th2)-biased immunity and suppressed CD8+T cell immunity after viral exposure, suggesting that we have successfully established a RVED mouse model. Then based on this model, we further added Poly(U) (TLR7/8 agonist) and CpG (TLR9 agonist) in FIRSV to see if RVED could be ameliorated. As a result, mice inoculated with FIRSV supplemented with Poly(U) and CpG had a much relieved weight loss and pneumonia, as well as suppressed Th2-biased immunity and strengthened CD8+T cell function. Thus, the insufficient stimulation of TLR7/8 and (or) TLR9 might play a role in the development of RVED, which could provide evidence for using TLR agonists as vaccine adjuvants to confer a protective immune response against RSV.

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  • Yating Du, Lihui Huang, Xueyao Wang, Qingjia Cui, Xiaohua Cheng, Lipin ...
    2017 Volume 11 Issue 4 Pages 460-468
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: July 17, 2017
    JOURNALS FREE ACCESS

    We retrospectively analyzed newborns with deafness gene mutations and summarized the relationship between genotype and phenotype to provide a basis for genetic counseling. We studied 582 subjects positive for deafness gene mutations that were treated in the otology outpatient department of Beijing Tongren Hospital, Capital Medical University, between April 2012 and April 2016. The subjects were divided into 3 categories: a diagnosed group (group A), which was further subdivided into subgroups A1 (homozygous and compound heterozygous GJB2 mutations) and A2 (homozygous and compound heterozygous SLC26A4 mutations); a drug-induced deafness group (group B, mitochondrial (Mt) gene mutations); and a mutation carrier group (group C), which was further subdivided into the subgroups C1 (GJB2 heterozygous mutations), C2 (SLC26A4 heterozygous mutations), C3 (GJB3 heterozygous mutations), and C4 (double gene mutations). Partial sequences positive for GJB2 or SLC26A4 were sequenced and analyzed for mutations. Subjects underwent otoscopic examination and comprehensive audiological evaluation, and temporal bone computerized tomography and/or inner ear magnetic resonance imaging were performed. GJB2 235delC was the most common mutation locus. The highest proportion of deafness detected during universal newborn hearing screening was for drug-induced deafness, whereas the lowest was for the diagnosed group. GJB2 gene mutations mainly resulted in flat-type, profound-to-severe sensorineural hearing loss (SNHL). SLC26A4 gene mutation was mainly associated with high-frequency drop-type and profound-severe SNHL and was closely related to enlargement of the vestibular aqueduct.

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  • Han Wang, Weiren Liu, Mengxin Tian, Zheng Tang, Xifei Jiang, Peiyun Zh ...
    2017 Volume 11 Issue 4 Pages 469-474
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: August 07, 2017
    JOURNALS FREE ACCESS

    As a rare type of liver cancer, intrahepatic cholangiocarcinoma (ICC) has become an increasingly important malignancy and continues to present significant therapeutic challenges. Since coagulopathy is associated with poor prognosis in hepatocellular carcinoma (HCC), and prognostic factors of ICC after curative resection were still not clear, we aim to analyze the characteristics of ICC patients with coagulopathy and its correlation to prognosis. From January 2000 to June 2011, 541 ICC patients, after curative resection, were enrolled in our study. Survival curves were depicted by the Kaplan-Meier method and analyzed by the log-rank test. The Cox proportional hazard regression was adopted for multivariate survival analysis. Student's t test was performed to analyze the difference between the coagulopathy group and the normal group. The correlation between coagulation parameters and prognosis was also evaluated. The incidence rate of at least one coagulation parameter abnormality was 22.6% (122/541) while PT was the most common factor (8.87%, 48/541). The one-year survival rate of patients with coagulopathy was significantly lower than that of patients with normal coagulation (p < 0.01). In a univariate analysis, patients with prolonged PT was associated with shortened DFS (p < 0.05). Meanwhile, PT was negatively correlated with pre-albumin level. TNM stage, CA19-9, GGT, and pre-albumin level were independent prognostic factors of DFS in the multivariate analysis. In conclusion, the incidence rate of coagulopathy of ICC patients is lower than HCC patients. Prolonged PT, advanced TNM stage, low pre-albumin level, and high CA19-9 and GGT level were correlated with high recurrence rate and poor prognosis.

