text:
Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial
Interview with director of GCP Alliance – Europe
Experience of Computerizing Site Management Processes
For the first time the President of ASCO gave a lecture to our oncologists
Thoughts of ASCO President 2009-2010. Prof.D.Blayney.
Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
11.07.2016 Site TV	Academy, clinical trials, new treatment
Georgina V. Long, M.D., Ph.D., Daniil Stroyakovskiy, M.D., Helen Gogas, M.D., Evgeny Levchenko, M.D., Filippo de Braud, M.D., James Larkin, M.D., Claus Garbe, M.D., Ph.D., Thomas Jouary, M.D., Axel Hauschild, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., Vanna Chiarion Sileni, M.D., Celeste Lebbe, M.D., Mario Mandalà, M.D., Michael Millward, M.D., Ana Arance, M.D., Ph.D., Igor Bondarenko, M.D., Ph.D., John B.A.G. Haanen, M.D., Ph.D., Johan Hansson, M.D., Ph.D., Jochen Utikal, M.D., Ph.D., Virginia Ferraresi, M.D., Nadezhda Kovalenko, M.D., Ph.D., Peter Mohr, M.D., Volodymyr Probachai, M.D., Dirk Schadendorf, M.D., Ph.D., Paul Nathan, M.D., Caroline Robert, M.D., Antoni Ribas, M.D., Ph.D., Douglas J. DeMarini, Ph.D., Jhangir G. Irani, M.A., Michelle Casey, Ph.D., Daniele Ouellet, Ph.D., Anne-Marie Martin, Ph.D., Ngocdiep Le, M.D., Ph.D., Kiran Patel, M.D., and Keith Flaherty, M.D.
Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with BRAF V600 mutations.1,2 However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months.3,4 Most reported resistance mechanisms reactivate the MAPK pathway.5-7 In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway8-10 can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors.11-13 Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients with BRAF V600 mutation–positive metastatic melanoma, as compared with chemotherapy, and is not associated with paradoxical activation.14
The combination of BRAF and MEK inhibition, as compared with single-agent BRAF inhibition, delayed the emergence of resistance and decreased the incidence of cutaneous hyperproliferative lesions in preclinical models.12,15,16 This finding was confirmed in an unblinded, randomized, phase 2 study of a combination of dabrafenib and trametinib, as compared with dabrafenib alone, with crossover permitted at the time of disease progression for those receiving dabrafenib alone.17The median progression-free survival was 9.4 months with combination therapy versus 5.8 months with dabrafenib alone (hazard ratio for progression or death in the dabrafenib–trametinib group, 0.39; 95% confidence interval [CI], 0.25 to 0.62; P<0.001) and the corresponding response rate was 76% versus 54% (P=0.03).17 The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–trametinib group than in the dabrafenib-only group (7% vs. 19%).
We conducted a double-blind, randomized, phase 3 study without crossover to compare the combination of dabrafenib and trametinib with dabrafenib alone as first-line therapy in patients who had metastatic melanoma with BRAF V600E or V600K mutations.
Eligible patients had histologically confirmed, unresectable stage IIIC or stage IV metastatic melanoma with BRAF V600E or V600K mutations, as determined by means of an investigational-use-only polymerase-chain-reaction assay (ThxID BRAF Assay, bioMérieux) performed at a central reference laboratory. Patients were not eligible if they had previous systemic anticancer therapy (including BRAF or MEK inhibitors). Patients with brain metastases that had been definitively treated and stable for at least 12 weeks were eligible to participate. Additional inclusion and exclusion criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. Written informed consent was obtained from all study patients.
Study Design and Treatments
From May 2012 through January 2013, we screened 947 patients at 113 centers worldwide. We randomly assigned 423 of these patients, in a 1:1 ratio, to receive either a combination of oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) or oral dabrafenib (150 mg twice daily) and placebo. Patients were stratified according to the baseline lactate dehydrogenase level and BRAF genotype (Figure S1 in the Supplementary Appendix).
Study End Points
The primary end point was investigator-assessed progression-free survival, defined as the time from randomization until radiologic disease progression or death from any cause. The secondary end points were overall survival, response rate, response duration, safety, and pharmacokinetics, as defined in the Supplementary Appendix. An independent central review committee whose members were unaware of study-group assignments reviewed radiologic findings on which a sensitivity analysis of progression-free survival was based. No interim analyses were performed for efficacy or futility with respect to the primary end point.
Study Assessments
Tumor assessments were conducted according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1,18 at baseline, at week 8, every 8 weeks until week 56, and then every 12 weeks until disease progression, death, or withdrawal from the study. Patients who were eligible for continued treatment beyond progression underwent tumor assessments according to the protocol. (Eligibility criteria for this assessment are provided in the Supplementary Appendix.) All responses were confirmed on either computed tomography or magnetic resonance imaging, with scanning obtained at least 4 weeks after the first RECIST response. Adverse events were graded by the site investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0,19 throughout the study until 30 days after the discontinuation of study treatment.
Study Oversight
This study was funded by the sponsor, GlaxoSmithKline. The protocol was approved by the institutional review board or human research ethics committee at each participating center and complied with country-specific regulatory requirements. The study was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. The first and last authors and representatives of the sponsor designed the study. Data collection was performed by staff members employed at each study site and was monitored by the sponsor. The first author wrote the initial drafts of the manuscript, with support from the last author and representatives of the sponsor. All authors and sponsor representatives had full access to the study data and were involved in the data analysis. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy of the data and the fidelity of the study to the protocol, which is available at NEJM.org. No one who is not listed as an author contributed to the writing of the manuscript.
This report is based on data as of August 2013, when the prespecified number of disease progressions or deaths (whichever came first) had occurred. The study was initially designed with a power of more than 90% to detect a 41% reduction in the risk of disease progression or death (hazard ratio, 0.59) in the dabrafenib–trametinib group, as compared with the dabrafenib-only group, at a one-sided type I error rate of 0.025. The study was overenrolled by approximately 24% (423 actual enrollees vs. the target of 340). To increase the precision of the median progression-free survival estimate in the dabrafenib–trametinib group, the final analysis was planned after 193 events had occurred, which maintained the same ratio of events to patients as originally planned. As a result, the power increased from 90% to 95%. A prespecified interim analysis of overall survival was planned at the time of the analysis of progression-free survival. The stopping boundary for the interim analysis of overall survival was a two-sided alpha level of less than 0.00028. A final overall survival analysis will be conducted when 70% of the patients who underwent randomization have died or been lost to follow-up.
We used a Kaplan–Meier analysis to estimate progression-free and overall survival, and treatment comparisons were made with the use of a stratified log-rank test. Post hoc subgroup analyses were performed with the use of an unstratified log-rank test. Efficacy was determined in all patients in the intention-to-treat population; safety analyses were performed in all patients who received at least one dose of a study drug. Treatment beyond progression was defined as the receipt of a study drug more than 15 days after radiologic progression, as defined by RECIST.
Of 947 patients who were screened, 423 patients were randomly assigned to receive either dabrafenib plus trametinib (211 patients) or dabrafenib plus placebo (212 patients) (Table 1TABLE 1 Characteristics of the Patients at Baseline (Intention-to-Treat Population)., and Figure S1 in the Supplementary Appendix). The lack of a BRAF V600E or V600K mutation was the most common reason for exclusion (in 245 patients). Baseline characteristics were similar in the two study groups (Table 1). The median follow-up time was 9 months (range, 0 to 16). Details of patient status and follow-up are provided in Figure S1 in the Supplementary Appendix.
In the intention-to-treat population, the estimated median progression-free survival (the primary end point) was longer in the dabrafenib–trametinib group than in the dabrafenib-only group (9.3 months vs. 8.8 months); the hazard ratio for disease progression or death was 0.75 (95% CI, 0.57 to 0.99; P=0.03) (Figure 1AFIGURE 1 Progression-free Survival and Subgroup Analyses.). The progression-free survival benefit favored ºthe dabrafenib–trametinib group in most of the subgroups that were analyzed (Figure 1B).
In patients with an elevated lactate dehydrogenase level, the median progression-free survival was 7.1 months in the dabrafenib–trametinib group as compared with 3.8 months in the dabrafenib-only group (hazard ratio for disease progression or death, 0.64; 95% CI, 0.42 to 0.95), with 49 events in each group (64% vs. 69%) (Figure 1C). Among patients in the two study groups, there were fewer events in the subgroup with a normal lactate dehydrogenase level: 53 events (40%) in the dabrafenib–trametinib group versus 60 events (43%) in the dabrafenib-only group (hazard ratio, 0.83; 95% CI, 0.57 to 1.20) (Figure S2A in the Supplementary Appendix).
Within the first 2 months after randomization, data for 6 patients in the dabrafenib–trametinib group and 18 patients in the dabrafenib-only group were censored in the progression-free survival analysis (for details, see the Results section in the Supplementary Appendix). Of the 18 patients in the dabrafenib-only group for whom data were censored, 13 had disease progression on the basis of clinical indications (without radiologic confirmation), as determined by the investigator, or had started a new anticancer therapy. In preplanned sensitivity analyses, when clinical progression or initiation of a new anticancer therapy was considered as an event, the hazard ratio for progression and the median progression-free survival for the dabrafenib–trametinib group remained stable (i.e., the median remained the same when clinical progression was considered or decreased by 0.1 month when the initiation of a new anticancer therapy was considered). In contrast, the median progression-free survival in the dabrafenib-only group decreased by 1.2 months when clinical progression was considered and by 1.6 months when the initiation of a new anticancer therapy was considered (Table S1 in the Supplementary Appendix).
