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1.  Cost-Effectiveness Analysis Comparing Continuation of ART with Conversion to IUI in Patients with Low Follicle Numbers 
Fertility and sterility  2014;102(2):435-439.
Objective
To compare the cost-effectiveness of proceeding with oocyte retrieval versus conversion to intrauterine insemination (IUI) in patients with 4 or fewer mature follicles during assisted reproductive technology (ART) cycles.
Design
Probabilistic decision analysis. The cost-effectiveness of completing ART cycles in poor responders was compared to converting the cycles to IUI.
Setting
Analysis of published data.
Patient(s)
Not applicable.
Interventions
Cost-effectiveness analysis.
Main Outcome Measure(s)
Cost-effectiveness, which was defined as the average direct medical costs per ongoing pregnancy.
Results
In patients with 1 to 3 mature follicles, completing ART was more cost-effective if the cost of a single ART cycle was between $10,000 – $25,000. For patients with 4 mature follicles, if an ART cycle cost less than $18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI.
Conclusion(s)
In patients with 4 or fewer mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed to oocyte retrieval, rather than converting to IUI. However, important factors such as age, prior ART failures, other fertility factors, and medications used in each individual case, need to be considered before this analysis model can be adapted by individual practices.
doi:10.1016/j.fertnstert.2014.05.015
PMCID: PMC4119511  PMID: 24951366
Poor responders; intrauterine insemination; assisted reproductive technologies; cost effectiveness
2.  Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia 
Leukemia  2014;29(2):346-355.
Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects we developed a OSU-2S targeted delivery immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.
doi:10.1038/leu.2014.199
PMCID: PMC4272672  PMID: 24947019
CLL; OSU-2S; phosphatases; ROR1; immunonanoparticle; ROR1 transgenic mice
3.  PubChem structure–activity relationship (SAR) clusters 
Background
Developing structure–activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information.
Results
Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named “PubChem SAR clusters”, were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity.
Conclusions
The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.
Graphical abstract
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0070-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0070-x
PMCID: PMC4492103  PMID: 26150895
PubChem; PubChem3D; Structure–activity relationship (SAR); Cluster analysis; Molecular similarity; BioSystems; MeSH
4.  PubChem structure–activity relationship (SAR) clusters 
Background
Developing structure–activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information.
Results
Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named “PubChem SAR clusters”, were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity.
Conclusions
The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.
Graphical abstract
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0070-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0070-x
PMCID: PMC4492103  PMID: 26150895
PubChem; PubChem3D; Structure–activity relationship (SAR); Cluster analysis; Molecular similarity; BioSystems; MeSH
5.  Crystallization and preliminary X-ray study of the deaminase AmnE from Pseudomonas sp. AP-3 
The deaminase AmnE from Pseudomonas sp. AP-3 was expressed in E. coli and purified. Crystallization and preliminary X-ray crystallographic analysis were performed for this recombinant enzyme.
The amnE gene from Pseudomonas sp. AP-3 has been verified as encoding a deaminase with 142 amino-acid residues. In order to change the substrate specificity via structure-based protein engineering, the amnE gene, after gene-code optimization, was chemically synthesized and cloned into the expression vector pET-28a. The protein was expressed in Escherichia coli BL21 (DE3) and purified by Ni2+-chelating affinity chromatography. Diffraction-quality crystals were obtained using the hanging-drop vapour-diffusion method and diffracted to a resolution of 2.09 Å. The crystals belonged to the orthorhombic space group C2221, with unit-cell parameters a = 63.23, b = 88.93, c = 137.83 Å.
