Miracle-dz/UniFAR-FTUs huggingface dataset:
Current and advancing systemic treatment options for soft tissue sarcomas

Introduction: Soft tissue sarcomas are a collection of rare malignancies, the treatment of which has evolved over time. Although cytotoxic chemotherapy remains the cornerstone of management of metastatic disease, many new treatments have been developed or show great promise in the treatment of soft tissue sarcoma. Research into the different underlying pathogenesis of individual subtypes has driven progress in treatment. This has allowed development of treatments targeted to specific subtypes of sarcoma. Areas covered: We provide a review of the current field of systemic therapy in soft tissue sarcoma. This is followed by an in-depth analysis of recent developments in treatment, as well as new treatments that are aimed at specific subtypes of sarcoma, and the biological rationale behind these therapies. We also look in detail at the promising new agents currently in development. Expert opinion: Much progression has been made in treatment of soft tissue sarcomas with multiple exciting new treatments in development. However outcomes in general remain poor. Further research into the underlying pathogenesis of soft tissue sarcomas may help deliver more effective systemic therapies. Increased collaboration between basic science, translational and clinical investigators is required at national and international levels to maximise progress.
Basolateral localization of native ClC-2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS-2 domain di-leucine motif

The Cl– channel ClC-2 is expressed in transporting epithelia and has been proposed as an alternative route for Cl– efflux that might compensate for the malfunction of CFTR in cystic fibrosis. There is controversy concerning the cellular and membrane location of ClC-2, particularly in intestinal tissue. The aim of this paper is to resolve this controversy by immunolocalization studies using tissues from ClC-2 knockout animals as control, ascertaining the sorting of ClC-2 in model epithelial cells and exploring the possible molecular signals involved in ClC-2 targeting. ClC-2 was exclusively localized at the basolateral membranes of surface colonic cells or villus duodenal enterocytes. ClC-2 was sorted to the basolateral membranes in MDCK, Caco-2 and LLC-PK1-μ1B, but not in LLC-PK1-μ1A cells. Mutating a di-leucine motif (L812L813) to a di-alanine changed the basolateral targeting of ClC-2 to an apical location. The basolateral membrane localization of ClC-2 in absorptive cells of the duodenum and the colon is compatible with an absorptive function for this Cl– channel. Basolateral targeting information is contained in a di-leucine motif (L812L813) within CBS-2 domain at the C-terminus of ClC-2. It is speculated that ClC-2 also contains an apical sorting signal masked by L812L813. The proposal that CBS domains in ClC channels might behave as regulatory sites sensing intracellular signals opens an opportunity for pharmacological modulation of ClC-2 targeting.
Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Significance Alzheimer’s disease is a neurodegenerative disorder whose molecular origins have been associated with the dysregulation of a set of metastable proteins prone to aggregation. Under conditions of cellular and organismal health, the protein homeostasis system prevents effectively the misfolding and aggregation of these metastable proteins. Although it is well established that such regulatory mechanisms become progressively impaired with aging, resulting in an accumulation of protein deposits, the specific nature of such impairment has remained incompletely characterized. Through a gene coexpression analysis, here we identify the endosomal–lysosomal and ubiquitin–proteasome systems, and more generally the protein trafficking and clearance mechanisms, as key components of the protein homeostasis system that maintains the metastable proteins in their functional states. Alzheimer’s disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal–lysosomal and ubiquitin–proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer’s disease.
Durability of Fly Ash-Based Geopolymer Structural Concrete in the Marine Environment

The use of supplementary cementitious materials as partial replacements of the cement in concrete will play a significant role with respect to the environmental control of greenhouse effects and global temperature reduction. The development of geopolymer concrete (GPC), in which all of the portland cement is replaced with fly ash (in combination with sodium hydroxide and sodium silicate solutions), offers a promising alternative to ordinary portland cement concrete. This paper evaluates the durability characteristics of low-calcium fly ash-based geopolymer concrete that was subjected to a corrosive marine environment. A series of GPC beams, which contained fly ash with 8- and 14-M concentrations of NaOH and SiO2=Na2O solutions, respectively, and were centrally reinforced with a 13-mm rebar, were tested for accelerated corrosion exposurewith wet and dry cycling in artificial seawater and an induced current. A sudden rise in the current intensity that is attributable to specimen cracking was indicative of durability. The test results indicated excellent resistance of the geopolymer concrete to chloride attack, with a longer time to corrosion cracking relative to ordinary portland cement concrete. DOI: 10.1061/(ASCE)MT.1943- 5533.0000632. © 2013 American Society of Civil Engineers. CE Database subject headings: Geomaterials; Concrete; Fly ash; Sea water; Corrosion; Durability. Author keywords: Geopolymer concrete; Fly ash; Accelerated seawater corrosion; Durability.
Folic acid reduces doxorubicin‐induced cardiomyopathy by modulating endothelial nitric oxide synthase