At the time of the interim survival analysis, 40 patients (19%) in the dabrafenib–trametinib group and 55 patients (26%) in the dabrafenib-only group had died (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). At 6 months, the overall survival rate was 93% in the dabrafenib–trametinib group and 85% in the dabrafenib-only group. However, the between-group difference did not cross the prespecified stopping boundary (two-sided P=0.00028). At the time of this report, neither group had reached a median overall survival (Figure 2AFIGURE 2 Overall Survival.). Patients with an elevated lactate dehydrogenase level appeared to derive a greater survival benefit from combination therapy over monotherapy, with deaths of 24 of 77 patients (31%) and 36 of 71 patients (51%), respectively. The median survival among patients with an elevated lactate dehydrogenase level receiving combination therapy was 13.7 months versus 8.9 months among those receiving dabrafenib alone (hazard ratio for death, 0.48; 95% CI, 0.29 to 0.80) (Figure 2B). In contrast, among patients with a normal lactate dehydrogenase level, deaths were reported in only 16 of 133 patients (12%) receiving combination therapy and 19 of 140 patients (14%) receiving dabrafenib alone (Figure S2B in the Supplementary Appendix).
The overall response rate as assessed by investigators was 67% (95% CI, 60 to 73) in the dabrafenib–trametinib group versus 51% (95% CI, 45 to 58) in the dabrafenib-only group (P=0.002) (Table 2TABLE 2 Disease Response, According to the Type of BRAF Mutation.). In the dabrafenib–trametinib group, 22 patients (10%) had a complete response, and 118 (56%) had a partial response. In the dabrafenib-only group, 18 (9%) had a complete response, and 90 (43%) had a partial response. The median duration of response was 9.2 months in the dabrafenib–trametinib group and 10.2 months in the dabrafenib-only group on the basis of data that were highly censored because the majority of investigator-assessed responses (60%) were still ongoing. Within each of the two study groups, the response rates were slightly lower in the BRAFV600K subgroup than in the predominant V600E subgroup (Table 2).
Other Anticancer Therapies
Fewer patients in the dabrafenib–trametinib group than in the dabrafenib-only group received a second type of anticancer therapy (43 [20%] vs. 65 [31%]) (Table S2 in the Supplementary Appendix). In contrast, more patients in the dabrafenib–trametinib group than in the dabrafenib-only group continued treatment beyond progression (41 [19%]) vs. 34 [16%]), including at the time of data cutoff (19 [46%] vs. 7 [21%]). Ipilimumab was the most common subsequent anticancer therapy in the two groups; however, fewer patients in the dabrafenib–trametinib group than in the dabrafenib-only group received ipilimumab (19 [9%] vs. 32 [15%]). A similar number of patients in the two groups received subsequent therapy with vemurafenib: 12 (6%) in the dabrafenib–trametinib group and 13 (6%) in the dabrafenib-only group. No patients received monoclonal antibodies targeting programmed death 1 and programmed death ligand 1.
Among patients who received at least one dose of a study drug, permanent discontinuations were reported in 19 of 209 patients (9%) in the dabrafenib–trametinib group and 11 of 211 patients (5%) in the dabrafenib-only group. In addition, dose reductions were required in 52 patients (25%) and 28 patients (13%), respectively, and interruption of a study drug because of adverse events occurred in 103 patients (49%) and 70 patients (33%), respectively. In both the dabrafenib–trametinib group and the dabrafenib-only group, pyrexia was the most common reason for dose interruptions (in 67 patients [32%] and 28 patients [13%]) and dose reductions (in 27 patients [13%] and 6 patients [3%]). The most common reason for permanent discontinuation was pyrexia in the dabrafenib–trametinib group (in 5 patients [2%]) and a decreased ejection fraction in the dabrafenib-only group (in 3 patients [1%]).
The most common adverse events in the two study groups were pyrexia, fatigue, nausea, headache, chills, diarrhea, arthralgia, rash, and hypertension (Table 3TABLE 3 Adverse Events.). Fewer patients in the dabrafenib–trametinib group than in the dabrafenib-only group had incident cutaneous squamous-cell carcinoma (2% vs. 9%) or cutaneous hyperkeratoses (3% vs. 32%). Papillomas, alopecia, and the hand–foot syndrome were also less common in the dabrafenib–trametinib group. However, pyrexia, hypertension, peripheral edema, and diarrhea were more common in the dabrafenib–trametinib group than in the dabrafenib-only group (proportion of patients with pyrexia, 51% vs. 28%) (Table 3, and Figure S3 in the Supplementary Appendix). There were no cases of retinal-vein occlusion. Of the 107 patients in the dabrafenib–trametinib group who had pyrexia, 67 (63%) had a second episode, and 50 (47%) had three or more episodes. The median time to the onset of the first episode of pyrexia was 4.3 weeks, and the median duration was 3 days. During an acute episode of pyrexia, 63% of patients had a dose interruption and 25% had a dose reduction, with resolution of pyrexia in 97% of the patients. Glucocorticoids were used for 3 weeks or more as prophylaxis for pyrexia in 30 patients in the dabrafenib–trametinib group after the first or second event. Pharmacokinetic analysis showed a possible association between pyrexia and exposure to the hydroxy-dabrafenib metabolite and, to a lesser extent, to dabrafenib in the two study groups. Similarly, trametinib exposure was associated with pyrexia in the combination group (see the Methods and Results sections and Figure S4 and S5 in the Supplementary Appendix).
Grade 3 or 4 adverse events occurred in 73 patients (35%) in the dabrafenib–trametinib group and 79 patients (37%) in the dabrafenib-only group. Noncutaneous cancers and new primary melanomas were uncommon (Table S3 in the Supplementary Appendix). Four deaths related to adverse events occurred in the dabrafenib–trametinib group: three from cerebral hemorrhage (two during receipt of study treatment and one 5 days after cessation) and one from pneumonia (22 days after cessation of treatment). All four events were considered by the investigator to be unrelated to study treatment. No deaths related to adverse events occurred in the dabrafenib-only group (Table S3 in the Supplementary Appendix).
In this phase 3 study, we found a significant 25% relative reduction in the risk of disease progression among patients with metastatic melanoma with BRAF V600E or V600K mutations who received first-line treatment with a combination of dabrafenib and trametinib, as compared with dabrafenib alone. The combination therapy, as compared with monotherapy, was associated with a 37% relative reduction in the risk of death at the interim survival analysis, but this result did not cross the prespecified stopping boundary. Notably, this difference in survival was observed despite the increased use of new therapies after the discontinuation of monotherapy, including therapies with a proven survival benefit (e.g., ipilimumab).20,21 The overall response rate was also significantly higher in the group receiving both dabrafenib and trametinib. Resistance to single-agent BRAF inhibition is acquired predominantly through reactivation of the MAPK pathway.5-7,22-26 Our study shows that the inhibition of the MAPK pathway at two nodes rather than one decreases the risk of progression (and therefore delays resistance) by 25%.
In a post hoc subgroup analysis, we found that patients with poorer prognostic features appeared to benefit more from a combination of dabrafenib and trametinib than did those in the overall study population. At the time of the interim survival analysis, patients with an elevated lactate dehydrogenase level who received the combination therapy, as compared with monotherapy, had a 52% relative reduction in the risk of death (hazard ratio, 0.48). Since events tend to occur earlier in patients with poorer prognostic features, longer follow-up will be required to assess the effects of combination therapy as compared with monotherapy in patients with better prognostic features, such as a normal lactate dehydrogenase level or stage M1a or M1b melanoma (i.e., only distant skin, subcutaneous, or nodal metastases or lung metastases).
Our study used a control regimen that had a proven survival benefit.2 It had a double-blind design and did not allow crossover at the time of progression. In addition, the median progression-free survival of 8.8 months in the dabrafenib-only group was longer than that in previous trials of dabrafenib and vemurafenib in which the median progression-free survival was 5.5 to 6.9 months.1-4,17,27-29 The long plateau at the median progression-free survival point in the dabrafenib-only group may account in part for its increased value in our study (Figure 1A). In addition, the preplanned sensitivity analysis showed that the median progression-free survival for dabrafenib was unstable. Data for patients who had clinical progression or received a new anticancer therapy without radiographic evidence of progression were censored (which occurred more frequently in the dabrafenib-only group than in the combination-therapy group in the first 2 months of the study). Thus, the median progression-free survival for the dabrafenib group decreased from 8.8 months to 7.6 months when clinical progression was included as an event and decreased from 8.8 months to 7.2 months when receipt of a new anticancer therapy was included.
Patients receiving the combination therapy required more dose modifications than did those receiving monotherapy. There was no significant between-group difference in the frequency of adverse events, including grade 3 and 4 toxic effects. However, the types of toxic effects differed. Hyperproliferative cutaneous events, including cutaneous squamous-cell carcinoma and other events related to paradoxical activation of the MAPK pathway, which show the oncogenic potential of BRAF inhibitors,11-13 were significantly abrogated by the addition of the MEK inhibitor trametinib.12 There were no deaths in either study group that were considered by the investigators to be related to treatment.
Pyrexia occurred more frequently in the combination group than in the monotherapy group and was the most common reason for treatment discontinuation. Although there was an apparent relationship between pyrexia and exposure to the hydroxy-dabrafenib metabolite and trametinib in this study, the cause of pyrexia remains unknown. Pyrexia has been shown to respond well to immediate temporary cessation of dabrafenib or both dabrafenib and trametinib, which were restarted once the patient was well and afebrile for at least 24 hours; prophylactic glucocorticoids may prevent recurrent episodes.30 The education of patients regarding pyrexia and the need to interrupt treatment at the first sign of this side effect is critical to ensure that the episode is not prolonged or complicated by dehydration or hypotension.
In conclusion, in our study involving previously untreated patients who had metastatic melanoma with BRAF V600E or V600EK mutations, the combination of dabrafenib and trametinib, as compared with dabrafenib alone, reduced the risk of progression by 25% and improved the response rate. At the time of the interim analysis, overall survival was longer in the combination group, but the prespecified stopping boundary was not crossed.
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Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study →
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
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Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study
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Q: Get dummies for ordinal variables and change column names automatically? I'm doing these in python, but I thought maybe there is a faster way to do this.
After doing pd.get_dummies(dataset[a column name]) for ordinal variables, I'm manually checking number of columns and putting 1, 2, 3,.. at the end of each new column names.
In python, could we write more efficient codes so that python gets dummies for ordinal variables and rename column names with numbers attached in order? (i.e. if I give g, it renames columns as g1, g2, g3 columns)
dummie_g = pd.get_dummies(d["gen"])
dummie_g.describe()
dummie_g.columns = ['g1','g2','g3']

