dataesr/scientific-paragraphs-categorization huggingface dataset:
RNA was then isolated as per protocol. Reverse transcription was carried out using the TaqMan MicroRNA Reverse Transcription Kit (Invitrogen, 4366596). miRNA expression was assessed by qPCR, and values were calibrated to the control C. elegans miR-39 (Cel-miR-39-3p). Single tube TaqMan assays (Invitrogen, 4427975) for hsa-miR-720 were carried out as follows: 95 °C for 10 min, then 40 cycles of 95 °C for 15 s and 60 °C for 60 s. All analyses were performed in triplicate and the data were normalized to hsa-miR-16 (Invitrogen, 4427975). Serum levels of miR-720 in patients versus healthy individuals are presented as average fold-change ± SD.
1b ). Both ADAM8 siRNAs effectively reduced the levels of ADAM8 compared to the siCtrl. As siADAM8-2 was previously shown to be slightly more effective in downregulating ADAM8 function in MDA-MB-231 cells  [24] , it was selected to knockdown ADAM8 for the miRNA array assay. RNA was isolated from two independent cultures of MDA-MB-231 cells 72 h post-transfection with siADAM8-2. The RNA preparations were subjected to TaqMan low-density miRNA array card analysis. The relative miRNA expression in the siADAM8 RNA preparations compared to the siCtrl RNA was calculated using the SDS software. A threshold increase or decrease of twofold was used as the cut-off, and 68 miRNAs were differentially regulated greater than or equal to twofold upon ADAM8 knockdown with siADAM8-2 (Fig. 1c ). Of these 68 miRNAs, 66 miRNAs were downregulated and 2 miRNAs were upregulated.
The data from this and two other replicate experiments were quantified. The value of pERK1/2 in the 3D culture is given relative to the 2D culture, which was set to 1. 0. b HEK-293 cells were transfected as above with empty vector (EV) or with vectors expressing ADAM8 (WT) or remnant form (Rem. ) for 48 h. WCEs were analyzed for pERK1/2 and β-tubulin. The data from this and two independent replicate experiments were quantified. The value of pERK1/2 in the control EV DNA was set to 1. 0. c, d MDA-MB-231 cells were cultured in serum-free medium for 24 h, and treated with 25 μM of ERK inhibitor FR180204 or control carrier DMSO for an additional 24 h. WCEs and RNA were collected. WCEs were subjected to Western blotting for pERK1/2 and β-tubulin (c). The data from this and two independent replicate experiments were quantified.
) migration values given. e ATP assay. Transfected cells were grown for 24 h and ATP levels were measured using an ATPlite 1Step assay. Ctrl was set to 100 % (mean ± SD from three independent experiments). *P < 0. 05, ***P < 0. 001, Student's t test. Not sig. not significant orthotopic mouse model was performed using control MDA-MB-231 cells (shCtrl-3 clone), which express high levels of ADAM8 and miR-720. In our preliminary analysis, the plasma levels of miR-720 appeared to vary between individual mice (data not shown). Thus, plasma was collected from each 6-week-old female NOD/SCID mouse (n = 5) a day before TNBC cell inoculation into the mammary fat pad, and used to establish baseline miR-720 levels for each individual mouse. On day 1, 2. 5 × 10 6 shCtrl-3 MDA-MB-231 cells were implanted into the fourth inguinal mammary fat pad and primary tumor growth was monitored by palpation and caliper measurement twice a week thereafter (Fig.
8a ). Little growth of the tumors was detected within the first 7-9 days, as reported previously  [24]. Plasma was collected 7 days after cell implantation when the tumors were barely palpable. Tumor growth was followed for a total of 21 days (Fig. 8a ). A significant increase in miR-720 levels of about 40-fold was detected in the blood of mice at the 7-day time point (Fig. 8b ) and remained elevated above 10-fold to day 21 (data not shown). It was interesting to note that the mice with the two fastest growing tumors (mouse 1 and mouse 2) had the highest miR-720 levels at day 7. Thus, substantial increases in miR-720 levels can be detected early, prior to the increase in tumor growth when tumor sizes are fairly small. Fig. 6  miR-720 maintains the migratory and invasive properties of SUM-149 cells.