doi:10.1107/S1744309113016709
PMCID: PMC3702332  PMID: 23832215
AmnE; Pseudomonas sp. AP-3
7.  Efficacy of Laparoscopic Mini Gastric Bypass for Obesity and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis 
Background. Controversies on the utility of laparoscopic mini gastric bypass (LMGB) in weight loss and type 2 diabetes mellitus (T2DM) control still exist. Methods. We conducted a comprehensive literature search of PubMed, EMBASE, and Cochrane Library. Review Manager was used to perform the meta-analysis and the weighted mean difference (WMD) and/or odds ratio with 95% confidence interval (95% CI) were used to evaluate the overall size effect. Results. The literature search identified 16 studies for systematic review and 15 articles for meta-analysis. Compared with LAGB, LSG, and LRYGB, LMGB showed significant weight loss [WMD, −6.58 (95% CI, −9.37, −3.79), P < 0.01 (LAGB); 2.86 (95% CI, 1.40, 5.83), P = 0.004 (LSG); 10.33 (95% CI, 4.30, 16.36), P < 0.01 (LRYGB)] and comparable/higher T2DM remission results [86.2% versus 55.6%, P = 0.06 (LAGB); 89.1% versus 76.3%, P = 0.004 (LAGB); 93.4% versus 77.6%, P = 0.006 (LAGB)]; LMGB also had shorter learning curve and less operation time than LRYGB [WMD, −35.2 (95% CI, −46.94, −23.46)]. Conclusions. LMGB appeared to be effective in weight loss and T2DM remission and noninferior to other bariatric surgeries. However, clinical utility of LMGB needs to be further validated by future prospective randomized controlled trials.
doi:10.1155/2015/152852
PMCID: PMC4488176  PMID: 26167173
8.  Simplified Tai Chi Resistance Training versus Traditional Tai Chi in Slowing Bone Loss in Postmenopausal Women 
Background. This study examined whether simplified Tai Chi resistance training is superior to traditional Tai Chi in slowing bone loss in postmenopausal women. Methods. This prospective trial included 119 postmenopausal women (age: 52–65 years). Subjects were randomly assigned to participate in a traditional Tai Chi program (TTC, n = 40), a simplified Tai Chi resistance training program (TCRT, n = 40), or a blank control group (routine activity, n = 39). The TTC involved traditional Yang Style Tai Chi. The primary outcome was the change of lumbar bone mass density (L2–L4) at 12 months over the baseline. Femoral neck and Ward's triangle were also measured using dual-energy X-ray absorptiometry. Results. The L2–L4 density was significantly lower at 12 months in comparison to the baseline in the blank control group. In both the TCRT and TTC groups, the L2–L4 density was comparable to the baseline. There was a trend for less bone loss in the TCRT than in the TTC group. Similar findings were observed with femoral neck and Ward's triangle. Conclusion. Simplified Tai Chi resistance training could slow bone loss in menopausal women. The results also suggested, but did not confirm, superiority to traditional Tai Chi.
doi:10.1155/2015/379451
PMCID: PMC4475529  PMID: 26136808
9.  Major Role of NAD-Dependent Lactate Dehydrogenases in the Production of l-Lactic Acid with High Optical Purity by the Thermophile Bacillus coagulans 
Applied and Environmental Microbiology  2014;80(23):7134-7141.
Bacillus coagulans 2-6 is an excellent producer of optically pure l-lactic acid. However, little is known about the mechanism of synthesis of the highly optically pure l-lactic acid produced by this strain. Three enzymes responsible for lactic acid production—NAD-dependent l-lactate dehydrogenase (l-nLDH; encoded by ldhL), NAD-dependent d-lactate dehydrogenase (d-nLDH; encoded by ldhD), and glycolate oxidase (GOX)—were systematically investigated in order to study the relationship between these enzymes and the optical purity of lactic acid. Lactobacillus delbrueckii subsp. bulgaricus DSM 20081 (a d-lactic acid producer) and Lactobacillus plantarum subsp. plantarum DSM 20174 (a dl-lactic acid producer) were also examined in this study as comparative strains, in addition to B. coagulans. The specific activities of key enzymes for lactic acid production in the three strains were characterized in vivo and in vitro, and the levels of transcription of the ldhL, ldhD, and GOX genes during fermentation were also analyzed. The catalytic activities of l-nLDH and d-nLDH were different in l-, d-, and dl-lactic acid producers. Only l-nLDH activity was detected in B. coagulans 2-6 under native conditions, and the level of transcription of ldhL in B. coagulans 2-6 was much higher than that of ldhD or the GOX gene at all growth phases. However, for the two Lactobacillus strains used in this study, ldhD transcription levels were higher than those of ldhL. The high catalytic efficiency of l-nLDH toward pyruvate and the high transcription ratios of ldhL to ldhD and ldhL to the GOX gene provide the key explanations for the high optical purity of l-lactic acid produced by B. coagulans 2-6.