dummie_e=pd.get_dummies(d["educ"])
dummie_e.describe()
dummie_e.columns = ['e1','e2','e3','e4']

dummie_a=pd.get_dummies(d["type"])
dummie_a.describe()
dummie_a.columns=['a1','a2','a3','a4','a5','a6']

dummie_n=pd.get_dummies(d["name"])
dummie_n.describe()
dummie_n.columns=['n1','n2']

dummie_dpt=pd.get_dummies(d["dpt"])
dummie_dpt.describe()
dummie_dpt.columns=['h1','h2','h3','h4','h5','h6','h7','h8','h9','h10','h11','h12','h13','h14','h15']

A: There is a parameter called prefix for get_dummies to add the prefix for the columns after getting dummies. You can use it like
pd.get_dummies(d["gen"],prefix='g')

An improved version of you code might be :
dfs = {}
# use dicts over repeating n varaibles.
for i,j in zip(["gen","educ","type","name","dpt"],["g","e","a","n","h"]):
    dfs['dummies_'+j] = pd.get_dummies(d[i],prefix=j)

redpajama_set_name: RedPajamaStackExchange


text:
Tag Archives: Rosalinda
comedy, drama, entertainment, humor, Philippines, television, variety show
Carla Abellana Renews Ties with GMA
March 24, 2015 ralphierceBubble Gang, Bubble Gang GMA, Carla Abellan re-signs, Carla Abellana, Carla Abellana re-signs GMA, Carla Abellana renews contract, Dennis Trillo, Geoff Eigenmann, GMA, GMA Artist Center, GMA artists, GMA Network, GMA new teleserye, GMA new teleseryes, GMA News, GMA News and Public Affairs, GMA upcoming teleserye, GMA upcoming teleseryes, Ismol Family, Ismol Family GMA, My Husband's Lover, My Husband's Lover GMA, Rosalinda, Rosalinda GMA, Ryan Agoncillo, Sunday All Stars, Sunday All-Stars GMA, Tom Rodriguez 6 Comments
A new contract with GMA and a new teleserye await Carla Abellana. (Photo credit: GMA Network)
Amid the declining population of GMA's roster of artists, there are some who stayed loyal with the network despite its declining fortunes.
One such talent was Carla Abellana, who opted to remain a Kapuso for another three years. An upcoming teleserye produced by GMA News and Public Affairs awaits her, in addition to existing roles in 'Ismol Family' and recurring appearances in 'Sunday All-Stars'.
Best known of late for her team-ups with Tom Rodriguez and Dennis Trillo in 'My Husband's Lover', Carla first earned a major role in 2009's 'Rosalinda', alongside former on-screen partner Geoff Eigenmann. While more famous for dramatic roles, she did dabble into comedy via 'Bubble Gang', and is currently part of 'Ismol Family' alongside Ryan Agoncillo.
Now GMA must hope that Carla remains a valuable asset moving forward. GMA cannot afford any losses at this point, so keeping Carla and other artists, along with improving the aspect of talent development, is a must.
entertainment, music, Philippines, reality show, television
Last Sunday Night on Philippine TV, and Upcoming Teleseryes
September 30, 2013 ralphierceABS-CBN, Andi Eigenmann, Bianca King, Carla Abellana, Cheridel Alejandrino, Dennis Trillo, Dingdong Dantes, Dugong Buhay, Elevator Girl, Galema: Anak ni Zuma, Genesis, GMA, Heart Evangelista, Jessy Mendiola, Kapamilya Gold, Klarisse de Guzman, Maghihintay Pa Rin, Magkano Ba ang Pag-Ibig, Maria la del Barrio, Maria Mercedes, Marian Rivera, MariMar, Mitoy Yonting, Muling Buksan ang Puso, My Husband's Lover, Rhian Ramos, Rosalinda, The Mega and the Songwriter, The Voice of the Philippines, Tom Rodriguez, Twitter 3 Comments
It was an eventful Sunday night on Philippine TV. ABS-CBN's 'The Voice of the Philippines' finally crowned a winner, as Mitoy Yonting won the final showdown over Klarisse de Guzman. The final showdown of 'The Voice of the Philippines' proved to be a ratings and social media hit. Over at TV5, 'The Mega and the Songwriter' also trended on Twitter, in large part to the performance of the Singing Elevator Girl Cheridel Alejandrino. And both GMA networks experienced an abrupt on-air interruption after a fire broke out at the basement of its headquarters in Quezon City, which was later put under control without any reported injuries.
Meanwhile, contrary to my prediction in a previous article, the new ABS-CBN teleserye 'Galema: Anak ni Zuma' will actually have its series debut on the Kapamilya Gold afternoon slot, replacing 'Dugong Buhay'. The series will make its debut today, and will star Andi Eigenmann in her afternoon soap debut.
Over at primetime, the Kapamilya network's highly rated teleserye 'Muling Buksan ang Puso' will finish its run this week, with its series finale scheduled for Friday, October 4. The remake of 'Maria Mercedes' will replace the former beginning October 7, and will mark the return of Jessy Mendiola to the primetime slot. 'Maria Mercedes' will be the fourth local adaptation of a Thalia-starred series, after GMA's 'MariMar', 'Rosalinda', and ABS-CBN's 'Maria la del Barrio'.
Switching over to the Kapuso side, GMA will likewise debut a new afternoon series entitled 'Magkano Ba ang Pag-Ibig', which will mark the acting return of Heart Evangelista. The new series will replace the Bianca King-starred 'Maghihintay Pa Rin' beginning today, September 30.
And finally the Kapuso network also announced that the highly rated and controversial teleserye 'My Husband's Lover' will conclude on October 11, as seen on the network teasers. The teasers also announce a new replacement for MHL, entitled 'Genesis', and will officially mark the return of Dingdong Dantes to primetime. However, Dantes will not be paired with his usual off-screen partner Marian Rivera; instead he will be paired by another returning Kapuso star in Rhian Ramos. Barring any hitches, the series debut of 'Genesis' will be on October 14.
entertainment, Philippines, television
If ABS-CBN and GMA Traded Shows…
September 21, 2013 ralphierceABS-CBN, Digimon, Dragon Ball, Eat Bulaga, GMA, GMA Network, Meteor Garden, Mr. Bean, Naruto Shippuden, Pokemon, PTV-4, Rosalinda, Slam Dunk, Spongebob Squarepants, Studio 23, TV5, YuYu Hakusho 23 Comments
Mr. Bean will return to ABS-CBN, but the character may be better off showing his comedic artistry to the Kapusos at GMA 7.
While watching a Tagalized and 'intentionally' edited episode of 'Spongebob Squarepants' on ABS-CBN, I saw a program advisory at the bottom promoting the return of the Mr. Bean series on the Kapamilya network. Ok, that's a given, because they need a program to fill in the usually off-peak early morning schedules. But Mr. Bean? You got to be kidding.
Mr. Bean, as I know, has been the property of ABS-CBN for a decade now. It began airing on Studio 23 on Saturday nights, with the animated shows in the morning. Then it was moved to the main Channel 2, and aired sporadically on weekday mornings, regardless of the live or animated version. Before that it used to air on PTV 4 and ABC (now TV5).
I always don't like the way ABS-CBN aired Mr. Bean. They tend to edit some skits and combine one from a particular episode with another from a different episode. Worse, they only allotted 15 minutes of airtime, as opposed to the 30 minutes in a full episode. The airing of Mr. Bean on the Kapamilya network is both an insult and a disgrace to loyal Mr. Bean faithful.
So what if ABS-CBN and GMA traded their morning programs for each other? It has been well-documented that a few shows would move from one station to another in order to either give way to other programs or to purchase airing rights for future production. I have seen several programs air on both Kapuso and Kapamilya stations; programs such as 'Eat Bulaga', 'Meteor Garden' and 'Rosalinda' come to mind. But if I were the boss of either networks, I would suggest that ABS-CBN must give up Mr. Bean and send it to GMA, and in return GMA will trade rights for the animes such as 'Pokemon', 'Dragon Ball', 'Yu Yu Hakusho' (Ghost Fighter), 'Slam Dunk' and others in exchange for ABS-CBN's 'Digimon', 'Naruto Shippuden' and others. Of course, I would like to see a different morning look in both the Kapuso and Kapamilya stations.
In the meantime, ABS-CBN and GMA will continue to air 'boring' programming during the off-peak morning hours. Unless they make up their minds and trade their programs for each other, weekday mornings will continue to remain that way: 'boring'.