c Total RNA was collected from serum samples and miR-720 levels were determined using RT-qPCR. Relative miR-720 levels in serum of TNBC patients with high ADAM8, low ADAM8 and normal individuals are presented. *P <0. 05, ***P < 0. 001, ****P < 0. 0001, Welch's t test. NS not significant of five miRNAs that can serve as predictive markers of poor prognosis in patients with IBC, which we have found also frequently express ADAM8 (data not shown). Similarly, Park and coworkers reported upregulation of miR-720 in blood of patients with metastatic ER+/HER2breast cancer  [66]. Consistently, miR-720 is upregulated in a variety of other tumors including colorectal and bladder cancers, malignant melanoma, renal cell carcinoma and multiple myeloma  [46, 63, 65, [67] [68] [69] [70] [71]. In contrast, Li et al.
Acknowledgements We thank  Stephen Ethier ,  Nader Rahimi ,  Joerg Bartsch  and  Srimathi Srinivasan  for providing valuable cell lines and cloned DNAs. We gratefully acknowledge  Gordon Huggins  for use of his ABI real-time cycler for microarray card reading. This work was supported by grants from the  DOD   W81XWH-11-1-0814 , the  NIH   R01 CA129129  and  P01 ES011624 , and  ArtBeCAUSE.
Prescription mistakes may be lowered and the e iciency in the drug supply system may be increased due to fewer drug orders and shipments  (Blomberg 2001; CDC 2003; Rieder 2002). The major advantages of using FDCs to treat people with TB are simplified treatment and drug management and decreased probability of monotherapy (Blomberg 2001). Moreover, FDCs tend to improve adherence in various settings (Connor 2004). Cochrane Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews.
Types of participants Male and female adolescents and adults (aged 15 years or older), newly diagnosed with pulmonary TB, confirmed by sputum smear or culture, or both, or according to the World Health Organization (WHO) definition for a case of tuberculosis (TB): participants in which a health worker has diagnosed TB and has decided to treat with a full course of TB treatment (WHO 2010). We excluded children, people with extrapulmonary TB, and those previously treated for TB. We excluded children due to di iculties in childhood TB treatment with the available fixed-dose combinations (FDCs)  (WHO 2009; WHO 2014). We excluded studies that included both adults and children, unless subgroup data for adults were available from the study report.
Secondary outcomes 1. Sputum smear or culture conversion. 2. Time to sputum smear or culture conversion. 3. Time to relapse. 4. Treatment adherence (as defined by the trial authors). 5. Acquisition of drug resistance (as defined by the trial authors). 6. Patient satisfaction characterized as: a. general satisfaction; b. no problems swallowing; c. acceptable taste. 7. Adverse events characterized as: a. serious (death, hospitalizations); b. those leading to discontinuation of therapy; c. other adverse events. For sputum smear or culture conversion we took culture conversion data instead of sputum smear data when both were available. We assessed dichotomous outcomes at two to three months, at the end of treatment (EOT), and at follow-up when data were available. For treatment adherence and acquisition of drug resistance, we used the definitions suggested by the trial authors (see Table  1 ).
Data extraction and management Two review authors (CRG and AVR) independently extracted data from the included trials using a standardized data extraction sheet. For all included trials, we extracted information regarding the number of randomized participants and the number of participants whose outcomes were measured. We extracted the number of events and the number of participants assessed in each treatment arm for dichotomous outcomes. For continuous outcomes, we extracted the arithmetic means and standard deviations, together with the number of participants in each group. We resolved discrepancies regarding the extracted data with another two review authors (MRF and DRC) when necessary. When we required additional details, we contacted the trial authors by email. For all included trials we extracted the following information when available.
Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews trial: sequence generation; allocation concealment; blinding (study participants, investigators, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias. For each of these components, we assigned a judgment regarding the risk of bias of either 'low', 'high', or 'unclear' (if insu icient detail was reported, or insu icient information was provided and the risk of bias was unknown) (Higgins 2011). We recorded the results in the standard 'Risk of bias' table in Review Manager (RevMan) (RevMan 2014), and summarized the findings in a 'Risk of bias' table and 'Risk of bias' graph.
