Introduction
With modern techniques facilitating limb conservation, amputation for extremity soft-tissue sarcoma (ESTS) is now rare. We sought to determine the indications and outcomes following ...major amputation for ESTS and whether amputation is prognostic of oncological outcomes in primary disease.
Patients and Methods
Patients undergoing major amputations for ESTS from 2004 to 2014 were identified from electronic patient records.
Results
The amputation rate in primary localized disease was 4.1%. Overall, 69 patients were identified, including 23 (33.3%) amputations for primary localized disease, 36 (52.2%) amputations for recurrent disease, and 10 (14.5%) amputations for metastatic disease. The local recurrence rate for localized disease at 3 years was 10.4%. Three-year overall survival (OS) was 50.3% following curative amputation, with a median survival of 41 months, and median OS following palliative amputation was 6 months. In the context of primary, localized disease, patients undergoing amputation had a greater proportion of high-grade tumors (69.6% vs. 41.1%;
p
= 0.009) of greater size (median 16.0 vs. 9.0 cm;
p
= 0.003) when compared with patients undergoing limb-conserving surgery. The rates of systemic relapse and disease-specific survival were poorer following amputation compared with limb-conserving surgery, however mode of surgery (amputation vs. limb conservation) was only prognostic for OS.
Conclusions
Amputation maintains an important role in ESTS and achieves durable local control in those unsuitable for limb-conserving surgery. Survival following amputation in the presence of metastatic disease is poor and should be reserved for patients with significant symptoms.
The flavoenzyme monoamine oxidase (MAO) regulates mammalian behavioral patterns by modulating neurotransmitters such as adrenaline and serotonin. The mechanistic basis which underpins this enzyme is ...far from agreed upon. Reported herein is that the combination of a synthetic flavin and alloxan generates a catalyst system which facilitates biomimetic amine oxidation. Mechanistic and electron paramagnetic (EPR) spectroscopic data supports the conclusion that the reaction proceeds through a radical manifold. This data provides the first example of a biorelevant synthetic model for monoamine oxidase B activity.
MAO copycat: Mimicry of monoamine oxidase B (MAO B) under aerobic and ambient conditions has been accomplished using a model flavin. Kinetic and EPR studies have offered mechanistic insight, ultimately allowing an appreciation of kinetic similarity to already published data concerning MAO B. A rate‐contributing hydrogen‐atom transfer from the amine substrate to the flavin acceptor is proposed for both the model system and MAO B.
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. ...Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells—the target for rituximab—in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.
This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.
Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 51%) or the tocilizumab group (81 49%). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 45% of 38 patients) and the tocilizumab group (23 56% of 41 patients; difference 11% 95% CI −11 to 33, p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 36% of 33 patients vs tocilizumab group 20 63% of 32 patients; difference 26% 2 to 50, p=0·035). Occurrence of adverse events (rituximab group 76 70% of 108 patients vs tocilizumab group 94 80% of 117 patients; difference 10% –1 to 21) and serious adverse events (rituximab group 8 7% of 108 vs tocilizumab group 12 10% of 117; difference 3% –5 to 10) were not significantly different between treatment groups.
The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.
Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.
An overlooked aspect of agglomeration economies, which are positive externalities that stem from the geographic clustering of industry, is that firms contribute to the externality in addition to ...benefiting from the externality. This insight suggests that if firms are heterogeneous they will differ in the net benefits they receive from agglomerating. We argue that firms with the best technologies, human capital, training programs, suppliers, or distributors will gain little, yet competitively suffer when their technologies, employees, and access to supporting industries spill over to competitors. Therefore, these firms have little motivation to geographically cluster despite the existence of agglomeration economies. Conversely, firms with the weakest technologies, human capital, training programs, suppliers, or distributors have little to lose and a lot to gain; therefore, these firms are motivated to geographically cluster. As a result, when firms are heterogeneous we expect agglomeration to be characterized by adverse selection. We find supportive evidence of these arguments by examining the location choice and survival of foreign greenfield investments in U.S. manufacturing industries.
Abstract
Since the first report of SARS-CoV-2 in China in 2019, there has been a huge debate about the origin. In this work, using a different method we aimed to strengthen the observation that no ...evidence of genetic manipulation has been found by (1) detecting classical restriction site (RS) sequence in human SARS-CoV-2 genomes and (2) comparing them with other recombinant SARS-CoV-like virus created for experimental purposes. Finally, we propose a novel approach consisting in the generation of a restriction endonucleases site map of SARS-CoV-2 and other related coronavirus genomes to be used as a fingerprint to trace the virus evolution.
Abstract Background Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are ...widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level. Methods We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics. Results Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis. Conclusions Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.
New methods for peptide modification are in high demand in drug discovery, chemical biology, and materials chemistry; methods that modify natural peptides are particularly attractive. A Pd-catalyzed, ...C–H functionalization protocol for the olefination of phenylalanine residues in peptides is reported, which is compatible with common amino acid protecting groups, and the scope of the styrene reaction partner is broad. Bidentate coordination of the peptide to the catalyst appears crucial for the success of the reaction.
Digital agriculture is exciting attention because of an expectation that food systems will be disrupted by new digital technologies through improvements in precision, efficiency, volume, speed of ...process or identity of product. This is against the background of the drive for sustainability in food systems. A diversity of technology applications is unilaterally emerging in all food chains with benefits realized through human acceptance and adoption in business processes. This paper focuses on Australia but the lessons apply to digital agriculture globally. We propose that sustainable food systems frameworks identify the relation of individual changes to broader systemic change, to relate individual changes to one another and to understand how multiple changes within a system can trigger major shifts in entire agri-food chains. With this rapidly-changing landscape in mind, we argue that food system frameworks cover five domains: production, market, capitals, governance and data technologies. We analyse experience from agricultural systems, compare it to digitization in non-agricultural systems and conclude that change will be both disruptive and cumulative. We consider the role of systems governance to be under-reported. Governance will prove critical in areas of IP legislation, policy harmonization and targeted investment.
This case report describes the care of a 75-year-old gentleman with metastatic head and neck cancer who was highly symptomatic with intractable tenacious oropharyngeal secretions. The patient ...reported subjective benefit from oral atenolol. A literature review was undertaken and identified no previous studies on the use of β-blockers for secretions in malignant disease, although some anecdotal evidence for their use in motor neuron disease. The proposed underlying mechanism is that β1-blockade reduced the protein content of salivary secretions, hence reducing its viscosity. Further studies of both the role of β-adrenoreceptors in the control of secretion viscosity and the potential role of β-blockers in alleviating symptomatic tenacious secretions are warranted.
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