doi:10.1128/AEM.01864-14
PMCID: PMC4249196  PMID: 25217009
10.  Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium 
Purpose.
Inhibiting mechanistic target of rapamycin (mTOR) by pharmacological or genetic approaches can extend lifespan in mammals. The kinase activity of mTOR is controlled by upstream regulatory proteins and its subcellular localization. The purpose of this study was to characterize age-related alterations and functional consequences of mTOR signaling in the postmitotic RPE cells.
Methods.
Activity of mTOR complex 1 (mTORC1) was monitored by measuring phosphorylation status of its downstream effector protein S6, in either cultured human RPE cells or RPE explants prepared from mice at different ages. Subcellular distribution of mTOR was investigated by immunofluorescent staining of RPE culture or flatmount. The signaling of mTORC1 was modulated by either overexpression of a small guanosine triphosphatase, Ras homolog enriched in brain (Rheb), or disruption of the Ragulator complex with small interference RNA targeting p18. The effects of mTOR pathway on degradation of phagocytosed photoreceptor outer segments (POS) were determined by measuring the turnover rate of rhodopsin.
Results.
Aged RPE cells had more lysosome-associated mTOR and had increased response to amino acid stimulation. The lysosome distribution was essential for mTORC1 function, as disruption of the Ragulator complex abolished mTORC1 activation by amino acids. Increased mTORC1 activity caused decreased rate of degradation of internalized POS in the RPE.
Conclusions.
Aging changes the subcellular localization and function of mTOR in the RPE. Increased mTORC1 inhibits POS degradation and may further exacerbate lysosome dysfunction of aged RPE.
Aged RPE cells had increased lysosome distribution of mTOR and increased response to amino acid stimulation. Higher mTOR activity inhibited degradation of phagocytosed POS in the RPE.
doi:10.1167/iovs.14-14758
PMCID: PMC4280880  PMID: 25491300
mTOR; aging; eye; signaling; lysosome; retinal pigment epithelium
11.  Clinical and pathological analysis of 116 cases of adult adrenal cortical adenoma and literature review 
OncoTargets and therapy  2015;8:1251-1257.
Background
The aim of this study is to investigate origin, gross features, microscopic features, immunohistochemical properties, and differential diagnosis of adrenal cortical adenoma (ACA) in patients ≥20 years old.
Methods
The clinicopathological features of 116 cases of ACA and the immunohistochemical features of 50 cases of ACA were evaluated, and the relevant literature was reviewed.
Results
In our cohort, 76.72% (89/116) of the cases were functional, and 27 cases had non-functional, benign adrenal adenomas. ACA presented as an island tumor with an envelope, and the mean tumor size was 3.6 cm (range 1–5 cm), with a mean tumor weight of 9.28 g (range 5–113 g). The shape of the tumor cells was consistent, and mitosis was rarely observed. Forty of the 46 patients with cortisol-secreting ACA had tumors containing granule cells. Primary aldosteronism was observed in 43 cases. Thirty-eight cases had endoscopically visible tumors, with clear cells and lipid-rich cytoplasm arranged in irregular patches or strips. Cortisol-producing ACAs were associated with atrophy of the non-tumorous cortex. Adrenocortical adenomas displayed positive immunohistochemical staining for MELAN-A, Syn (46 of 50 cases of ACA), NSE (44 of 50 cases of ACA), Vim (42 of 50 cases of ACA) and Ki-67 <5% (24 of 50 cases of ACA; the remaining 26 cases were negative for Ki-67).