Sensitivity analysis We performed the following sensitivity analyses. 1. We conducted a sensitivity analysis to explore the impact of the 'Risk of bias' assessment on the main analysis. We analysed separately the two trials at low risk of selection bias (Bartacek 2009; Lienhardt 2011) (see Data and analyses: Comparison 2 'Fixed-dose combinations versus single-drug formulations as available data: sensitivity analysis by risk of bias'). 2. We performed a sensitivity analysis to explore the impact of missing data on the main analysis, for primary and secondary dichotomous outcomes related to treatment e icacy. We conducted this analysis as an ITT analysis. We kept participants in the intervention groups to which they were randomized, regardless of the intervention to which they ended the followup, and included all randomized participants in the analysis.
Cochrane Database of Systematic Reviews We included 13 RCTs in quantitative analyses, which included 5824 randomized participants. All trials compared FDCs versus singledrug formulations for the treatment of pulmonary TB in newly diagnosed participants. The trials and the meta-analyses were underpowered to allow us to confidently detect or exclude clinically important changes on the primary dichotomous outcomes related to treatment e icacy (treatment failure and relapse), the sputum smear or culture conversion at EOT, death, and adverse events (see Table  5 ). A combined endpoint of treatment failure, relapse, or death We did not identify any trials that examined the combined outcome.
Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews 2. Daily regimen for the whole treatment versus daily regimen during in the intensive phase followed by intermittent regimen in the continuation phase. 3. Supervised treatment versus self-administered treatment during the intensive phase. 4. Trials with four drugs as FDCs versus trials with three or two drugs as FDCs during the intensive phase. There were subgroup di erences on relapse in three subgroup analyses. These di erences are due almost exclusively to one trial, Teo 1999, which used a FDCs with three active oral ingredients (H, R and Z) in the intensive phase for the intervention group and singledrug formulations for all participants in the continuation phase. In addition, there was a daily treatment during the intensive phase which was followed by intermittent treatment in the continuation phase.
Assessment of reporting biases The funnel plot for sputum smear or culture conversion at two months in the comparison of treatment with FDCs versus singledrug formulations showed no inherent risk of publication bias in the trials included in the meta-analyses, although these analyses included few trials (Figure  5 ). The funnel plot for death showed a similar result (figure not shown). Cochrane Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews.
Cochrane Database of Systematic Reviews There is a lack of data regarding some important outcomes such as acceptability (outcome concerning patients) and acquisition of drug resistance (clinically and bacteriologically relevant outcomes). We analysed general satisfaction, which only Chaulet 1995 recorded, and no problems swallowing and acceptable taste, which Bartacek 2009 recorded. There rest of the included trials had limited data about acceptability. Only three trials reported acquisition of drug resistance (Chaulet 1995; Lienhardt 2011; Teo 1999; see the 'Characteristics of included studies' section). TB therapy in real clinical practice may di er from the procedures in clinical trials. Firstly, clinical trials implement interventions that are more similar to directly observed treatments (DOT) than to self-administered treatments.
Potential biases in the review process We minimized the biases in the review process by performance of an exhaustive search strategy, which included the most important bibliographic databases of clinical trials, without time or language limitations. The Information Specialist of the Cochrane Infectious Diseases Group, Vittoria Lutje, performed the search and we checked the reference lists of relevant studies, which decreased the probability that we missed important studies. We were able to obtain all the published papers of the trials and all available data. Two review authors independently performed study selection and 'Risk of bias' assessments of included trials. We consulted a third review author to resolve any disagreements. Two review authors independently performed data extraction. We excluded one RCT that met the inclusion criteria from the quantitative analysis because disaggregate results were unavailable.
text related to their Figure  2  is not about sputum smear rate at EOT; c. Lienhardt 2011 is mentioned twice in the references section. We assessed the risk of bias of the included trials using the 'Risk of bias' assessment tool and in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), recorded the results in a standard table in RevMan (RevMan 2014), and summarized the findings in a 'Risk of bias' table (Figure  3 ) and a 'Risk of bias' graph (Figure  4 ). We summarized the quality of the evidence for the main outcomes, and reported the RCT data in 'Summary of findings' tables (Summary of findings for the main comparison; Summary of findings table 2).