redpajama_set_name: RedPajamaCommonCrawl


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Pixar hits rare dud with 'The Good Dinosaur'
Dennis Anderson Staff Writer
Strange and disconnected, The Good Dinosaur masks the limits of its narrative within a beautiful landscape. Finding itself locked into the middle ground of the Pixar canon, The Good Dinosaur struggles to combine the childlike fantastical with enough adults elements to craft a film that connects all audiences. As a children's feature, it works, but there's always an underlying feeling that it's attempting to be more, as if there's a message just waiting to burst forth. The Good Dinosaur just never finds its voice.
A sight for the eyes, the film is almost worth a view just for the visual splendors. The world of The Good Dinosaur seems plucked out of every Rockwell painting, with glowering mountain ranges and auburn swept fields. There's certainly an American aspect to the film, a mid-western inflection that affects every dinosaur, with occupations reminiscent of an old western. With the long-necked protagonist hailing from a family of rural farmers, and teaming up with Tyrannosaurus cowboys, The Good Dinosaur familiarizes its world.
It is disappointing then, how much the narrative lets down the surrounding world. Following the plight of the runt-sized Arlo as he loses his family, the film is set up like many animated features before it. That itself is inherently an issue for the film. Invoking images of better films like The Lion King and The Land Before Time, The Good Dinosaur feels so familiar, like something we've seen before. The adventure of the small Apatosaurus attempting to reach his family feels devoid of dramatic tension, as any feeling of tension that comes up within the film, and there are several potential ones, is immediately set upon by good feelings and hope. Arlo himself is a less than convincing lead, with his motivations and demeanor a strange mixture of the Cowardly Lion and Littlefoot. The inclusion of the dog-like human boy Spot is a welcome change from the neurotic Arlo, but even his moments feel like stepping stones along the plot, instead of the grasping moments.
It may seem as if the film itself is a terrible one, and it isn't, it's just disappointing. With a growing catalogue of great films, the release of Inside Out earlier this year being the latest one, Pixar has made itself known as the animated studio that doesn't fail, which seems to understand and cultivate original film ideas. The idea for The Good Dinosaur seemed solid enough, the execution just didn't come through. Devoid of laughs and intriguing dialogue, the film pandered to sight gags and regional accent jokes to its overall detriment. The idea of Tyrannosaurus cowboys, and Velociraptor cattle rustlers jostling seem more like a mad lib instead of an actual film idea, and it showed. There's a certain affable weirdness to Pixar films, as they consistently delve into the valley of the uncanny, but within The Good Dinosaur the weirdness felt just that: weird. A hallucinogenic scene involving Arlo and Spot and a couple fermenting apples feel out of place, and less like an actual attempt at wayward humor, and more as a grasp to placate the millennial generation.
As a children's film, The Good Dinosaur is run of the mill, but it falters when it attempts to become anything more than just that. An interesting idea without interesting characters becomes uninteresting, and at the end of the day, not even the savants at Pixar can save The Good Dinosaur from itself.


There are long delays on the M62 motorway in Leeds following the closure of two lanes.
Lanes one and two are currently out of use on the westbound carriageway between junction 29 for the M1 and junction 28 for the A650 due to a broken down vehicle.
Traffic is queuing with delays of around 30 minutes being reported.
An earlier accident on Oxford Place in Leeds city centre has now been cleared.


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Q: Laravel installer installation failed When I try this to install Laravel:
composer global require "laravel/installer"

i will get this error:
Installation failed, deleting ./composer.json.
The following exception is caused by a lack of memory and not having swap     configured
Check https://getcomposer.org/doc/articles/troubleshooting.md#proc-open-fork-failed-errors for details

The following exception is caused by a lack of memory and not having swap configured
Check https://getcomposer.org/doc/articles/troubleshooting.md#proc-open-fork-failed-errors for details

I guess i fixed it with these commands. I this the right way? Does anyone knows?
sudo dd if=/dev/zero of=/swapfile bs=1024 count=512k
mkswap /swapfile
swapon /swapfile

I'm using Digitalocean and using 512 MB / 20 GB Disk / Ubuntu 16.04.3 x64

A: Rather global require use composer create-project --prefer-dist laravel/laravel project

or create a composer.json file. put the content in it, then run composer install because composer install takes less memory then composer update.
Hope this helps.


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Pearl in the Morning
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Chinese teacher sentenced to death for poisoning students
Leave a Comment	/ International News, News / By admin
A Chinese Nursery teacher Ms. Wang Yun, has been sentenced to death for poisoning 25 children and killing one more. she is reported to have added Sodium Nitrate to the children's morning porridge which caused 23 of them to faint and throw up. The court in Jiaozuo found her guilty and sentenced her to death.
Ms. Wang has in other incidents poisoned other people including her husband who suffered minor injuries. She was also found guilty of poisoning another teacher's student's porridge after arguments concerning student management issues. There are no immediate details about the child who succumbed to the poison.
The Global Times Newspaper's report on Ms. Wang reads she is "despicable and vicious, and the consequences of her crimes were extremely serious, and she deserves to be severely punished." Sodium Nitrate is used in curing meat and is highly harmful to human health when consumed in large amounts
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Presentations for
Myths & Mysteries of the Rocky Mountain West
Sat., June 11, 2016
East Library
5550 N. Union Blvd.
click here to make reservations for this free event
Dennis Daily—Lone Eagle: The White Sioux
In 1956, Colorado Springs resident Floyd Shuster Maine published a book titled Lone Eagle: The White Sioux. The autobiography, a supposed true account, outlined a fascinating tale of two long-separated brothers, one raised in New Jersey, the other orphaned as a baby and raised by Oglala Sioux Chief Big Elk in South Dakota. When the two meet as adults, previously unaware of each other's existence, Lone Eagle's story unfolds. Who were these two men and could their story be true?
Beau Driver—"A Well Located Chautauqua": The Garden of the Gods Summer School and Assembly of 1902
This presentation examines the Garden of the Gods Summer School and Chautauqua of 1902. As the first program of this type offered in Colorado Springs, it attracted thousands of students and notable professors, politicians, and instructors. By reviewing the reports on the assembly, the lectures, events, and the people who participated in this momentous event in Colorado Springs history, Driver will illuminate how the administrators of Colorado Springs attempted to build an image of the town as a cosmopolitan oasis on the frontier and how the ideas of the Chautauqua presenters helped to create a narrative on the meaning of the United States and of the West in the minds of the attendees.
Susan Fletcher—Myths & Mysteries in the Museum
This presentation will focus on the untruths/half-truths that well-meaning docents and tour guides sometimes accidentally pass along to the public, leading to some common misperceptions about Colorado history. Fletcher will offer the audience a glimpse into the museum world, including how docents and guides are trained, the ways in which false information gets perpetuated, and how historical research can clear up myths. The presentation will also deal with mysteries at museums including un-attributable documents found in archives, museum collections with unclear provenance, and other matters that puzzle staff.
Joyce B. Lohse—Baby Doe Tabor: A Matchless Spirit
Myths and ghost stories surround Elizabeth "Baby Doe" Tabor, the Matchless Silver Queen of Leadville. Lohse will share information gathered and adventures experienced while writing and researching her award-winning biography, Baby Doe Tabor: Matchless Silver Queen. During her journey, Lohse's quest for truth was occasionally interrupted by spiritual coincidences which were difficult to ignore. Ms. Lohse will recount those tales, which add a new and different dimension to the colorful story of Baby Doe Tabor.
Richard Marold--Winfield Scott Stratton: How Many Marriages?
Winfield Scott Stratton lived in the Pikes Peak region from 1872 until 1902. He married Zura Stewart on July 26, 1876, and separated from her in November 1876. The Strattons legally divorced on January 25, 1879. Later, Stratton discovered gold on July 4, 1891, in the Cripple Creek/Victor gold fields. There is no record of him ever entering another marriage, but after he died on September 14, 1902, and his will was read, at least 13 different woman filed suits against his estate each claiming him as her husband. How many marriages did he really have?
Doris McCraw—Doc Susie & Hollywood: Myths of 19th Century Women Doctors in Colorado
The story of Dr. Susan Anderson, in the book Doc Susie, while a worthwhile biography, can lead one to believe that her story is the story of all women doctors of her time. With the addition of the popular television show, Dr. Quinn Medicine Woman, the misconception of the western female physician experience grew to become myth. Colorado attracted many pioneering female physicians, so that by the 1900s and the discovery of gold in Cripple Creek, the state had become home to numerous women doctors whose presence and actual experiences left a legacy that remains today.
Michael L. Olsen—"Not a pepper nor an onion": The Myth of the Bloodless Conquest of New Mexico in 1846
For more than a century, from the 1850s to the 1960s, the myth persisted that the American conquest of New Mexico was "bloodless," that no resistance was met, and that the population of New Mexico welcomed the conquerors. Yet, within a few months of the arrival of the U.S. Army of the West in August 1846, more than 300 Mexican citizens and Taos Indians had lost their lives opposing the American takeover. Why was this myth perpetuated and why did it endure? What consequences are faced today in multicultural relations in the Southwest because of the myth? This presentation will explore the historical events and ask these questions.
Steve Ruskin—Killer Rats & Missing Links: An Analysis of Two Regional Hoaxes that had National Impact
In the first two years of Colorado's statehood (1876–1877), two regional hoaxes become national (even international) phenomena: the supposed death of a young girl on Pikes Peak by swarms of killer rats (invented by the signal station sergeant John O'Keefe), and the discovery of a purported "missing link," nicknamed the "Solid Muldoon," near Pueblo (invented by the famous huckster George Hull). This presentation will revisit these two hoaxes and discuss why such hoaxes were so easily perpetrated.
Pamela Owens and Bernard (Beau) Schriever—Breaking from the Hurd: Toward a Real History of the Place Known as Bents' First Stockade
In 1960, Charles Wesley Hurd released his self-published book entitled Bents' Stockade: Hidden in the Hills, in which he claimed to have identified the remains of the first trading post established by the Bent brothers, along Turkey Creek on what is now Fort Carson. Although the historical documentation was available at the time to refute Hurd's claim, and one archaeologist did so, the myth has been perpetuated to the present among the public. In part, this situation is due to the lack of communication between archaeologists and the public regarding the site. However, it is also likely due to the emotional strength of Hurd's story, which makes the reader want to unquestionably believe him. Regardless of the reason for the myth's persistence, the real history of the place that Hurd mistakenly identified as Bents' first stockade is fascinating in its own right and deserves to be rediscovered and told.
John Stansfield—Weathering the Weird & Wild: Tall Tales & True of Army Life at the Pikes Peak Summit
The U.S. Army Signal Corps maintained a weather and scientific observation station on top of Pikes Peak from 1873 to 1888. Reports telegraphed from the station to an expectant outside world presented images of extreme meteorological, electrical, and natural phenomena. The messages often suggest the many daily hardships of living at 14,000 feet. And some describe the quite unnatural natural history which emanated from the overcharged imaginations of summit residents. This presentation will explore some of the discoveries, struggles, wonder, and humor of those who staffed the Pikes Peak signal station.
Katherine Scott Sturdevant—Manifest Destiny Comes to the Great American Desert: How Expansionist Legends Fared in the Rocky Mountain West
From the earliest documented accounts of explorers in the Great Plains and Rocky Mountain West, people applied theories and expectations to the region that grew quickly to legendary proportions. Some people did so from habitual prejudices and fears, others from excitement, patriotism, and faith. Many folks leapt to the legendary from unabashed boosterism, evangelizing for their points of view, or for their business self-interests. Frontier legends are inherently colorful and titillating. They also have caused fools to rush in where angels fear to tread, and to rationalize cruel destruction. Using the ideas and actions from the original words of regional people, we can see both the human comedy and tragedy of living by the legends.
Rick Sturdevant—UFO Sightings Across the Rocky Mountain West: A Historical, Non-Hysterical Survey
For countless decades, people around the world have reported seeing unidentified flying objects (UFOs). Concentrating on reports from the Rocky Mountain West, this presentation outlines some of the most familiar, and a few lesser known UFO sightings. It weighs UFO sightings and media reactions to them against a number of official U.S. government studies, and it assesses the popular durability of UFOs as myth or mystery.
Eric Swab—Henry Law's Lanter City: The Next Cripple Creek?
"Landren" is an unexplained label on Robert Ormes' Pikes Peak Atlas. In "History and Mysteries of Catamount Ranch Open Space," both "Lander City" and "Lanter City" are mentioned as mysteries to be solved. What was this many-named place? This presentation will expose the story of Lanter City and explore its historical context.
Tamilla K. Wright—Remember Who You Are
A Colorado native's journey to dispel family lore uncovers new discoveries about Colorado's unbelievably twisted past. A few local ghost stories have led to identifying long lost historical facts that might have been overlooked. Wright also shares tricks on how you too can uncover your past. Just be prepared when you learn the good, the bad, and the fabulously scandalous that make up your genealogy.
Nethery Wylie—How do I look?: Western Women in Photographs
How true are the often-made generalizations about women in the early 20th century American West? Did these ladies conform to the stereotypes of the demure late Victorian? Of the strident suffragette? Of the wanton flapper? This presentation examines historic photographs for evidence of what Western women were actually wearing and doing in the early 1900s. How women look, how they dress and carry themselves is a cultural obsession of the present day and of times past. Our contemporary picture of the past is often influenced by stereotypes, such as the patriarchal father with his modest daughter, or its' opposite, uncontrolled women misbehaving in public. Visual examples of a ranch girl in long skirt and bonnet or flappers at a night club are easily available. But what else did the camera witness?
Click here to go to the 2016 symposium schedule.
Click here to go to the 2016 symposium presenters' biographies.


