dataesr/scientific-paragraphs-categorization huggingface dataset:
These data are of great clinical value in sequencing for this mutation in patients with acquired resistance to osimertinib. Navitoclax (ABT-263), a BCL-2 family inhibitor, enhances the apoptotic response of late-resistant EGFR T790M cells with decreased sensitivity to EGFR inhibition. The combination of navitoclax with the third-generation EGFR TKI WZ4002 (in preclinical development) induced more apoptosis compared to WZ4002 alone in both in vivo and in vitro analyses. This approach could be an effective strategy for treating EGFR T790M-positive cancers that have a decreased apoptotic response to EGFR inhibition  (68). Additionally, the combination of WZ4002 with trametinib, another MEK inhibitor, prevents the development of acquired resistance in EGFR-mutant lung cancer models  (77). A phase Ib trial is ongoing to evaluate the safety and tolerability of the osimertinib/navitoclax combination in patients with EGFR-mutant NSCLC following resistance to prior EGFR TKIs (NCT02520778).
In vitro, a combination of osimertinib with the MEK 1/2 inhibitor selumetinib prevented emergence of resistance in PC9 (Ex19del) cells and delayed resistance in NCI-H1975 (L858R/ T790M) cells. In vivo, concomitant osimertinib with selumetinib caused regression of osimertinib-resistant tumors in an EGFR-mutant/T790M transgenic model  (69). This association, among others, is being evaluated in the phase Ib TATTON trial (NCT02143466) designed to evaluate the safety, tolerability, and preliminary antitumor activity of osimertinib in combination with durvalumab (an anti-PD-L1 monoclonal antibody), savolitinib (MET inhibitor) or selumetinib in patients with advanced EGFR-mutant NSCLC who have progressed on an EGFR TKI. Preliminary results from the osimertinib/durvalumab arm were recently presented  (78).
The investigator-assessed ORR was 67% in nine patients with T790M+ tumors, compared to 21% in 14 T790M-NSCLC. Interstitial lung disease was reported in 38% (13/34) of patients, which is higher than would be expected with either drug alone, including five grade 3/4 events (78). Thus, recruitment in the osimertinib + durvalumab arm was stopped but expansion cohorts of the MET and MEK inhibitor combinations are ongoing. In addition, the phase III CAURAL trial (NCT02454933) is being conducted in second-line metastatic EGFR-mutant T790M+ NSCLC patients testing osimertinib plus durvalumab vs. osimertinib monotherapy. This study was also stopped prematurely due to the pulmonary toxicity observed in the TATTON trial. Dual EGFR blockage is being evaluated in a phase I trial (NCT02496663) combining osimertinib with the anti-EGFR monoclonal antibody necitumumab to assess safety and determine the optimal dose in patients with EGFR-mutant advanced NSCLC who have progressed on a previous EGFR TKI.
As was reported, the dual vascular endothelial growth factor receptor (VEGFR) and EGFR blockade inhibit tumor growth in EGFR TKI resistance xenograft models  (79). This hypothesis was confirmed in two phase II clinical trials in EGFR-mutant NSCLC treatment-naïve patients, the randomized Japanese (JO25567) trial comparing erlotinib plus bevacizumab vs. erlotinib alone, and the single-arm Caucasian (BELIEF) trial. Median PFS was similar and encouraging in both trials supporting the combination in the first-line setting  (80, 81). Following this strategy, a phase I trial was designed to evaluate the safety of two osimertinib-based combination strategies, with necitumumab or ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with advanced EGFR T790M+ NSCLC after progression on first-line EGFR TKI therapy (NCT02789345).
The clinical development of osimertinib represents one of the fastest cancer drug development programs, taking just 2 years, 8 months, and 1 week from the first patient dosed to the first approved indication. Until recently, patients with advanced NSCLC with EGFR-activating mutations who progress on a first-line EGFR TKI have traditionally been treated with a platinum-doublet chemotherapy. These combinations show ORRs of approximately 30%, marginally higher than those observed in the T790M-populations, but significantly lower than those reported in T790M+ cohorts across osimertinib phase I-III trial development. In addition, given the encouraging CNS efficacy, osimertinib is also attractive as frontline treatment for patients with brain and/or leptomeningeal metastases. The phase III FLAURA (NCT02296125) trial will hopefully soon answer the issue of where osimertinib should be positioned.