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  • Wenlong Li, Rong Li, Huanjun Liu, Xi Guo, Abdul Sami Shaikh, Pingli Li ...
    2017 Volume 11 Issue 4 Pages 475-482
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: August 28, 2017
    JOURNALS FREE ACCESS

    Cyclosporin A (CyA) is an immunosuppressive agent widely used in clinical therapy. In the therapeutic process, the blood concentration of CyA should be monitored to avoid or prevent rejection and toxicity. The objectives of this study were to compare the correlation of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the CyA concentration in human blood and to provide evidence for the rational usage of EMIT in clinical practice. Blood samples collected from 132 patients undergoing a liver or kidney transplant or patients with aplastic anemia at Qilu Hospital of Shandong University were tested using the two methods. The calibration curve was linear from 25-500 ng·mL-1 for LC-MS/MS and from 50-450 ng·mL-1 for EMIT. The inter- and intra-day RSDs were less than 15%. The CyA blood concentration according to EMIT was 3.5 ng·mL-1 more than that according to LC-MS/MS. The 95% confidence interval was –10.0~16.9 ng·mL-1. The CyA blood concentration according to the two methods did not differ significantly (p > 0.05). LC-MS/MS and EMIT were suitable methods for determining the CyA blood concentration. The two methods were closely correlated (r2 = 0.969), but the CyA blood concentration according to EMIT was slightly higher than that according to LC-MS/MS. The clinical significance of this finding needs to be further evaluated.

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Brief Report
  • Ang Lv, Honggang Qian, Hui Qiu, Jianhui Wu, Ying Li, Zhongwu Li, Chuny ...
    2017 Volume 11 Issue 4 Pages 483-489
    Published: August 31, 2017
    Released: September 12, 2017
    [Advance publication] Released: August 28, 2017
    JOURNALS FREE ACCESS

    This report aims to investigate the feasibility and outcomes of neoadjuvant imatinib mesylate (IM) administration followed by organ-preserving surgery (OPS) for patients with locally advanced duodenal gastrointestinal stromal tumor (GIST). Between 2012 and 2015, 10 consecutive patients with locally advanced duodenal GISTs were treated in Peking University Cancer Hospital. Multidisciplinary assessment was implemented, and pancreaticoduodenectomy (PD) was initially indicated as the most probable surgical procedure for all 10 patients. To attempt to create opportunities of less-invasive OPS for patients, neoadjuvant IM was administered followed by radical resection. All data were prospectively collected, and the short- and long-term outcomes of the treatment strategy were analyzed. The median treatment duration of neoadjuvant IM administration was 5 mo (range 2-18 mo). Significant tumor shrinkage (from 9.2 to 5.9 cm on average) was observed in all patients, and partial response was achieved in eight patients (80.0%) according to the Response Evaluation Criteria in Solid Tumors 1.1. No tumor perforation occurred, and nine patients (90.0%) underwent successful OPS with four different operation types. Postoperative morbidity rate of OPS was 55.6% (5/9), and no mortality occurred. After a median follow-up of 36 mo, one patient developed multiple distant metastases, but no local recurrence was observed. For long-term follow-up, patients who underwent OPS did not show any degradation in quality of life, whereas the patient who underwent PD suffered weight loss of ~10 kg. In conclusion, in patients with locally advanced duodenal GISTs, neoadjuvant IM administration followed by OPS is a feasible treatment strategy which leads to favorable short- and long-term outcomes.

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Communication
  • Qi Tang, Hongzhou Lu
    2017 Volume 11 Issue 4 Pages 490-495
    Published: August 31, 2017
    Released: September 12, 2017
    JOURNALS FREE ACCESS

    More than 30 drugs for antiretroviral therapy (ART), including integrase inhibitors (INIs), have been approved by the U.S. Food and Drug Administration (FDA) as of 2017. Integrase is the third essential enzyme in the cycle of human immunodeficiency virus (HIV) replication. INIs can effectively inhibit the replication of HIV and HIV is less prone to develop resistance to INIs clinically. Previous studies based on 7 phase III clinic trials indicate that INIs have satisfactory efficacy and tolerability in patients infected with HIV. The latest advances in INIs indicate that: i) dolutegravir (DTG)-based regimens are more efficacious, tolerable, and safer forms of first-, second-, and third-Line ART; ii) current studies have indicated that DTG monotherapy fails both virologically and clinically; and iii) whether the most cost-effective treatment for DTG is to replace efavirenz (EFV) as a first-line ART, to replace protease inhibitors (PIs) in second-line ART, or to replace both as a monotherapy is unclear. Given these circumstances, further study of INIs in terms of drug interactions, dose reduction, drug convenience, and drug costs is warranted.

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