Metalloproteinase Inhibitors: Status and Scope from Marine Organisms

Marine environment has been the source of diverse life forms that produce different biologically active compounds. Marine organisms are consistently contributing with unparalleled bioactive compounds that have profound applications in nutraceuticals, cosmeceuticals, and pharmaceuticals. In this process, screening of natural products from marine organisms that could potentially inhibit the expression of metalloproteinases has gained a huge popularity, which became a hot field of research in life sciences. Metalloproteinases, especially, matrix metalloproteinases (MMPs) are a class of structurally similar enzymes that contribute to the extracellular matrix degradation and play major role in normal and pathological tissue remodeling. Imbalance in the expression of MMPs leads to severe pathological condition that could initiate cardiac, cartilage, and cancer-related diseases. Three decades of endeavor for designing potent matrix metalloproteinase inhibitory substances (MMPIs) with many not making upto final clinical trials seek new resources for devising MMPIs. Umpteen number of medicinally valuable compounds being reported from marine organisms, which encourage current researchers to screen potent MMPIs from marine organisms. In this paper, we have made an attempt to report the metalloproteinase inhibiting substances from various marine organisms

The use of ‘PICO for synthesis’ and methods for synthesis without meta-analysis: protocol for a survey of current practice in systematic reviews of health interventions

INTRODUCTION: Systematic reviews involve synthesis of research to inform decision making by clinicians, consumers, policy makers and researchers. While guidance for synthesis often focuses on meta-analysis, synthesis begins with specifying the ’PICO for each synthesis’ (i.e. the criteria for deciding which populations, interventions, comparators and outcomes are eligible for each analysis). Synthesis may also involve the use of statistical methods other than meta-analysis (e.g. vote counting based on the direction of effect, presenting the range of effects, combining P values) augmented by visual display, tables and text-based summaries. This study examines these two aspects of synthesis. OBJECTIVES: To identify and describe current practice in systematic reviews of health interventions in relation to: (i) approaches to grouping and definition of PICO characteristics for synthesis; and (ii) methods of summary and synthesis when meta-analysis is not used. METHODS: We will randomly sample 100 systematic reviews of the quantitative effects of public health and health systems interventions published in 2018 and indexed in the Health Evidence and Health Systems Evidence databases. Two authors will independently screen citations for eligibility. Two authors will confirm eligibility based on full text, then extract data for 20% of reviews on the specification and use of PICO for synthesis, and the presentation and synthesis methods used (e.g. statistical synthesis methods, tabulation, visual displays, structured summary). The remaining reviews will be confirmed as eligible and data extracted by a single author. We will use descriptive statistics to summarise the specification of methods and their use in practice. We will compare how clearly the PICO for synthesis is specified in reviews that primarily use meta-analysis and those that do not. CONCLUSION: This study will provide an understanding of current practice in two important aspects of the synthesis process, enabling future research to test the feasibility and impact of different approaches

Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors

Critical elements of synthesis questions are incompletely reported: survey of systematic reviews of intervention effects

Objectives: To examine the characteristics of population, intervention and outcome groups and the extent to which they were completely reported for each synthesis in a sample of systematic reviews (SRs) of interventions. Study design and setting: We coded groups that were intended (or used) for comparisons in 100 randomly sampled SRs of public health and health systems interventions published in 2018 from the Health Evidence and Health Systems Evidence databases. Results: Authors commonly used population, intervention and outcome groups to structure comparisons, but these groups were often incompletely reported. For example, of 41 SRs that identified and/or used intervention groups for comparisons, 29 (71%) identified the groups in their methods description before reporting of the results (e.g., in the Background or Methods), 12 (29%) defined the groups in enough detail to replicate decisions about which included studies were eligible for each synthesis, 6 (15%) provided a rationale, and 24 (59%) stated that the groups would be used for comparisons. Sixteen (39%) SRs used intervention groups in their synthesis without any mention in the methods. Reporting for population, outcome and methodological groups was similarly incomplete. Conclusion: Complete reporting of the groups used for synthesis would improve transparency and replicability of reviews, and help ensure that the synthesis is not driven by what is reported in the included studies. Although concerted effort is needed to improve reporting, this should lead to more focused and useful reviews for decision-makers

PENGARUH PAJAK TANGGUHAN DAN TAX BOOK RATIO TERHADAP KINERJA PERUSAHAAN (Studi kasus pada Perusahan Pertambangan Subsektor Batubara yang terdaftar di BEI Tahun 2012-2016)