The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO‐induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO‐induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre‐treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO‐induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre‐treatment with FA prevented DOXO‐induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S‐glutathionylation, and attenuated DOXO‐induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO‐induced cardiomyopathy.
Determination of parallelism and nonparallelism in bioassay dilution curves

There is a lack of consensus among investigators who use a variety of immunoassay techniques (e.g., enzyme-linked immunosorbent assay [ELISA] and radioimmunoassay) regarding the protocols for describing and forming standard reference or calibration curves and interpolating serum antibody concentrations. This confounds the issue of detecting the presence or absence of parallelism between standard reference serum and serially diluted serum sample curves. These curves must be parallel to support the assumption that the antibody-binding characteristics are similar enough to allow the determination of antibody levels in the diluted serum sample. There is no universal and widely adopted strategy for assessing parallelism in bioassays, and without an assurance of parallelism, investigators are not able to calculate reliable estimates for antibody concentrations in serum samples. Furthermore, single-point (dilution) serum assays do not provide information related to parallelism and nonparallelism, and this, too, may lead to considerable error when calculating antibody concentrations. When assay methodology, technique, and precision improve to the extent that standard reference serum and serially diluted serum sample curves are fit with little error, standard analysis of variance techniques are overly sensitive to negligible departures from parallelism. We present a series of guidelines that compose a protocol for assessing parallelism between bioassay dilution curves that are applicable to data derived from ELISAs. These criteria should be applicable, with minor modifications, to most immunoassay experimental situations and, most importantly, are not dependent on the mathematical model used to form the standard reference curve. These guidelines have evolved in our laboratories over the past 4 years during the performance of thousands of ELISAs for antibodies to the capsular polysaccharides of Neisseria meningitidis groups A and C and Haemophilus influenzae type b.
Symposium 3: Obesity-related cancers Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin

Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to signiﬁcantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro , in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro , this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may inﬂuence inﬂammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a signiﬁcant factor in obesity-related colon cancer. Molecular proﬁling of colon tumours will be a useful tool in future strategies to characterise the inﬂuence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.
Cleavage and polyadenylation of messenger RNA precursors in vitro occurs within large and specific 3′ processing complexes.

We have investigated the assembly of complexes associated with in vitro cleavage and polyadenylation of synthetic pre‐mRNAs by native gel electrophoresis. Incubation of SP6‐generated pre‐mRNA containing the adenovirus L3 polyadenylation site in HeLa cell nuclear extract results in the rapid assembly of specific complexes. Formation of these complexes precedes the appearance of cleaved intermediates and polyadenylated products and is dependent on an intact polyadenylation signal within the pre‐mRNA. The specific complexes do not form on RNAs with point mutations in the AAUAAA sequence upstream of the L3 polyadenylation site. Furthermore, such mutant RNAs cannot compete for factors involved in the assembly of specific complexes on wild‐type pre‐mRNA. Upon complex formation a 67‐nucleotide region of the L3 pre‐mRNA is protected from RNase T1 digestion. This region contains both the upstream AAUAAA signal and the GU‐rich downstream sequences. Cleavage and polyadenylation occur within the specific complexes and the processed RNA is subsequently released. We propose that the assembly of specific complexes represents an essential step during pre‐mRNA 3′ end formation in vitro.
Fourier approach to homogenization problems

This article is divided into two chapters. The classical problem of homogenization of elliptic operators with periodically oscillating coefficients is revisited in the first chapter. Following a Fourier approach, we discuss some of the basic issues of the subject: main convergence theorem, Bloch approximation, estimates on second order derivatives, correctors for the medium, and so on. The second chapter is devoted to the discussion of some non-classical behaviour of vibration problems of periodic structures.
Increased uptake of non‐pathogenic E. coli via the follicle‐associated epithelium in longstanding ileal Crohn's disease

In Crohn's disease (CD), inflammation is driven by luminal commensal micro‐organisms; however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle‐associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non‐pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr‐EDTA, horseradish peroxidase, and non‐pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non‐exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K‐12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr‐EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co‐localizing with dendritic cells, and augmented tissue release of TNF‐α. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Analysis of Wrinkled Membranes Bounded With Macro-Fiber Composite (MFC) Actuators