The overall response rate (ORR) was 29% and was comparable in both T790M+ and T790M-tumors (32 vs. 25%), and median PFS was 4. 7 months (95% CI, 4. 3-6. 4) (32). However, the dual EGFR inhibition resulted in increased toxicity with various grades 3-4 adverse events (AEs) (mainly rash, diarrhea, and fatigue) reported in up to 46% of patients (32). A randomized phase II/III trial (NCT02438722) of afatinib plus cetuximab vs. afatinib alone is currently open in treatment-naïve patients with advanced EGFR-mutant NSCLC. Third-Generation EGFR TKis Many third-generation EGFR inhibitors are currently being consecutively developed to more effectively target the T790M mutation. Unlike second-generation TKIs, as these drugs exhibit increased specificity for T790M and thus mutant EGFR compared to wild-type EGFR, they are well tolerated resulting in few wild- type EGFR adverse effects.
Ib/Ph. II Group 1: advanced EGFR-mutant Phase Ib: MTD or RP2D of nazartinib Recruiting phase Ib/II NSCLC progressing under G/E/A Phase II: ORR Ph. II Group 2: advanced NSCLC not been previously treated with any EGFR TKI and harbor de novo T790M mutation Nazartinib NCT02323126; Nivolumab Anti-PD-1 antibody EGFR mutant/T790M+ NSCLC progressing PFS On hold phase II under first-line EGFR TKI G/E/A, gefitinib/erlotinib/afatinib; MTD, maximum tolerated dose; NCT number, http://clinicaltrials. gov identification number; NSCLC, non-small-cell lung cancer; ORR, objective response rate; PFS, progression-free survival; RP2D, recommended phase 2 dose.
Background: Food products containing non-nutritive sweeteners (NNSs) instead of sugar have become increasingly popular in the last decades. Their appeal is obviously related to their calorie-free sweet taste. However, with the dramatic increase in their consumption, it is reasonable and timely to evaluate their potential health benefits and, more importantly, potential adverse effects. The main aim of this scoping review was to map the evidence about health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area. Methods: We systematically searched Ovid MEDLINE, EMBASE and the Cochrane CENTRAL databases for studies on NNSs (artificial sweeteners or natural, non-caloric sweeteners, either used individually or in combination) using text terms with appropriate truncation and relevant indexing terms.
All human studies investigating any health outcomes of a NNS intervention or exposure were eligible for inclusion. No studies were excluded based on language, study design or methodological quality. Data for each health outcome were summarized in tabular form and were discussed narratively. Results: Finally, we included 372 studies in our scoping review, comprising 15 systematic reviews, 155 randomized controlled trials (RCTs), 23 non-randomized controlled trials, 57 cohort studies, 52 case-control studies, 28 cross sectional studies and 42 case series/case reports. In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity are the most investigated health outcomes. Overall there is no conclusive evidence for beneficial and harmful effects on those outcomes.
Search strategy Ovid MEDLINE (ovidsp. ovid. com), EMBASE (www. embase. com) and the Cochrane CENTRAL database (www. cochranelibrary. com) were searched from inception to October Week 2 2015 for studies on AS and to January Week 3 2016 for studies on NNCS and NNS, using text words with appropriate truncation and relevant indexing terms (MeSH). The search was in the form [terms for artificial sweeteners/ natural, non-caloric sweeteners/nonnutritive sweeteners] and [human studies]. Electronic searches were limited neither in time nor in language. Electronic searches were followed by hand searching of reference lists of relevant review articles and included primary studies. Electronic searches were updated in May Week 4 2017.
Data extraction and management Titles and abstracts were screened for inclusion by a single reviewer (SL). Only clearly irrelevant records were excluded at this stage. All potentially relevant abstracts and full papers were screened for inclusion by two reviewers independently using an inclusion/exclusion form specifically developed for the purpose of this scoping review (SL and IT). In case of disagreement, the subject was discussed among the two reviewers until a mutual decision could be made. When this was not possible, a third reviewer (JM) was consulted. A data extraction sheet was designed and piloted. Then two reviewers (SL and IT) independently extracted the following data for each included primary study: 1) first author; 2) year of publication; 3) study location; 4) study design; 5) aim of the study; 6) main characteristics and size of the study sample; 7) main characteristics of intervention/exposure and control; 8) outcome measures with direction of effect.