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Expression of tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 in patients with polymyositis and dermatomyositis
Qing-Lin Peng1,2,
Xiao-Ming Shu1,
Xiao-Lan Tian1,
Xin Lu1 &
Guo-Chun Wang1,2
The aim of this study was to investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in patients with polymyositis (PM) and dermatomyositis (DM), and their relation to clinical manifestations.
Serum levels of TWEAK were detected in 98 PM/DM patients and 37 healthy controls by using the ELISA method. Total RNA isolated from fresh-frozen muscle tissue samples of 36 PM/DM patients and 10 healthy controls were used for analyzing the mRNA levels of TWEAK and Fn14 by quantitative reverse transcription polymerase chain reaction (RT-PCR). Immunofluorescence staining of TWEAK and Fn14 was conducted on muscle biopsy specimens from 23 PM/DM patients and seven healthy controls.
Serum levels of TWEAK were significantly decreased in the PM/DM patients compared to those in the healthy controls (P < 0.001), and serum TWEAK levels negatively correlated with serum CD163 levels in PM/DM patients (r = -0.49, P < 0.001). The expression of Fn14 mRNA was significantly increased in the muscle tissue of PM/DM patients than in the muscle tissue of healthy controls (P < 0.01), whereas the expression of TWEAK mRNA in PM/DM patients was not statistically different from that of the healthy controls (P > 0.05). Fn14 mRNA levels in muscle tissue positively correlated with muscle disease activity (r = 0.512, P < 0.01). Patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than patients without oropharyngeal dysphagia (P < 0.05). The results of immunofluorescence staining showed that 19 out of 23 PM/DM patients were TWEAK-positive, and 20 out of 23 PM/DM patients were Fn14-positive. No detectable expressions of TWEAK or Fn14 were observed in the healthy controls.
TWEAK-Fn14 axis may be involved in the pathogenesis of PM/DM. Further understanding of TWEAK-Fn14 function in PM/DM may help to define therapeutic targets for PM/DM.
Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of muscle disorders characterized by symmetrical proximal muscle weakness, decreased muscle endurance, and inflammatory infiltrates in skeletal muscle tissue [1, 2]. Polymyositis (PM) and dermatomyositis (DM) are two common subsets of IIM. Although the pathological mechanism of IIM remains unclear, recent studies suggest that an interplay between adaptive immune, innate immune, and nonimmune mechanisms may be responsible for the damage and dysfunction that occur in myopathic muscle tissue [3]. Multiple players - such as adaptive immune cells [4], cytokines and chemokines [5–7] - may be involved in the pathogenesis of IIM.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a recently identified pro-inflammatory cytokine belonging to the TNF superfamily [8]. TWEAK has emerged as a multifunctional cytokine that regulates multiple cellular responses, including pro-inflammatory activity; angiogenesis; and cell proliferation, differentiation, migration and apoptosis [9]. The only known signaling receptor for TWEAK is fibroblast growth factor-inducible 14 (Fn14), which was first recognized by differential display technique [10]. TWEAK exerts pleiotropic functions through binding to Fn14 and activating downstream signaling pathways. Fn14 is a type I transmembrane protein and is highly inducible by various growth factors, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Fn14 is predominantly expressed on the surface of epithelial cells, endothelial cells and other non-hematopoietic cells [9, 11].
TWEAK was found to activate nuclear factor-кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways and to reduce MyoD levels in cultured myoblasts [12, 13], thereby inducing the proliferation of myoblasts and inhibiting their differentiation into myotubes [13]. In addition, several studies have demonstrated that the TWEAK-Fn14 axis plays a crucial role in muscle atrophy [14–16]. According to the findings of Bhatnagar et al., TWEAK causes myotube atrophy by stimulating the activity of the ubiquitin-proteasome system, autophagy and caspases [15]. Coincidentally, Alger et al. reported the expression of autophagic genes (beclin and LC3) at the protein level in PM/DM muscle biopsy specimens but not in healthy controls, suggesting the potential role of autophagy in mediating muscle fiber death in myositis [17]. Considering the role of TWEAK in stimulating autophagy and impairing myogenesis, we hypothesized that the TWEAK-Fn14 axis may be involved in the pathomechanism of PM/DM and set out to study whether TWEAK-Fn14 participates in the pathogenesis of PM/DM. Additionally, increased levels of TWEAK were found in many types of autoimmune diseases, such as rheumatoid arthritis [18], systemic sclerosis [19], and systemic lupus erythematosus [20], suggesting a crucial role of TWEAK in autoimmune disorder. However, information about TWEAK-Fn14 expression in PM and DM is limited.
Therefore, in order to further explore the role of TWEAK in the pathogenesis of PM/DM, we investigated the levels of circulating TWEAK in sera and the expression of TWEAK and Fn14 in the muscle tissues of patients with PM/DM at the mRNA and protein levels.
From the inpatients and outpatients who visited China-Japan Friendship Hospital between 2009 and 2012, 98 patients with PM/DM were recruited for this study. Their diagnoses of PM/DM were based on the Bohan and Peter criteria [21]. Additionally, 37 healthy, age-matched and sex-matched volunteers were selected to be the healthy control group during the same time period. Muscle tissues from 10 trauma patients without muscle disease were used as normal controls for examination of TWEAK and Fn14 in muscle tissue. For each individual patient, serum sampling and disease activity evaluation were done at the same time. For patients who carried out muscle biopsy in our department, muscle biopsy was also done at the time of serum sampling. This study was performed with the approval of the Human Ethics Board of China-Japan Friendship Hospital (Beijing, China). Written informed consent was obtained from all participating individuals.
Measurement of serum TWEAK levels and serum CD163 levels
Fresh venous blood samples were centrifuged shortly after clot formation, and serum samples were collected. All samples were stored at -70°C before use. TWEAK was detected in the sera of 98 PM/DM patients and 37 healthy controls using a commercially available ELISA kit (Bender MedSystems, Vienna, Austria). The assays were performed according to the manufacturer's protocol. Briefly, 100 μl distilled water were added to all standard wells, blank wells and sample wells, then 50 μl of each sample, in duplicate, were added to the designated wells. After incubating at room temperature for 3 hours, the plates were washed and incubated with 100 μl of 3,3′,5,5′-tetramethylbenzidine (TMB) substrate solution. About 10 minutes later, stop solution was added, and absorbance was measured using the ELISA reader at 450 nm with 630 nm as the reference wavelength. A standard curve for each assay was generated, and serum TWEAK concentration was calculated. The assays for each sample were performed three times.
Serum CD163 levels were measured by using a quantitative ELISA kit (R&D Systems, Minneapolis, MN, USA). The assays were performed according to the manufacturer's protocol. Each sample was measured three times.
Assessment of disease activity
Disease activity was measured by the 2005 myositis disease activity assessment tool (MDAAT) established by the International Myositis Assessment and Clinical Studies (IMACS) group [22], which consists of the myositis disease activity assessment visual analog scales (MYOACT) and the myosits intention-to-treat index (MITAX). In the previous studies, our data showed that the MYOACT could be used to reliably evaluate disease activity in Chinese patients with PM/DM [23]. Therefore, we used MYOACT to evaluate the disease activity of PM/DM patients following the guidelines for physician scoring of disease activity.
Real time RT-PCR
Total RNA was isolated from fresh-frozen muscle tissue using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol. Two μg of total RNA was reverse transcribed using the GoTaq® 2-Step RT-qPCR system (Promega, Madison, WI, USA) according to the manufacturer's protocol. Fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed using the ABI PRISM 7500 system (Applied Biosystems, Foster City, USA) according to standard methods. The following primers were used for amplifying TWEAK, Fn14 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH): TWEAK, forward: 5′-CCCTGCGCTGCCTGGAGGAA-3′, reverse: 5′-AGACCAGGGCCCCTCAGTGA-3′; Fn14, forward: 5′-CCAAGCTCCTCCAACCACAA-3′, reverse: 5′-TGGGGCCTAGTGTCAAGTCT-3′; GAPDH forward: 5′-ATCACCATCTTC CAGGAGCGA-3′, reverse: 5′- CCTTCTCCATGGTGGTGAAGAC-3′. Real time RT-PCR for TWEAK, Fn14 and GAPDH was conducted in triplicate for each sample. The GAPDH gene was used as an internal control: 2−Δ CT was used to compute the expression value of target genes.
