Tropomyosin receptor kinase inhibitors in the management of sarcomas.

Purpose of review Genetic aberrations resulting in tropomyosin receptor kinase (TRK) fusion proteins can drive oncogenesis and are postulated to occur in up to 1% of solid tumours. However, TRK fusions in adult sarcomas are rare and there is a significant challenge in identifying patients with sarcomas harbouring TRK fusions in the clinical setting. Despite a recent European Society of Medical Oncology consensus article regarding screening of tumours for TRK fusions, economical and practical limitations present a barrier to widespread screening of sarcomas.Recent findings Larotrectinib and entrectinib are pan-TRK inhibitors which have both received FDA approval for the management of solid tumours harbouring NTRK fusions. Initial results of a number of clinical trials have demonstrated promising efficacy and safety data, including dramatic and durable responses in patients with sarcomas. As such, TRK inhibitors represent a promising treatment option in a small cohort of adult sarcoma patients, where currently treatment options are limited. The emergence of acquired resistance is a concern associated with TRK inhibitor therapy and a number of second-generation agents targeting TRK kinase mutations driving acquired resistance have entered early-phase clinical trials.Summary With the growing appreciation of the implications of TRK fusions, this review will summarize the emerging clinical trial data of TRK inhibitors in sarcomas. Although in their infancy, clinical trial results are encouraging, and as further results and analyses are released, we will have a greater understanding of their impact on clinical practice and the management of patients with sarcomas

Elevation of marcophage migration inhibitory factor level acute myocardial infarction but not in acute myocardial ischaemia

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Dynamic sensitivity of photon-dressed atomic ensemble with quantum criticality

We study the dynamic sensitivity of an atomic ensemble dressed by a single-mode cavity field (called a photon-dressed atomic ensemble), which is described by the Dicke model near the quantum critical point. It is shown that when an extra atom in a pure initial state passes through the cavity, the photon-dressed atomic ensemble will experience a quantum phase transition showing an explicit sudden change in its dynamics characterized by the Loschmidt echo of this quantum critical system. With such dynamic sensitivity, the Dicke model can resemble the cloud chamber for detecting a flying particle by the enhanced trajectory due to the classical phase transition. © 2009 The American Physical Society.published_or_final_versio

Primary biliary cirrhosis and scleroderma complicated by Barrett's oesophagus A case report

Oesophageal problems are common in patients with scleroderma. but the association of primary biliary cirrhosis and scleroderma is uncommon. A Barrett's oesophagus identified in a patient with primary biliary cirrhosis and scleroderma is described. The Barrett's oesophagus was probably a complication of scleroderma and resulted from low lower-oesophageal sphincter pressure and severe gastro-oesophageal reflux

SOXE neofunctionalization and elaboration of the neural crest during chordate evolution

During chordate evolution, two genome-wide duplications facilitated acquisition of vertebrate traits, including emergence of neural crest cells (NCCs), in which neofunctionalization of the duplicated genes are thought to have facilitated development of craniofacial structures and the peripheral nervous system. How these duplicated genes evolve and acquire the ability to specify NC and their derivatives are largely unknown. Vertebrate SoxE paralogues, most notably Sox9/10, are essential for NC induction, delamination and lineage specification. In contrast, the basal chordate, amphioxus, has a single SoxE gene and lacks NC-like cells. Here, we test the hypothesis that duplication and divergence of an ancestral SoxE gene may have facilitated elaboration of NC lineages. By using an in vivo expression assay to compare effects of AmphiSoxE and vertebrate Sox9 on NC development, we demonstrate that all SOXE proteins possess similar DNA binding and homodimerization properties and can induce NCCs. However, AmphiSOXE is less efficient than SOX9 in transactivation activity and in the ability to preferentially promote glial over neuronal fate, a difference that lies within the combined properties of amino terminal and transactivation domains. We propose that acquisition of AmphiSoxE expression in the neural plate border led to NCC emergence while duplication and divergence produced advantageous mutations in vertebrate homologues, promoting elaboration of NC traits.published_or_final_versio