Conclusion
Prediction of endocrine syndrome in functional ACA was possible based on its structure and morphologic features, which could prevent an unanticipated postoperative crisis. However, a clinical study is needed to validate these findings.
doi:10.2147/OTT.S81831
PMCID: PMC4455871  PMID: 26064059
adrenal cortical adenoma; pathological features; immunohistochemical staining; pathological analysis
12.  Genome Sequence of Bacillus coagulans P38, an Efficient Polymer-Grade l-Lactate Producer from Cellulosic Substrates 
Genome Announcements  2015;3(3):e00495-15.
Bacillus coagulans P38 is an efficient polymer-grade l-lactic acid producer from a cellulosic carbon source. Here, the draft 3.37-Mb genome sequence of this potential strain may provide useful information to further improve the strain performance for higher titers and, importantly, to understand the mechanism of its high tolerance for 2-furfural.
doi:10.1128/genomeA.00495-15
PMCID: PMC4440960  PMID: 25999580
13.  Estimation of Sensitive Proportion by Randomized Response Data in Successive Sampling 
This paper considers the problem of estimation for binomial proportions of sensitive or stigmatizing attributes in the population of interest. Randomized response techniques are suggested for protecting the privacy of respondents and reducing the response bias while eliciting information on sensitive attributes. In many sensitive question surveys, the same population is often sampled repeatedly on each occasion. In this paper, we apply successive sampling scheme to improve the estimation of the sensitive proportion on current occasion.
doi:10.1155/2015/172918
PMCID: PMC4451016  PMID: 26089958
14.  Nab-paclitaxel, docetaxel, or solvent-based paclitaxel in metastatic breast cancer: a cost-utility analysis from a Chinese health care perspective 
Background
Paclitaxel and docetaxel are commonly used for metastatic breast cancer in the People’s Republic of China. To improve the safety and efficacy of paclitaxel, an albumin-bound formulation (nab) is now available in the People’s Republic of China (Abraxane®). To provide health economic data for the key stakeholders, a cost-utility analysis comparing nab-paclitaxel to docetaxel, both as alternatives to paclitaxel, was conducted.
Methods
A meta-analysis of clinical outcomes Phase III trials comparing nab-paclitaxel (260 mg/m2 every [q] 3 weeks) or branded docetaxel (100 mg/m2 q 3 weeks), to solvent-based branded paclitaxel (175 mg/m2 q 3 weeks) was undertaken to provide safety and clinical data. Resource use data for the delivery of anticancer therapy and for the treatment of grade 3/4 toxicity was collected from a time and motion study conducted in three Chinese cancer centers and from a survey of clinicians. Using the Time Trade-Off technique, health utility estimates were derived from interviewing 28 breast cancer patients from one cancer center in the People’s Republic of China. All costs were reported in 2014 US dollars.
Results
Nab-paclitaxel had the most favorable safety profile, characterized with the lowest incidence of grade 3/4 neutropenia, febrile neutropenia, anemia, and stomatitis. When the median number of cycles delivered from the clinical trials was applied, nab-paclitaxel had a cost per course of $19,752 compared with $8,940 and $13,741 for paclitaxel and docetaxel, respectively. As an alternative to paclitaxel, the cost per quality-adjusted life-year (QALY) gained with nab-paclitaxel suggested better value than with docetaxel ($57,900 vs $130,600).
Conclusion
Nab-paclitaxel appears to be a cost-effective option compared with docetaxel and paclitaxel, for metastatic breast cancer in the People’s Republic of China.
doi:10.2147/CEOR.S82194
PMCID: PMC4435086  PMID: 25999749
taxanes; Abraxane; cost analysis; breast cancer; People’s Republic of China
15.  LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer 
Oncotarget  2015;6(13):11652-11663.