Cochrane Database of Systematic Reviews Baseline drug susceptibility test : initially drug resistant participants 0% (0/38 tested) HIV status of participants: not reported Interventions 6 months treatment regimen (2HRZE/4HR) Intervention 1. 2FDCs (isoniazid 150 mg and rifampicin 300 mg per tablet) during all treatment, complemented with pyrazinamide and ethambutol as single-drug formulations in the intensive phase. In continuation phase isoniazid supplementary was done to achieve the dose of 10 mg/kg (N = 20).
Cochrane Database of Systematic Reviews Intensive phase: 1. Regimen 1: isoniazid, rifampicin and pyrazinamide + streptomycin for 2 months (2SHRZ regimen). 2. Regimen 2: the same regimen, but given for only 1 month (1SHRZ regimen). 3. Regimen 3: the same as regimen 1 but without streptomycin (2HRZ regimen). The 3 regimens were given daily as FDCs or as separate formulations. Rifater (isoniazid 50 mg, rifampicin 120 mg, pyrazinamide 300 mg per tablet) was used as a FDC.
Wu 2015 {published data only} Wu JT, Chiu CT, Wei YF, Lai YF. Comparison of the safety and e icacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment. Clinics (São Paulo) 2015;70(6):429-34. Zaka-Ur-Rehman 2008 {published data only} Zaka-Ur-Rehman Z, Jamshaid M, Chaudhry A. Clinical evaluation and monitoring of adverse e ects for fixed multidose combination against single drug therapy in pulmonary tuberculosis patients. Pakistan Journal of Pharmaceutical Sciences 2008;21(2):185-94. Zhang 1996 {published data only} Zhang LX, Kan GQ, Tu DH, Wan LY, Faruqi AR. Fixed-dose combination chemotherapy versus multiple, single-drug chemotherapy for tuberculosis. Current Therapeutic Research 1996;57(11):849-56. Cochrane Database of Systematic Reviews Zhu 1998 {published data only} Zhu L, Yan B, Ma W.
Trials 2012;13:61. Punnotok 1995 {published data only} Punnotok J, Pumprueg U, Chakorn T. A comparison of two short course tuberculosis chemotherapy regimens, both using Rifater during an intensive phase, with a 3 year follow-up. Journal of the Medical Association of Thailand 1995;78(6):298-304. Soehardiman 2007 {published data only} Soehardiman D, Soepandi P, Nawas A. Comparison of Antituberculosis Drugs Between Fixed Dose Combinationand Combipack for New Cases of Pulmonary Tuberculosis in Persahabatan Hospital. Respirology. Proceedings of the 12th Congress of the Asian Pacific Society of Respirology. 2007; Vol. 12 (Suppl 4):A237. Cochrane Database of Systematic Reviews Sokolova 1993 {published data only} Sokolova GB, Koriakin VA, Khalbaeva IV, Elistratova NA, Ziia AV. Combined chemotherapy of patients with tuberculosisnew regimens and dosage forms.
2; Z: 20 to 25 Participants weighing 50 to 60 kg H: 6. 6 to 8; R: 10 to 12; Z: 20. 8 to 25 RCTAI 1989 Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis (Review) Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
Cochrane Database of Systematic Reviews and Clinical Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: NICE, 2011. Nunn AJ, Cook SV, Burgos M, Rigouts L, Yorke-Edwards V, Anyo G, et al. Results at 30 months of a randomised trial of FDCs and separate drugs for the treatment of tuberculosis. Zhang HQ, Xi XE, Wang YL, Han W, Zhang CX, Jiao JH. Side e ects of tuberculosis treatment with fixed-dose combinations.
Unfavorable outcome: a combined endpoint of: a. bacteriological failure or relapse by 18 months after treatment initiation; b. treatment changed after 5 months because of 2 positive sputum smear results or a clinical or radiographic deterioration in the absence of bacteriological confirmation; and c. death, definitely or probably attributable to TB. 2. Favorable response: sputum culture negative at 18 months (or 24 months, if the 18 months result was unavailable). NotesTwo publications for the same clinical trial (Lienhardt 2011; Nunn 2014). All outcomes were assessed according to the data provided in Lienhardt 2011. In Nunn 2014 the assessment was done at 30 months after initiation of treatment and is the most recent publication, but the results confirm those found in Lienhardt 2011 and the trial authors suggest that the follow-up should be limited to 18 months after initiation of treatment in this kind of clinical trialsCochrane Database of Systematic Reviews and 30 months in the follow-up phase.