Manipulation Strategies for the Rank Maximal Matching Problem

We consider manipulation strategies for the rank-maximal matching problem. In the rank-maximal matching problem we are given a bipartite graph $G = (A \cup P, E)$ such that $A$ denotes a set of applicants and $P$ a set of posts. Each applicant $a \in A$ has a preference list over the set of his neighbours in $G$, possibly involving ties. Preference lists are represented by ranks on the edges - an edge $(a,p)$ has rank $i$, denoted as $rank(a,p)=i$, if post $p$ belongs to one of $a$'s $i$-th choices. A rank-maximal matching is one in which the maximum number of applicants is matched to their rank one posts and subject to this condition, the maximum number of applicants is matched to their rank two posts, and so on. A rank-maximal matching can be computed in $O(\min(c \sqrt{n},n) m)$ time, where $n$ denotes the number of applicants, $m$ the number of edges and $c$ the maximum rank of an edge in an optimal solution. A central authority matches applicants to posts. It does so using one of the rank-maximal matchings. Since there may be more than one rank- maximal matching of $G$, we assume that the central authority chooses any one of them randomly. Let $a_1$ be a manipulative applicant, who knows the preference lists of all the other applicants and wants to falsify his preference list so that he has a chance of getting better posts than if he were truthful. In the first problem addressed in this paper the manipulative applicant $a_1$ wants to ensure that he is never matched to any post worse than the most preferred among those of rank greater than one and obtainable when he is truthful. In the second problem the manipulator wants to construct such a preference list that the worst post he can become matched to by the central authority is best possible or in other words, $a_1$ wants to minimize the maximal rank of a post he can become matched to

Ultra high resolution of PZT 30/70 domains as imaged by PFM

iezoforce microscopy (PFM) has been used to determine the domain structure of lead zirconate titanate (PZT) (30/70) on an indium tin oxide (ITO)/glass substrate with a TiO2 boundary layer. The PZT nucleates into the perovskite form in a random crystallographic manner, which leads to a random domain structure in the final film. Using PFM it has been possible to visualize the domain structure of the PZT and determine that the domain structure has features as fine as 8 nm herringbone patterns. The possible impact of these structures for future devices utilizing nanoscale features of PZT and especially FeRAM developments is highlighted

Tocilizumab Prevents Progression of Early Systemic Sclerosis Associated Interstitial Lung Disease

OBJECTIVE: Tocilizumab has demonstrated lung function preservation in two randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of quantitative radiographic lung involvement. In this post-hoc analysis, we assess tocilizumab's impact on lung function preservation, stratifying treatment arms by the degree of radiographic lung involvement. METHODS: The focuSSced trial was a phase 3, randomized placebo-controlled trial of tocilizumab in patients with SSc and progressive skin disease. Participants had baseline and serial spirometry along with high resolution chest CT at baseline and week 48. Quantitative interstitial lung disease and fibrosis were derived using computer software. We divided quantitative interstitial lung disease in mild (5-10%), moderate (>10-20%), or severe (>20%) categories. RESULTS: Of 210 participants recruited in the trial, 136 [65%] had interstitial lung disease. The majority of these participants had moderate-to-severe involvement defined by >10% lung involvement (77%). The tocilizumab arm demonstrated preservation of forced vital capacity over 48 weeks (least squared mean change in %predicted = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean decline in the %pFVC in the tocilizumab arm at 48 weeks were -4.1, 0.7, and 2.1, and in the placebo group were -10.0, -5.7, and -6.7, respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity. CONCLUSION: Tocilizumab in early SSc- associated interstitial lung disease with progressive skin disease stabilized forced vital capacity over 48 weeks, independent of the extent of quantitative radiographic interstitial lung disease or fibrosis

Prediction of Thromboembolic Events in Heart Failure Patients in Sinus Rhythm: The Hong Kong Heart Failure Registry

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