Trastuzumab resistance is leading cause of mortality in HER2-positive breast cancers, and the role of TGF-β-induced epithelial-mesenchymal transition (EMT) in trastuzumab resistance is well established, but the involvement of lncRNAs in trastuzumab resistance is still unknown. Here, we generated trastuzumab-resistant breast cancer cells with increased invasiveness compared with parental cells, and observed robust epithelial–mesenchymal transition (EMT) and consistently elevated TGF-β signaling in these cells. We identified long noncoding RNA activated by TGF-β (lnc-ATB) was the most remarkably upregulated lncRNA in TR SKBR-3 cells and the tissues of TR breast cancer patients. We found that lnc-ATB could promote trastuzumab resistance and invasion-metastasis cascade in breast cancer by competitively biding miR-200c, up-regulating ZEB1 and ZNF-217, and then inducing EMT. In addition, we also found that the high level of lnc-ATB was correlated with trastuzumab resistance of breast cancer patients. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose breast cancer patients to EMT and trastuzumab resistance.
PMCID: PMC4484483  PMID: 25871474
lnc-ATB; trastuzumab resistance; EMT; TGF-β; Breast cancer
16.  Laparoscopic resection of lower rectal cancer with telescopic anastomosis without abdominal incisions 
AIM: To assess laparoscopic radical resection of lower rectal cancer with telescopic anastomosis through transanal resection without abdominal incisions.
METHODS: From March 2010 to June 2014, 30 patients (14 men and 16 women, aged 36-78 years, mean age 59.8 years) underwent laparoscopic radical resection of lower rectal cancer with telescopic anastomosis through anus-preserving transanal resection. The tumors were 5-7 cm away from the anal margin in 24 cases, and 4 cm in six cases. In preoperative assessment, there were 21 cases of T1N0M0 and nine of T2N0M0. Through the middle approach, the sigmoid mesentery was freed at the root with an ultrasonic scalpel and the roots of the inferior mesenteric artery and vein were dissected, clamped and cut. Following the total mesorectal excision principle, the rectum was separated until the anorectal ring reached 3-5 cm from the distal end of the tumor. For perineal surgery, a ring incision was made 2 cm above the dentate line, and sharp dissection was performed submucosally towards the superior direction, until the plane of the levator ani muscle, to transect the rectum. The rectum and distal sigmoid colon were removed together from the anus, followed by a telescopic anastomosis between the full thickness of the proximal colon and the mucosa and submucosal tissue of the rectum.
RESULTS: For the present cohort of 30 cases, the mean operative time was 178 min, with an average of 13 positive lymph nodes detected. One case of postoperative anastomotic leak was observed, requiring temporary colostomy, which was closed and recovered 3 mo later. The postoperative pathology showed T1-T2N0M0 in 19 cases and T2N1M0 in 11 cases. Twelve months after surgery, 94.4% patients achieved anal function Kirwan grade 1, indicating that their anal function returned to normal. The patients were followed up for 1-36 mo, with an average of 23 mo. There was no local recurrence, and 17 patients survived for > 3 years (with a survival rate of 100%).
CONCLUSION: Laparoscopic radical resection of lower rectal cancer with telescopic anastomosis through transanal resection without abdominal incisions is safe and feasible.
doi:10.3748/wjg.v21.i16.4969
PMCID: PMC4408470  PMID: 25945011
Laparoscopic resection; Rectal neoplasms; Anus-preserving rectectomy; Telescopic anastomosis
17.  Evaluation of tobacco use on Chinese population through ATTOC model: a cross-sectional survey on hospitalized psychiatric patients 
Objectives: To evaluate the feasibility of Addressing Tobaccos through Organizational Change (ATTOC) intervention to Chinese psychiatric patients, and to better address tobacco use through the ATTOC intervention model in the context of China. Methods: The study was conducted in Mental Health Center of West China Hospital in 2010. A total of 100 hospitalized psychiatric patients were recruited to carry out ATTOC intervention. Subjects suffers from mental illness were diagnosed by professional psychiatrists according to the International Statistical Classification of Diseases (ICD-10) criteria. Results: The prevalence of tobacco use in hospitalized psychiatric patients were closely correlated with the type of mental illness, family smoking history, sex, age, marital status, education status, etc. However, most psychiatric patients knew little about these, and tended to ignore the importance of smoking cessation. Conclusions: The ATTOC intervention program of the U.S. may be suitable for hospitalized Chinese psychiatric patients, and it could be applied for the tobacco smoking treatment in China. However, the health effects of tobacco use still did not draw amount attentions from both the clinicians and general public. It is urgently needed to raise people’s awareness and carry out ATTOC intervention to control tobacco use, and ultimately terminate tobacco use.