ABSTRAK KInerja Perusahaan dilakukan dengan Pemanfaatan Sumberdaya yang ada dalam dalam hasil yang digambarkan dan ditujukan melalui alat analisis keuangan sebagai pengukur tingkat keberhasilan dalam memperoleh laba dan menunjukan prospek di masa yang akan datang. Penelitian ini bertujuan untuk mengetahui seberapa besar pengaruh pajak tangguhan dan tax to Book ratio terhadap Kinerja perusahaan. Model penelitian yang digunakan adalah analisis deskriptif dan assosiatif. Populasi dari penelitian ini adalah perusahaan manufaktur subsektor otomotif dan konsumen yang terdaftar di Bursa Efek Indonesia periode 2012-2016 berjumlah 13 perusahaan. Metode penelitian sampel menggunakan teknik purposive sampling dengan total sampel 6 perusahaan yang memenuhi kriteria. Analisis data dilakukakn dengan menggunakan regresi linier berganda. Hasil penelitian menunjukkan bahwa Kinerja perusahaan yang dilaksanakan oleh perusahaan manufaktur subsektor Batubara periode 2012-2016 memiliki rata-rata sebesar 0,100. Secara parsial pajak tangguhan berpengaruh terhadap Kinerja perusahaan dengan kontribusi pengaruh sebesar 9,3%. Sedangkan tax to Book ratiosecara parsial berpengaruh terhadap Kinerja perusahaan dengan kontribusi pengaruh sebesar 24,9%. Secara simultan pajak tangguhan dan tax to Book ratio berpengaruh terhadap Kinerja perusahaan dengan kontribusi 34,2 % pada perusahaan manufaktur subsektor Batubara yang terdaftar di Bursa Efek Indonesia periode 2012-2016. Kata kunci: Pajak tangguhan, Tax to Book ratio dan Kinerja Perusahaan

Are lower rates of surgery amongst older women with breast cancer in the UK explained by co-morbidity?

Background: Around 60% of women greater than or equal to 80 years old, in the UK do not have surgery for their breast cancer (vs<10% of younger age groups). The extent to which this difference can be accounted for by co-morbidity has not been established. Methods: A Cancer Registry/Hospital Episode Statistics-linked data set identified women aged greater than or equal to 65 years diagnosed with invasive breast cancer (between 1 April 1997 and 31 March 2005) in two regions of the UK (n=23 038). Receipt of surgery by age was investigated using logistic regression, adjusting for co-morbidity and other patient, tumour and treatment factors. Results: Overall, 72% of older women received surgery, varying from 86% of 65–69-year olds to 34% of women aged greater than or equal to 85 years. The proportion receiving surgery fell with increasing co-morbidity (Charlson score 0=73%, score 1=66%, score 2+=49%). However, after adjustment for co-morbidity, older age still predicts lack of surgery. Compared with 65–69-year olds, the odds of surgery decreased from 0.74 (95% CI: 0.66–0.83) for 70–74-year olds to 0.13 (95% CI: 0.11–0.14) for women aged greater than or equal to 85 years. Conclusion: Although co-morbidity is associated with a reduced likelihood of surgery, it does not explain the shortfall in surgery amongst older women in the UK. Routine data on co-morbidity enables fairer comparison of treatment across population groups but needs to be more complete

Evidence synthesis software

It can be challenging to decide which evidence synthesis software to choose when doing a systematic review. This article discusses some important questions to consider in relation to the researcher’s chosen evidence synthesis approach. Software can support researchers in a range of ways. Here, the example of EPPI-Reviewer is used to explore a range of conditions and software solutions. Some review teams, for example, value collaboration across time and geographical space; in-built bias assessment tools; and line-by-line coding for qualitative textual analysis. EPPI-Reviewer has text mining automation technologies. Version 5 supports data sharing and re-use across the systematic review community. Open source software will soon be released. EPPI-Centre will continue to offer the software as a cloud-based service. The software is offered via a subscription with a one-month (extendible) trial available and volume discounts for ‘site licences’. It is free to use for Cochrane and Campbell reviews. The next EPPI-Reviewer version is being built in collaboration with NICE using ‘surveillance’ of newly published research to support ‘living’ iterative reviews. This is achieved using a combination of machine learning and traditional information retrieval technologies to identify the type of research each new publication describes and determine its relevance for a particular review, domain or guideline. While the amount of available knowledge and research is constantly increasing, the ways in which software can support the focus and relevance of data identification are also fast developing. Software advances are maximising the opportunities for the production of relevant and timely reviews

Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial

<p>Abstract</p> <p>Background</p> <p>Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.</p> <p>Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.</p> <p>First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective.</p> <p>Methods Design</p> <p>In the current Phase I/II-CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.</p> <p>Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re-irradiation at 12 months, secondary endpoint is progression-free survival.</p> <p>Discussion</p> <p>The Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning.</p> <p>Trial Registration</p> <p>NCT01166308</p