In 2017, after the update search of databases, 48 further studies were eligible for inclusion. In total, 24 systematic reviews (Table  2 ), 175 randomized controlled trials (RCTs), 29 non-randomized controlled clinical trials (non-RCTs), 62 cohort studies, 52 casecontrol studies and 36 cross-sectional studies were included in this scoping review. We also found 42 case studies.
Strength and limitations of this scoping review The strength of our scoping review is its inclusion of all types of primary studies and systematic reviews which investigate any health effect of any NNS in any population. We are therefore able to present a comprehensive overview of the available scientific evidence on health effects of NNS. Our scoping review might be limited by the following factors. Firstly, the literature search was conducted in three major and comprehensive databases, but we might have inadvertently missed relevant studies listed in other databases. Secondly, the title abstract screening was conducted by one reviewer who might have inadvertently excluded relevant studies at the first stage of the screening. This limitation might be evened out by conducting the literature search in two steps.
Discussion of findings in light of other evidence summaries In our scoping review we found a large number of studies of different designs, investigating effects of different types of NNS in different populations on a variety of health outcomes. Systematic reviews to summarize the available evidence are already available (Table  2 ). However, they often have methodological limitations (e. g. language limitation of the search, electronic search in only one database, etc. ) or a narrow scope. There are systematic reviews, which also included key words for "diet soda" and "diet beverage" in their search strategy. There are several, primarily observational studies, where the exposure is defined as "diet", which may indicate NNS-containing beverages, but further details are often not provided. Therefore, it is clearly a challenge when trying to synthesize the evidence to decide, how to deal with studies describing the intervention/exposure as "diet beverage", "diet drink" or "diet soda" only.
3 (a). These separation measurements have been obtained with the same DFT technique as the other curves except that EDFA2 was kept powered on (without an input signal) during the measurements, so that all the ASE noise it generates is constantly injected into the cavity through the WDM. Because of the particular dispersion of our cavity, some ASE components are group-velocity matched with the driving beam, guaranteeing efficient noise transfer. As can be seen, the separation between two CSs vary quite erratically in these conditions, and we can observe long portions of the data roughly matching bound states measured without noise, with random transitions between them. A second illustration is provided in Fig. 3(c ). Here the pseudo-color plot is made up of a vertical concatenation of oscilloscope recordings of the temporal intensity of the light leaving the cavity over successive roundtrips (bottom to top).
The measurement is performed with a 40 GHz sampling oscilloscope and measured with a 65 GHz bandwidth photodiode. A bound state of two CSs with a separation of about 20 ps is initially observed but transitions to a separation of about 12 ps after a short burst of ASE noise is injected into the cavity at time t ≃ 7 s. In fact, it is mostly with this method, applied many times, that we have forced the system to visit all the separations that bound states of two CSs can possibly adopt, and accumulated the data shown in black, blue, and green in Fig. 3 (a). We must also point out here that the influence of EDFA2 ASE noise on bound states prevent us from directly targeting a specific separation at the excitation stage. Indeed, at that stage, EDFA2 must be powered on to amplify the addressing pulses.
FUNDING INFORMATION Marsden fund of the Royal Society of New Zealand; Rutherford Discovery Fellowships of the Royal Society of New Zealand. Julien Fatome also acknowledges the financial support from the European Research Council (ERC starting grant PETAL #306633) and the Conseil Régional de Bourgogne Franche-Comté (International Mobility Program) which has allowed him to visit The University of Auckland to contribute to this work.
Methods: The database included diagnosis/histology, surgery, radiotherapy, systemic treatments and treatment response. Treatment patterns and outcomes of patients with metastatic disease, excluding adipocytic sarcoma and GIST were analyzed. Results: Of 888 total patients, 145 were included based on having metastatic disease and appropriate subtypes. All patients received treatment with systemic therapy being most common (74%, n = 107), followed by radiotherapy (30%, n = 44) and surgery (23%, n = 33). Doxorubicin, alone or in combination, was the most common first line systemic therapy (65%, n = 46). Drugs without license in sarcoma were used in 38-83% of treatments depending on treatment line. 24% of frontline patients demonstrated an objective response, decreasing to 11% objective responses in second line but no responses were documented beyond second line, with median PFS declining with each additional line.