PMCID: PMC4483824  PMID: 26131197
Tobacco use; ATTOC intervention; tobacco prevalence; hospitalized psychiatric patients
18.  Machine Learning in Intelligent Video and Automated Monitoring 
The Scientific World Journal  2015;2015:570145.
doi:10.1155/2015/570145
PMCID: PMC4408639  PMID: 25950020
19.  Fibrosarcoma arising from gouty tophi: report of a unique case and review of literature 
Fibrosarcoma is a malignant mesenchymal tumor. To the author’s best knowledge, no previous case of fibrosarcoma arising from gouty tophi has been reported. Here we reported the first case of fibrosarcoma arising from gouty tophi. A case of 58-year-old man was presented with a mass with ulcer and infection in the second joint of left middle finger for 2 months, with long standing gouty tophi. The tumor was biopsied and the biopsy showed complete excision of the tumor. With the pathological and immunohistochemical features considered, the diagnosis of fibrosarcoma associated with gouty tophi was made. The clinical findings, pathological characteristics and treatment were described.
PMCID: PMC4467003  PMID: 26097616
Fibrosarcoma; sarcoma; gouty tophi; gout
20.  γδ T Cells as a Major Source of IL-17 Production During Age-Dependent RPE Degeneration 
Purpose.
Chronic inflammation is a key factor contributing to the progression of age-related macular degeneration (AMD). The goals of the current study were to develop an improved mouse model with retinal pathologic features similar to those of AMD and to characterize the immunoreactive cells in the outer retina and choroid during degeneration of the retinal pigment epithelium (RPE).
Methods.
Mice deficient in nuclear erythroid 2-related factor 2 (Nrf2) at 12 months of age were fed a high-fat, cholesterol-rich diet for up to 16 weeks. Ocular phenotype was monitored by optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) in live animals, and was further validated by retinal histopathology. Immunofluorescence staining of either cryosections or RPE flat mounts was used to define immunoreactive cells. Flow cytometry analyses were further performed to define the subsets of intraocular T lymphocytes.
Results.
After 16 weeks on a high-fat (HF) diet, 58% of the eyes from Nrf2−/− mice had progression of retinal lesions. Major histocompatibility complex class II (MHC II)-positive microglia, FoxP3+ regulatory T cells (Tregs), and CD3+ IL-17-producing T cells were detected in either the retina or sub-RPE space. Flow cytometry analyses further revealed that most of the IL-17-producing cells were CD3+ CD4− TCRγδ+ cells.
Conclusions.
The results suggest that the T cell-mediated immune responses played important roles in controlling the progression of AMD-like phenotype in Nrf2-deficient mice.
γδ T lymphocytes infiltrated in degenerating RPE and produced IL-17.
doi:10.1167/iovs.14-15166
PMCID: PMC4203278  PMID: 25212781
age-related macular degeneration; IL-17; inflammation; T lymphocyte
21.  Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro 
Acta Pharmacologica Sinica  2015;36(4):517-527.
Aim:
To investigate the effects of physalin B insolated from Physalis divericata on human colon cancer cells in vitro and its anticancer mechanisms.
Methods:
Human HCT116 colon cancer cell line was tested. Cell viability and apoptosis were detected, and relevant proteins were measured using Western blot analyses. Autophagosomes were observed in stable GFP-LC3 HCT116 cells. Localization of autophagosomes and lysosomes was evaluated in GFP-LC3/RFP-LAMP1-co-transfected cells. Microtubules and F-actin microfilaments were observed with confocal microscope. Mitochondrial ROS (mito-ROS) was detected with flow cytometry in the cells stained with MitoSox dye.