Hematoxylin and eosin staining of muscle sections
H&E staining was applied on serial cryostat muscle biopsy sections according to the following steps. The muscle sections were stained with Harris Hematoxylin (Sigma-Aldrich, St Louis, MO, USA) for 5 minutes. After rinsing in running tap water for 20 minutes, the muscle sections were immersed in working eosin solution for 2 minutes. At last, the muscle sections underwent the dehydration of gradient ethanol, the transparency of dimethylbenzene, and then were mounted with Canada balsam (Sigma-Aldrich).
Immunofluorescence staining of muscle sections
8-μm-thick unfixed cryostat muscle sections were collected from diagnostic muscle biopsies. Anti-human TWEAK polyclonal antibodies (R&D systems) and anti-human Fn14 monoclonal antibodies (R&D systems) were used as primary antibodies for detecting TWEAK and Fn14 at a working concentration of 15 μg/ml. Rhodamine-conjugated anti-goat IgG (Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used as a secondary antibody. In summary, immunofluorescence staining was conducted according to the following steps: muscle sections were fixed with pre-cooled acetone at -20°C for 30 minutes and then rinsed four times in phosphate-buffered solution. Then, the tissue sections were blocked in 10% normal serum with 1% BSA in tris-buffered saline (TBS) for 2 hours at room temperature. After draining for a few seconds, primary antibodies diluted in TBS were applied to the tissue sections. After incubating overnight at 4°C, the tissue sections were treated with rhodamine-conjugated anti-goat IgG. This was followed by washing, mounting on glass slides, and visualization of fluorescence with an Olympus fluorescent microscope. An isotype-matched, non-binding antibody (normal goat IgG: sc-2028, Santa Cruz Biotechnology) was used as a negative control for the primary antibody. Two sections per tissue sample were used for immunofluorescence staining analysis.
When double staining was carried out, anti-human TWEAK goat polyclonal antibodies (R&D systems) and anti-human Fn14 rabbit monoclonal antibodies (Abcam, Cambridge, UK) were used as primary antibodies for detecting TWEAK and Fn14, and Rhodamine-conjugated donkey anti-goat IgG and FITC-conjugated donkey anti-rabbit IgG (both from Santa Cruz Biotechnology) were used as secondary antibodies.
Statistical analysis was performed using GraphPad Prism V.4.03 (GraphPad Software, San Diego, USA) and SPSS V.16.0 (SPSS, Chicago, USA). Quantitative variables were described as mean ± SD. Nonparametric distribution data were expressed as median value and IQR, and the data of unpaired samples were analyzed using the Mann-Whitney U-test. Spearman's correlation analysis was used to test for correlation. The Wilcoxon signed rank test was used on paired data when appropriate. A P-value equal to or less than 0.05 was considered statistically significant.
Clinical characteristics of PM/DM patients
The clinical features presented by the 98 patients who were recruited for this study are summarized in Table 1. According to criteria established by Bohan and Peter [21], 41 patients were diagnosed with PM, and the other 57 patients were diagnosed with DM. The mean age of these patients at onset of PM/DM was 50.6 years. There were more females than males in the cohort. The mean duration of disease was 5.3 years (range from 1.3 to 28.0 years). Twenty patients were examined as anti-Jo-1 antibody-positive at the time of blood sampling for the present study.
Table 1 Demographic and clinical features of PM/DM patients and healthy controls
In our cohort, 41 patients were newly diagnosed in our department, while the other 57 patients had been diagnosed with PM/DM and received different treatments before they were referred to our hospitial. The treatments received by the patients in our cohort varied according to the severity of their disease. All patients received corticosteroid at doses between 0.5 mg/kg and 1 mg/kg as part of their initial therapy after their diagnosis of PM/DM. Meanwhile, about 80% of our patients (78 out of 98) also received at least one or more immunosuppressants, among which were methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulin, hydroxychloroquine and mycophenolate mofetil.
Lower serum levels of TWEAK in patients with PM/DM
Serum levels of TWEAK were measured in 98 patients with PM/DM. The ELISA kit used in this study can detect all circulating TWEAK in sera. We found that the median value of serum TWEAK concentration in PM/DM patients was 442 pg/ml (range 81 to 1385 pg/ml), while the median value of that in healthy controls was 516 pg/ml (range 282 to 797 pg/ml). Therefore, serum levels of TWEAK were significantly lower in PM/DM patients compared to that in healthy controls (P <0.001). In addition, serum levels of TWEAK showed no statistical difference between PM and DM patients (P >0.05), as shown in Figure 1A. Among the 98 PM/DM patients in our cohort, 41 patients were newly diagnosed therefore the serum samples of these patients were collected before they received treatment. The other 57 patients were referred to our department, and they had received corticosteroids and other immunosuppressive treatment before we collected serum samples from them. However, we did not find a significant difference in serum TWEAK levels between these two groups of PM/DM patients (P >0.05), as shown in Figure 1B.
Serum levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in patients with polymyositis (PM)/dermatomyositis (DM) and in healthy controls. Serum TWEAK levels were determined by a specific ELISA. TWEAK levels in healthy subjects were compared to patienta with PM or DM (A). There was no statistical difference in serum TWEAK levels between patients previously untreated and patients who received treatments (B). No significant differences were observed when TWEAK levels were compared in patients with PM/DM sub-grouped based on antinuclear antibody (ANA) positivity (C), Jo-1 positivity (D), presence of interstitial lung disease (ILD) (E) and presence of oropharyngeal dysphagia (F). Correlation of serum levels of TWEAK with myositis disease activity assessment visual analog scales (MYOACT) global disease activity (G) and MYOACT muscle disease activity (H) were analyzed. Twelve newly diagnosed PM/DM patients had significantly decreased MYOACT global disease scores after treatment (I), however, no significant difference was observed in the patients' serum TWEAK levels before and after treatment (J). Serum CD163 levels were determined by a quantitative ELISA. Serum CD163 levels were significantly higher in PM/DM patients compared to healthy controls (K), and serum CD163 levels were found to be negatively correlated with serum TWEAK levels in PM/DM patients (L). The data for unpaired samples were analyzed by using the Mann-Whitney U-test. Spearman's correlation analysis was used to test for correlation. The Wilcoxon signed rank test was used on paired data. Horizontal bars indicate median levels.
We analyzed the correlation between serum TWEAK levels and clinical parameters. However, no significant differences were observed when TWEAK levels were compared in patients with PM/DM sub-grouped based on ANA positivity (Figure 1C), Jo-1 positivity (Figure 1D), presence of interstitial lung disease (ILD) (Figure 1E) and presence of oropharyngeal dysphagia (Figure 1F). What is more, no correlation was found between serum TWEAK levels and MYOACT global disease activity scores in 42 PM/DM patients (Figure 1G) or MYOACT muscle disease activity (Figure 1H). In our study cohort, 12 patients were newly diagnosed, and their serum samples before and after treatment were collected. After treatment, all the 12 patients were considered as in remission stage and their MYOACT global disease scores were significantly decreased (P <0.01), as shown in Figure 1I. However, by applying the Wilcoxon signed rank test, no significant difference was observed in the patients' serum TWEAK levels before and after treatment (P >0.05), as shown in Figure 1J.
As some studies have revealed that CD163 expressed by monocytes could act as a TWEAK scavenger in pathological conditions [24], we detected the serum levels of CD163 in PM/DM patients and healthy controls. Interestingly, we found that serum CD163 levels were significantly higher in PM/DM patients (median value/IQR 770.0 ng/ml, range 212.6 to 2033.1 ng/ml) compared to healthy controls (median value/IQR 544.0 ng/ml, range 313.0 to 859.8 ng/ml) (P <0.01) (Figure 1K), and serum CD163 levels were found to be negatively correlated (r = −0.49, P <0.001) with serum TWEAK levels in PM/DM patients (Figure 1L).
Increased expression of Fn14 mRNA in muscle tissue of patients with PM/DM