Methods The EMS (Evaluation Médicale & Sarcome or Medical Evaluation and Sarcoma) study was an observational, prospective survey of patients with sarcoma from an exhaustive patient cohort in the Rhône-Alpes region of France over a 2-year period from March 2005 to March 2007. This sub-analysis considered all incident cases of metastatic soft tissue sarcoma (STS) identified in the database, corresponding to the subtypes eligible for the PALETTE study. Data was collected from patient records.
EMS patient database The EMS study was initiated as a comprehensive prospective population-based cohort in Rhône-Alpes in 2005, including STS, GIST and osteosarcoma. The primary referral centres for inclusion in the database are the 43 pathology laboratories in this region, which accounts for 10% of the French population. All cases underwent central histological review  [18]. Methods for data collection in the EMS database have been described previously  [18, 19].
Patients All patients with a diagnosis of primary sarcoma included in the EMS database between 1st March 2005 and 28th February 2007 with metastatic disease (initially or during follow up) were included in the present study. The current analysis was restricted to patients with histological subtypes included in the PALETTE trial of pazopanib (i. e. key excluded subtypes: adipocytic sarcoma, osteosarcoma, gastrointestinal stromal tumour)  [14].
Data collection Data in the EMS database included demographics, medical history, diagnostic procedures, primary tumour characteristics, functional status at diagnosis (ECOG score  [20] ), treatments (surgery, radiotherapy or chemotherapy) and outcomes according to the French 2006 SOR guidelines  [20] , follow-up recurrence and survival. It was noted whether patients were treated in an expert centre  [21, 22]  to describe the likely extent of collaboration between a multi-disciplinary specialist STS medical team. Data was prospectively extracted from the patient records covering the period from first inclusion into the EMS database (between March 2005 and March 2007) until a cut-off point of February 2012.
Discussion The present study reported treatment patterns and outcomes in patients with metastatic STS, excluding liposarcoma and GIST, enrolled in an exhaustive prospective patient database in real life. Of the entire STS population, 40. 5% (145/358) were diagnosed with or subsequently developed metastatic disease. 26. 3% (76/289) of patients with localised STS had metastatic relapse,half the rate of metastatic relapse reported in the literature  [23]. Previous hospital case-series studies conducted in specialist centres may be enriched with more severe patients at higher risk for progression or relapse  [17] , whereas this study was population based including all incident cases. In this study, the treatment rate for metastatic STS in nonspecialist centres was lower, around 53%. Systemic chemotherapy was the most common firstline strategy for patients with metastatic STS with 68.
Acknowledgements We would like to thank all patients, centres and investigators who participated in this study, including  Marie-Pierre SUNYACH ,  Dominique DRAMAIS-MARCEL ,  Cécile AGOSTINI ,  Jocelyne PROVENCAL ,  Pierre MEEUS ,  Lionel VINCENT ,  Blaha BELGADI , and  Dominique BEAL ARDISSON. We would also like to thank  Adam DOBLE  who provided editorial assistance for this manuscript.
Biosensing Expression of Tissue-Specific RNA Mutations Gene structure including border splice site is not the only common element comparing CSPs between Bombyx and Tribolium. Another important common feature is found in the expression of CSP genes, in particular in its regulation via RNA editing. This could be extremely useful information to make a genetic or enzyme chip for detection of cell and tissue-specific mutations (Figure  3 ). RNA variance and protein diversity have been originally described in B. mori CSPs  [57] [58] [59] [60] [61] [62] [63]. Similarly, about twelve tag sequences (DT787080-EC010944; e-value: 11. 76938e-180 -1. 36145e-159) can be found in the EST database of the beetle T. castaneum for gene encoding AAJJ0283B and variants  [64, 65] , suggesting that RNA editing is a common feature of CSP gene expression in insects.