Results:
Physalin B inhibited the viability of HCT116 cells with an IC50 value of 1.35 μmol/L. Treatment of the cells with physalin B (2.5–10 μmol/L) induced apoptosis and the cleavage of PARP and caspase-3. Meanwhile, physalin B treatment induced autophagosome formation, and accumulation of LC3-II and p62, but decreased Beclin 1 protein level. Marked changes of microtubules and F-actin microfilaments were observed in physalin B-treated cells, which led to the blockage of co-localization of autophagosomes and lysosomes. Physalin B treatment dose-dependently increased the phosphorylation of p38, ERK and JNK in the cells, whereas the p38 inhibitor SB202190, ERK inhibitor U0126 or JNK inhibitor SP600125 could partially reduce physalin B-induced PARP cleavage and p62 accumulation. Moreover, physalin B treatment dose-dependently increased mito-ROS production in the cells, whereas the ROS scavenger NAC could reverse physalin B-induced effects, including incomplete autophagic response, accumulation of ubiquitinated proteins, changes of microtubules and F-actin, activation of p38, ERK and JNK, as well as cell death and apoptosis.
Conclusion:
Physalin B induces mito-ROS, which not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in HCT116 cells in vitro.
doi:10.1038/aps.2014.157
PMCID: PMC4387302  PMID: 25832431
physalin B; Physalis angulata L; HCT116 colon cancer cells; autophagy; reactive oxygen species; p38 mitogen-activated protein kinases; microtubule-associated proteins; apoptosis; ubiquitins; N-acetyl-L-cysteine
22.  Partially Overlapping Primer-Based PCR for Genome Walking 
PLoS ONE  2015;10(3):e0120139.
Current genome walking methods are cumbersome to perform and can result in non-specific products. Here, we demonstrate the use of partially overlapping primer-based PCR (POP-PCR), a direct genome walking technique for the isolation of unknown flanking regions. This method exploits the partially overlapping characteristic at the 3’ ends of a set of POP primers (walking primers), which guarantees that the POP primer only anneals to the POP site of the preceding PCR product at relatively low temperatures. POP primer adaptation priming at the genomic DNA/POP site occurs only once due to one low-/reduced-stringency cycle in each nested PCR, resulting in the synthesis of a pool of single-stranded DNA molecules. Of this pool, the target single-stranded DNA is replicated to the double-stranded form bound by the specific primer and the POP primer in the subsequent high-stringency cycle due to the presence of the specific primer-binding site. The non-target single stranded DNA does not become double stranded due to the absence of a binding site for any of the primers. Therefore, the POP-PCR enriches target DNA while suppressing non-target products. We successfully used POP-PCR to retrieve flanking regions bordering the gadA locus in Lactobacillus brevis NCL912, malQ in Pichia pastoris GS115, the human aldolase A gene, and hyg in rice.
doi:10.1371/journal.pone.0120139
PMCID: PMC4374871  PMID: 25811779
23.  Efficacy of recombinant adenoviral human p53 gene in the treatment of lung cancer-mediated pleural effusion 
Oncology Letters  2015;9(5):2193-2198.