Cochrane Database of Systematic ReviewsInclusion criteria: participants aged 18 years or more with active pulmonary TB, confirmed by sputum smear or culture or both, and with no history of previous TB treatment FDCs tablets with Rifater® (isoniazid 50 mg, rifampicin 120 mg and pyrazinamide 250 mg per tablet)+ etambuthol as single-drug formulation for the first 2 months (intensive phase) followed by Rifi-nah® 150 (isoniazid 100 mg and rifampicin 150 mg per tablet) or Rifinah® 300 (isoniazid 150 mg and rifampicin 300 mg per tablet) + etambuthol as single-drug formulation for 4 months (continuation phase) (N = 57).
There were no limitations in the design and execution of the trials. Cochrane Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews 3 Downgraded by 1 for imprecision. The optimal information size, considering an absolute > 0. 5% non-inferiority margin as clinically meaningful, is not reached. In addition, 1 side of the 95% CI does not exclude potential harm associated to FDCs. 4 We did not downgrade quality for indirectness. Di erences in dosages probably do not a ect the comparability of groups. 5 We did not downgrade quality due to inconsistency. Large heterogeneity (I statistic = 72%) can be explained by the limited number of events and the e ect of chance. 6 Downgraded by 1 for imprecision. The optimal information size, considering an absolute > 0.
Cochrane Database of Systematic Reviews and Clinical Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: NICE, 2011. Nunn AJ, Cook SV, Burgos M, Rigouts L, Yorke-Edwards V, Anyo G, et al. Results at 30 months of a randomised trial of FDCs and separate drugs for the treatment of tuberculosis. Zhang HQ, Xi XE, Wang YL, Han W, Zhang CX, Jiao JH. Side e ects of tuberculosis treatment with fixed-dose combinations. Cochrane Library Trusted evidence. Informed decisions. Better health. WHO 2010 World Health Organization. Guidelines for treatment of tuberculosis. WHO/HTM/TB/2009. 420. 4th Edition. Geneva: Nunn 2014 World Health Organization, 2010. WHO 2011 World Health Organization. WHO Model List of Essential The International Journal of Tuberculosis and Lung Disease 2014;18(10):1252-4.
Cochrane Library Cochrane Library Cochrane Library Cochrane Library Cochrane Library Cochrane Library Trusted evidence. Informed decisions. Better health. Trusted evidence. Informed decisions. Better health. Trusted evidence. Informed decisions. Better health. Trusted evidence. Informed decisions. Better health. Trusted evidence. Informed decisions. Better health. Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews Bartacek 2009 (Continued) Chaulet 1995 (Continued) Geiter 1987 (Continued) Risk of bias Other bias Allocation concealment: sealed, serially numbered, opaque randomization envelopes Blinding: none 6.
Fixed-dose combinations of drugs versus single drug formulations for treating pulmonary tuberculosis. Cochrane Database of Systematic Reviews 2012, Issue 7. [DOI: 10. 1002/14651858. CD009913] Comments: follow-up duration was 12 months after initiation of treatment. Sputum smear conversion ment rate was measured at 2, 4, 6, 9, and 12 months after initiation of treatment. Adverse events were as-sessed at each visit. Participant satisfaction with tablets was noted at 2 months Authors' judgement Support for judgement Low risk Using a computer random number generator. Low risk No blinding, but outcomes were unlikely to be influenced by lack of blinding (objective and measurable outcomes). Low risk No blinding of outcome assessment, but outcome measurement is unlikely to be influenced by lack of blinding (objective and measurable outcomes).
Single formulations of the same drugs in both phases (intensive and continuation) (N = 577). Doses used: the trial authors stated: "according to the national treatment standards of each respective country"The mean daily dosage of H, Z, and E at intensive phase in FDCs group was lower compared with single-drug formulations group, the R dose were similar in both groups. 3. Relapse rate at months 12. 4. Adverse events: serious; those leading to discontinuation of therapy and other adverse events. 5. Death. Bartacek 2009 (Continued)Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis (Review)Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Males: 74% (of 196 participants initially sensitive to isoniazid) Inclusion criteria: new pulmonary TB participants (aged 15 or more) confirmed by chest x-ray and sputum smear.