Therefore, the potential applications of CSPs are genetic chips not only for genomic analysis and biotyping, but also for RNA analysis and typing of a set of mutations crucial for cell tissue function (Figure  3 )  [57] [58] [59] [60] [61] [62] [63] [64] [65]. RNA editing ought to regulate gene expression in a versatile protein family such as CSPs, which could be extremely useful information in a search for genosensors and/or biosensors based on multi-gene family, multi-function and development/tissue-dependent RNA variance in insects. Distribution of EST-cDNAs encoding CSPs in the red flour beetle T. castaneum is in strong agreement with insecticide xenobiotic up-regulation in quasi all CSPs from most tissues of the adult insect body, particularly the gut (Figure  3A )  [29, 66]. The analysis of the currently available Tribolium EST database shows that AAJJ0330A (CB334791-CB337098) and AAJJ0012G (CB33646-CB336463) are highly expressed in the whole body of tribolium at the embryonic stage, refuting an olfactory function for these genes  [67, 68].
Acknowledgments We would like to thank  M. Bianchi ,  Z. Berezhiani ,  G. Dvali ,  A. Dolgov ,  C Gomez  and  O. Kanchelli , for useful discussions on these aspects. The author XWK also thanks  Hai-Bo Li  for helpful advice. A. A work was supported in part by the  MIUR  research grant " Theoretical Astroparticle Physics "  PRIN 2012CPPYP7. XWK's work is partly supported by the  DFG  and the  NSFC  through funds provided to the  Sino-German CRC 110 Symmetries and the Emergence of Structure in QCDwhen he was in Jülich , and by the  Ministry of Science and Technology of R. O. C. under Grant No. 104-2112-M-001-022  when he works in Taiwan from  April. The work by MK was performed within the framework of the Center FRPP supported by  MEPhI Academic Excellence Project  (contract  02. 03. 21. 0005, 27.
Another way will be to add polyphenol in addition to the polyphenols of a normal diet, but then both groups might receive sufficient polyphenol, and a possible effect of polyphenol might be overlooked. Both types of trials will give information, but different information. Background levels of exposures can be difficult to accurately determine due to limitations in currently available assessment methodologies of food intake, incomplete nutrient databases with which nutrient intake estimates are calculated, and temporal changes in exposure. This must be carefully considered in the trial design, including randomisation and subgroup analysis per baseline status. For smaller RCTs (say less than 400 to 500 participants), adjustment according to the baseline level of consumption or nutrient level in blood may be necessary  [12].
The great heterogeneity of national regulations regarding non-drug research mainly depends on the consideration of a dietary supplement as a drug or not and the level of intervention imposed on the patient. There is a need to harmonise the procedures for evaluating nutrition clinical trials in Europe. One of the deliverables of WP6 within ECRIN-IA has been to collect the different national regulation requirements and develop a pan-European human nutrition regulatory and ethics database  [56]. For the US Food and Drug Administration (FDA), if an Investigational New Drug (IND) is needed for a clinical investigation, evaluating a dietary supplement is determined by the intent of the clinical investigation. If the clinical investigation is intended only to evaluate the dietary supplement's effect on the structure or function of the body, an IND is not required.
Endnotes 1 Funded by the European Union Framework Programme 7 (EU FP7; grant agreement no. 284395), ECRIN-IA involved 23 countries and brought together diverse stakeholders to overcome barriers to clinical research in three particularly difficult areas (rare diseases, medical devices, and nutrition). Specifically, the project aimed to develop tools, services, and infrastructure to facilitate multinational clinical research in Europe, and to support the development of pan-European disease networks to drive clinical projects. This in turn was intended to improve Europe's attractiveness to industry, boost its scientific competitiveness, and result in better health care for European citizens. Originally planned for 4 years (2012 to 2015), the clinical trials work package was extended until 2017.
Acknowledgements The  ECRIN-IA grant  from the  EU   FP7  is thanked for support for meetings and for the conduct of this review. The  Mario Negri Institute  is thanked for housing the ECRIN-IA meeting in February 2013. Trials search coordinator  Sarah Louise Klingenberg , The  Cochrane Hepato-Biliary Group at The Copenhagen Trial Unit , is thanked for expert assistance conducting the database searches for this review. All participants of ECRIN-IA are thanked for participating in discussions identifying the bottlenecks in clinical research and the threats to internal validity of clinical research (and hence threats to external validity of clinical research) suggesting ways to remove the bottlenecks and erase the threats. All authors are involved in the  ECRIN-IA  project. ML, BS, CR, L, AS, CLV, and YB all work within the field of nutrition research.