The expression of TWEAK and Fn14 mRNA in the muscle tissue of 17 PM, 19 DM patients and of 10 healthy controls was analyzed by real time RT-PCR. The diagnoses of the 36 PM/DM patients were confirmed by pathological diagnoses of muscle biopsies. The expression of TWEAK mRNA in the muscle tissue of patients with PM/DM was not significantly different from that of the healthy controls (P >0.05) (Figure 2A). However, the expression of Fn14 mRNA was significantly higher in the muscle tissue of PM/DM patients than in the healthy controls (P <0.01) (Figure 2B). The Fn14 mRNA levels showed no significant difference between PM and DM patients (P >0.05) (Figure 2B). Interestingly, we found that patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than the patients without oropharyngeal dysphagia (Figure 2C). In addition, the Fn14 mRNA levels correlated with MYOACT muscle disease activity scores (r = 0.512, P <0.01), but did not correlate with MYOACT global disease activity score (P >0.05), as shown in Figure 2D and Figure 2E respectively.
Comparison of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and Fn14 mRNA levels of polymyositis (PM)/dermatomyositis (DM) and of healthy controls. Total RNA was isolated from fresh-frozen muscle tissue using TRIzol reagent, and fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed. The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene was used as an internal control. 2−Δ CT was used to compute the expression values of the target genes. (A) TWEAK mRNA levels in muscle tissue of PM, DM and healthy controls. (B) Fn14 mRNA levels in muscle tissue of PM, DM and healthy controls. (C) Fn14 mRNA levels were compared in PM/DM patients sub-grouped based on the presence of oropharyngeal dysphagia. (D) Correlation of Fn14 mRNA levels with myositis disease activity assessment visual analog scales (MYOACT) muscle disease activity scores. (E) Correlation of Fn14 mRNA levels with MYOACT global disease activity scores. The data of unpaired samples were analyzed by using the Mann-Whitney U-test. Spearman's correlation analysis was used to test for correlations. Horizontal bars indicate median levels.
High expression of TWEAK and Fn14 protein in PM/DM muscle biopsies
We analyzed the expressions of TWEAK and Fn14 in the muscle biopsies of 13 patients with DM, 10 patients with PM, and 7 healthy controls using immunofluorescence staining. The diagnoses of the 23 PM/DM patients received pathological confirmation. As shown in Table 2, strong expressions of TWEAK were observed in 8 of the 10 PM patients and in 11 of the 13 DM patients; none of the healthy controls showed obvious expression of TWEAK in muscle biopsies. Similarly, the results of immunofluorescence staining showed remarkable expression of Fn14 in 8 of the 10 PM patients and in 12 of the 13 DM patients; there was no significant expression of Fn14 in any of the healthy controls. Additionally, all patients who were Fn14-negative also showed no detectable TWEAK expression. However, the muscle biopsy of one DM patient stained positive for Fn14 but stained negative for TWEAK. Figure 3A and Figure 3B shows representative results of immunofluorescence staining of the muscle biopsies. Muscle biopsies from the healthy controls showed no significant TWEAK or Fn14 expression. And no obvious immunofluorescence signal was observed in PM/DM muscle biopsies staining with isotype control antibody.
Table 2 PM/DM patients with positive immunofluorescence staining for TWEAK and Fn14
Expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and Fn14 in patients with polymyositis (PM)/dermatomyositis (DM) and in healthy controls. (A) Muscle biopsies from patients with PM/DM showed significantly higher levels of the TWEAK protein compared to those of healthy controls. Anti-human TWEAK polyclonal antibodies were used as the primary antibody for detection at a working concentration of 15 μg/ml. Rhodamine-conjugated anti-goat IgG was used as a second antibody. (B) In PM/DM biopsies, expression of the Fn14 protein was remarkably higher than that of healthy controls. Anti-human Fn14 monoclonal antibodies were used as the primary antibody for detection at a working concentration of 15 μg/ml. Rhodamine-conjugated anti-goat IgG was used as a second antibody. Each muscle section was analyzed in duplicate, and results from one representative experiment are shown. Negative controls were conducted by staining muscle biopsies with isotype control antibody, and no obvious immunofluorescence signal was observed in negative controls. (C) Serial muscle biopsy sections of PM/DM patients were applied for TWEAK immunofluorescence staining and H&E staining, and a representative picture of the same type of field is shown. (D) Muscle biopsy sections of PM/DM patient were applied for TWEAK and Fn14 immunofluorescence staining and a representative staining is shown. To ensure comparability, images were obtained using identical exposure settings for each channel. The TWEAK immunoreactivity is predominantly observed around the infiltrating monocytes, and a mild expression of TWEAK on the sarcolemma of muscle fibers is also visible. While Fn14 are mainly expressed on the sarcolemma of muscle fibers. Therefore, TWEAK and Fn14 are frequently found to be coexpressed in the same myofibers on overlay images. Magnification is 200 ×.
Additionally, in order to analyze TWEAK expression relative to muscle pathology, we conducted H&E staining on serial muscle biopsy sections. Figure 3C showed the same type of field on TWEAK immunofluorescence staining and H&E staining. We observed a remarkably strong expression of TWEAK in the field where abundant infiltrating monocytes existed. TWEAK immunoreactivity was also observed around the sarcolemma of muscle fibers partially invaded or surrounded by monocytes, and membrane TWEAK staining was also visible in a large number of fibers that were not near inflammatory cells.
To further demonstrate the localization of the TWEAK and Fn14 protein, we carried out double staining for TWEAK and Fn14. As shown in Figure 3D, the expression of TWEAK was dramatically observed around the infiltrating monocytes, and a mild expression of TWEAK on the sarcolemma of muscle fibers was also visible, whereas Fn14 was mainly expressed on the sarcolemma of muscle fibers. We therefore found that TWEAK and Fn14 are frequently coexpressed in the same myofibers on overlay images (Figure 3D, merge). This was probably due to the soluble TWEAK protein secreted by inflammatory cells that could bind to the Fn14 expressed on the sarcolemma of muscle fibers.
In this study, we found a significantly lower level of serum TWEAK and a statistically higher level of serum CD163 in PM/DM patients compared to those in healthy controls. Serum CD163 levels were found to be negatively correlated with serum TWEAK levels in PM/DM patients. Relative quantification mRNA analysis showed that Fn14 mRNA expression in the muscle tissue of PM/DM patients was higher than in healthy controls, and Fn14 mRNA levels positively correlated with MYOACT muscle disease activity scores. However, there was no significant difference between the TWEAK mRNA expressions in the muscle tissue of PM/DM patients and of healthy controls. We also examined expressions of TWEAK and Fn14 in muscle biopsy specimens at the protein level and found that TWEAK and Fn14 expressions were significantly increased in PM/DM patients.
Serum levels of TWEAK were found to be elevated in rheumatoid arthritis [25] and systemic sclerosis [19]. In patients with systemic lupus erythematosus, urinary TWEAK level was found to be increased [26], but controversial results were obtained when serum TWEAK levels in systemic lupus erythematosus were investigated [26, 27]. These findings suggest that TWEAK probably plays an important pathogenic role in autoimmune disorders [28, 29]. However, in our study, we found that serum levels of TWEAK in PM/DM patients were significantly lower compared to those in healthy controls. We analyzed serum levels of TWEAK in 98 patients with PM/DM, and each sample was measured three times. Therefore, possible bias resulting from sample size is reduced. The interesting finding of lower serum TWEAK levels in PM/DM patients prompted us to find a reasonable explanation. Recently, it has been shown that CD163 can specifically bind and neutralize TWEAK [24] and that CD163-expressing monocytes/macrophages are able to bind and internalize exogenous TWEAK [30]. Taking into account molecular interaction between TWEAK and CD163 molecules, in the present study we evaluated serum CD163 levels in PM/DM patients, and we found a negative correlation between serum levels of TWEAK and CD163. These results probably gave a good explanation for the lower serum levels of TWEAK in PM/DM patients. Although the role of the serum TWEAK- CD163 interaction in PM/DM pathogenesis remains to be elucidated, our findings suggest a potential role of serum TWEAK and CD163 molecules in PM/DM.