Pleural effusion induced by lung cancer exerts a negative impact on quality of life and prognosis. The aim of the present study was to evaluate the value of the recombinant adenoviral human p53 gene (rAd-p53) in the local treatment of lung cancer and its synergistic effect with chemotherapy. The present study retrospectively recruited 210 patients with lung cancer-mediated pleural effusion who had adopted a treatment strategy of platinum chemotherapy. Pleurodesis was performed via the injection of cisplatin or rAd-p53. Long-term follow-up was conducted to investigate the therapeutic effects of cisplatin and rAd-p53 administration on pleural effusion and other relevant clinical indicators. The short-term effect of pleurodesis was as follows: The efficacy rate of rAd-p53 therapy was significantly higher compared with cisplatin therapy (71.26 vs. 54.47%), and the efficacy of treatment with ≥2×1012 viral particles of rAd-p53 for pleurodesis was significantly greater than treatment with 40 mg cisplatin (P<0.05). Furthermore, efficacy analysis performed 6 and 12 months after pleurodesis indicated that the efficacy rate of rAd-p53 was significantly greater than that of cisplatin (P<0.05). A comparison of median progression-free survival (PFS) time identified a significant difference (P<0.05) between rAd-p53 and cisplatin therapy (3.3 vs. 2.7 months); however, a comparison of median overall survival time identified no significant difference (P>0.05) between rAd-p53 and cisplatin therapy (9.6 vs. 8.7 months). In addition, Cox regression analysis indicated that PFS was not affected by clinical indicators such as age, gender, prognostic staging and smoking status; however, PFS was affected by pathological subtype (adenocarcinoma or squamous carcinoma) in the rAd-p53 group. rAd-p53 administration for pleurodesis exerts long-term therapeutic effects on the local treatment of lung cancer. Thus, a combination of rAd-p53 and chemotherapy may exert a synergistic effect and reverse multidrug resistance.
doi:10.3892/ol.2015.3054
PMCID: PMC4467335  PMID: 26137039
lung cancer; malignant pleural effusion; pleurodesis
24.  Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma 
Cancer research  2014;74(6):1752-1765.
Glioblastoma (GBM) is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric di-methylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell cycle arrest, apoptosis and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Lastly, PRMT5 attenuation enhanced GBM cell survival in a mouse xenograft model of aggressive GBM. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in GBM, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.
doi:10.1158/0008-5472.CAN-13-0884
PMCID: PMC3959215  PMID: 24453002
PRMT5; glioma; arginine; methylation; epigenetics; cancer
25.  Effects of Foxp3 gene modified dendritic cells on mouse corneal allograft rejection 
Objective: To investigate the effect of Foxp3 gene modified dendritic cells (Foxp3 + DC) on allogeneic T cells proliferation and to study the effect of Foxp3 + DC on corneal allograft rejection. Methods: Lentivirus-Foxp3 was transfected into DC2.4 cells, as Foxp3 + DC cells. 42 BALB/c mice were randomly divided into: Group A (n = 6), normal group; Group B (n = 12), Group C (n = 12) and Group D (n = 12), allograft groups, were treated with normal saline, DC2.4, Foxp3 + DC by intraperitoneal injection, respectively. Results: Compared with the control group, Foxp3 protein in the Foxp3 + DC cells increased significantly (P < 0.05); the expressions of CD80 and CD86 immunophenotypes of Foxp3 + DC cells decreased significantly (P < 0.05); IL-12 secretion reduced (P < 0.05), but IL-10 secretion was promoted (P < 0.05). The average transplant survival time in Group B was (14.833 ± 1.472) d, and Group C and Group D led to a statistically significant prolongation of transplant survival to (17.667 ± 1.366, 23.000 ± 2.000) d (P < 0.05) respectively. 14 d after transplantation, as compared with Group C and D, the expressions of IFN-γ in grafts markedly increased in Group B. 14 d after transplantation, as compared with Group B, the expressions of Foxp3 mRNA, IDO mRNA in grafts decreased remarkably in Group C and D (P < 0.05); as compared with Group C, the expressions of Foxp3 mRNA, IDO mRNA in grafts decreased remarkably in Group D (P < 0.05). Conclusion: Foxp3 + DC cells reduce the expression of costimulatory factors, reduce the secretion of IL-12, promote IL-10 production and inhibit the stimulation of alloreactive T cell proliferation response capacity. Foxp3 + DC cells play important roles in inhibiting corneal allograft immune response and prolonging graft survival time.
PMCID: PMC4443132  PMID: 26064298
Foxp3; lentivirus; DC2.4; corneal transplantation; immune tolerance

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