Our further research showed that TWEAK expression at the protein level was remarkably increased in the muscle tissue of PM/DM patients, but TWEAK expression at the mRNA level showed no statistical difference with that of healthy controls. As we know, leukocytes are the major source of TWEAK [9], and muscle cells are unlikely to express the TWEAK protein. Because most of the mRNA extracted from muscle tissues was derived from muscle cells, it is reasonable that TWEAK mRNA levels showed no difference between PM/DM patients and healthy controls. In addition, we analyzed TWEAK immunofluorescence staining relative to H&E staining on serial biopsy sections. We observed a remarkably strong expression of TWEAK in the field where abundant infiltrating monocytes existed. Moreover, we carried out double staining for TWEAK and Fn14 on muscle biopsy sections to demonstrate the localization of the TWEAK and Fn14 protein, and the result showed that the TWEAK immunoreactivity was predominantly observed around the infiltrating monocytes, and a mild expression of TWEAK on the sarcolemma of muscle fibers was also visible, whereas Fn14 was mainly expressed on the sarcolemma of muscle fibers. Therefore, it is probable that the marked evidence of TWEAK protein in the muscle tissues of PM/DM patients was not due to expression by muscle cells but was a product of locally infiltrating leukocytes, which was secreted by inflammatory cells and bound to the Fn14 expressed on the sarcolemma of muscle fibers.
In the study of Mustonen et al., TWEAK and Fn14 expression were assessed in experimental models of cardiac remodeling, and the results showed that the mRNA and protein levels of Fn14 were significantly upregulated, whereas the TWEAK mRNA and protein levels remained almost unchanged [31]. Therefore, their study challenged the previous assumptions of TWEAK expression in response to injury, and provided new insights into the role of ligand-independent Fn14 signaling in cardiac remodeling [31]. In contrast to cardiac remodeling, our study showed increased expression of TWEAK protein in locally infiltrating leukocytes and upregulated expression of Fn14 mRNA and protein on the sarcolemma of muscle fibers. The present study therefore suggested a possible role of TWEAK-Fn14 signaling in the pathogenesis of PM/DM.
Aberrant expression of TWEAK and/or Fn14 has been found to be linked with deleterious pathogenic effects in autoimmune diseases [9]. The TWEAK cytokine and its receptor, Fn14, are identified as critical regulators of skeletal muscle mass [9, 16]. It has been proposed that TWEAK causes Fn14 trimerization and subsequent activation of several signaling proteins including TRAF6, transforming growth factor-β activated kinase 1, I kappa B kinase, and MAPK leading to the activation of various transcription factors followed by gene expression [9, 32–34]. Moreover, Mittal et al. reported that TWEAK could suppress the regeneration and growth of myofibers after injury and that the expression of both TWEAK and Fn14 were increased in skeletal muscle after injury caused by intramuscular injections of cardiotoxin [35]. What is more, it is reported by Girgenrath et al. that Fn14 is highly expressed on muscle progenitor cells and TWEAK could inhibit myogenic differentiation [36]. Recently, it has been demonstrated by Enwere et al. that high concentrations of TWEAK could activate the canonical NF-кB pathway and impair myogenesis [37]. Therefore, the TWEAK-Fn14 axis may contribute to muscle atrophy by impairing skeletal muscle formation. It is worth mentioning that in PM/DM, impairment of muscle regeneration is also a critical characteristic of disease progression. Our study found that Fn14 expression was higher at both mRNA and protein levels in the muscle tissue of PM/DM patients. What is more, we analyzed the relationship between TWEAK and Fn14 expressions and clinical parameters, and found that patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than patients who did not suffer from oropharyngeal dysphagia. Furthermore, our study showed a moderate correlation between the Fn14 mRNA levels and muscle disease activity in PM/DM patients. Additionally, TWEAK protein levels were also significantly elevated in the muscle tissue of PM/DM patients, although their derivation needs to be further confirmed. Taken together, our findings suggest that the TWEAK-Fn14 axis is probably involved in the pathogenesis of PM/DM.
As stated by Morosetti et al., dysregulation of the TWEAK-Fn14 axis in inclusion-body myositis (IBM) muscle may play a dual role in the pathogenesis of IBM by inducing muscle wasting and inhibiting regenerative myogenesis [38]. In their study, TWEAK and Fn14 expression in the muscle tissues of six DM patients, six PM patients and three healthy controls was analyzed by immunohistochemistry. Results showed that only muscle fibers that were invaded or surrounded by monocytes and degenerating fibers next to inflammatory infiltrates showed increased membrane TWEAK and Fn14 immunoreactivity [38]. Our findings seem to be inconsistent with their results. However, in our study, a larger number of patients were analyzed for TWEAK and Fn14 expression. More importantly, all the patients whose biopsies were examined for TWEAK and Fn14 expression by immunofluorescence staining received confirmed pathological diagnoses. On the other hand, whether these contradictory findings are a result of ethnic diversity needs to be verified by further studies.
To our knowledge, our study was the first to systematically investigate the expression of TWEAK and Fn14 in a large cohort of PM/DM patients. The strength of our study is that all the PM/DM patients whose TWEAK and Fn14 expressions in muscle tissue were examined received pathological diagnoses. Muscle biopsy is the most crucial test for establishing the diagnosis of PM/DM and can be used to exclude other neuromuscular diseases [1, 39, 40]. Therefore, the bias resulting from false disease diagnoses was reduced in our study.
However, we acknowledge that our study has some limitations. First of all, our sample size of PM/DM patients whose expression of TWEAK and Fn14 in muscle tissue was investigated was relatively small. This was partly due to our strict selection only of patients who had pathologically confirmed diagnoses. Another limitation of our study is that the expression of TWEAK mRNA in peripheral blood lymphocytes was not examined.
In conclusion, our study showed that significantly high levels of TWEAK and Fn14 could be found in the muscle tissue of PM/DM patients, and Fn14 mRNA levels in muscle tissue positively correlated with muscle disease activity. Regardless of the precise mechanism, the TWEAK-Fn14 axis may probably be involved in the pathogenesis of PM/DM. Further understanding of TWEAK-Fn14 function in PM/DM may help to define therapeutic targets for PM/DM.
ANA:
antinuclear antibody
BSA:
bovine serum albumin
EGF:
Fn14:
fibroblast growth factor-inducible 14
GAPDH:
glyceraldehyde-3-phosphate dehydrogenase
H&E:
hematoxylin and eosin
IBM:
inclusion-body myositis
IIM:
idiopathic inflammatory myopathies
ILD:
interstitial lung disease
MAPK:
MYOACT:
myositis disease activity assessment visual analog scales
PDGF:
platelet-derived growth factor
polymyositis
RT-PCR:
reverse transcription polymerase chain reaction
TBA:
tris-buffered saline
TWEAK:
tumor necrosis factor-like weak inducer of apoptosis
VEGF:
vascular endothelial growth factor.
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This work was supported by the General Program of the National Natural Science Foundation of China (Grant No. 81172860), and the Science and Technology Commission Foundation of Beijing (No. Z121107001012005).
Department of Rheumatology, China-Japan Friendship Hospital, Ying Hua East Road, Chao Yang District, Beijing, 100029, China
Qing-Lin Peng
, Xiao-Ming Shu
, Xiao-Lan Tian
, Xin Lu
& Guo-Chun Wang
Graduate School of Peking Union Medical College, Beijing, China
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Correspondence to Guo-Chun Wang.
The authors declare no potential conflict of interest.
QLP and GCW contributed to study design, data collection, statistical analysis, interpretation of data and drafting the manuscript; XMS acquired the clinical data; XLT participated in the analysis of serum TWEAK levels; XL participated in study design, acquisition, analysis and interpretation of data. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors read and approved the final version.
Peng, Q., Shu, X., Tian, X. et al. Expression of tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 in patients with polymyositis and dermatomyositis. Arthritis Res Ther 16, R26 (2014) doi:10.1186/ar4454
Idiopathic Inflammatory Myopathy
Oropharyngeal Dysphagia
Real Time Reverse Transcription Polymerase Chain Reaction
Muscle Section


Mohammad Hashem, an atheist, was invited to the Alhadath Alyoum TV studio to participate in a debate with former Deputy Sheikh of Al-Azhar Mahmoud Ashour.
However, his statement that there is no scientific evidence for the existence of God and his attempt to talk about the Big Bang theory met with a barrage of insults from Sheikh Ashour and from TV host Mahmoud Abd Al-Halim, with Sheikh Ashour recommending psychiatric treatment and Abd Al-Halim refusing to allow him to remain on the show.
The TV host, apologizing to his viewers for subjecting them to "inappropriate" and "destructive ideas," advised Hashem "to leave the studio and go straight to a psychiatric hospital." The show aired on February 11.