In this paper we focus on a study which involves quantifying the effects of Macro Fiber Composite (MFC) actuators on the pattern and magnitude of wrinkles in a membrane when exposed to various loadings. An ABAQUS finite element code is employed for this research. The membrane in this study has a rectangular shape which is clamped at one edge and is free to move in the horizontal direction at the other edge. MFC actuators are bounded to the membrane to make a bimorph configuration.Copyright © 2010 by ASME
Discovery of large conical stromatolites in Lake Untersee, Antarctica

Lake Untersee is one of the largest (11.4 km2) and deepest (>160 m) freshwater lakes in East Antarctica. Located at 71°S the lake has a perennial ice cover, a water column that, with the exception of a small anoxic basin in the southwest of the lake, is well mixed, supersaturated with dissolved oxygen, alkaline (pH 10.4) and exceedingly clear. The floor of the lake is covered with photosynthetic microbial mats to depths of at least 100 m. These mats are primarily composed of filamentous cyanophytes and form two distinct macroscopic structures, one of which – cm‐scale cuspate pinnacles dominated by Leptolyngbya spp. – is common in Antarctica, but the second – laminated, conical stromatolites that rise up to 0.5 m above the lake floor, dominated by Phormidium spp. – has not previously been reported in any modern environment. The laminae that form the conical stromatolites are 0.2–0.8 mm in thickness consisting of fine clays and organic material; carbon dating implies that laminations may occur on near decadal timescales. The uniformly steep sides (59.6 ± 2.5°) and the regular laminar structure of the cones suggest that they may provide a modern analog for growth of some of the oldest well‐described Archean stromatolites. Mechanisms underlying the formation of these stromatolites are as yet unclear, but their growth is distinct from that of the cuspate pinnacles. The sympatric occurrence of pinnacles and cones related to microbial communities with distinct cyanobacterial compositions suggest that specific microbial behaviors underpin the morphological differences in the structures.
Steroid Avoidance or Withdrawal Regimens in Paediatric Kidney Transplantation: A Meta-Analysis of Randomised Controlled Trials

Background We combined the outcomes of all randomised controlled trials to investigate the safety and efficacy of steroid avoidance or withdrawal (SAW) regimens in paediatric kidney transplantation compared with steroid-based (SB) regimens. Methods A systematic literature search of PubMed, Embase, Cochrane Library, the trials registry and BIOSIS previews was performed. A change in the height standardised Z-score from baseline (ΔHSDS) and acute rejection were the primary endpoints. Results Eight reports from 5 randomised controlled trials were included, with a total of 528 patients. Sufficient evidence of a significant increase in the ΔHSDS was observed in the SAW group (mean difference (MD) = 0.38, 95% confidence interval (CI) 0.07–0.68, P = 0.01), particularly within the first year post-withdrawal (MD = 0.22, 95% CI 0.10–0.35, P = 0.0003) and in the prepubertal recipients (MD = 0.60, 95% CI 0.21–0.98, P = 0.002). There was no significant difference in the risk of acute rejection between the groups (relative risk = 1.04, 95% CI 0.80–1.36, P = 0.77). Conclusions The SAW regimen is justified in select paediatric renal allograft recipients because it provides significant benefits in post-transplant growth within the first year post-withdrawal with minimal effects on the risk of acute rejection, graft function, and graft and patient survival within 3 years post-withdrawal. These select paediatric recipients should have the following characteristics: prepubertal; Caucasian; with primary disease not related to immunological factors; de novo kidney transplant recipient; with low panel reactive antibody.
Evaluation of sorafenib for hepatocellular carcinoma by contrast-enhanced ultrasonography: a pilot study.

AIM To determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating early response to sorafenib for hepatocellular carcinoma (HCC). METHODS Fourteen advanced HCC patients who received sorafenib 400/800 mg/d for at least 4 wk and were followed up by CEUS were enrolled in this study. CEUS was performed before treatment and 2 and 4 wk after treatment, and images of the target lesion in the arterial phase were recorded for each patient. The images were analyzed by AtPI. Color mapping (CM) images obtained by AtPI were compared before and after the treatment. In these CM images, the mean arrival time of the contrast agent in the region of interest from the starting point [mean time (MT)] was calculated. In each patient, differences between MT before and MT 2 and 4 wk after the treatment were compared with responses evaluated 4-8 wk after the treatment by dynamic computed tomography (CT), and statistical analysis was performed. Modified response evaluation criteria in solid tumors was used for the response evaluation. RESULTS In CM images both 2 and 4 wk after the treatment, delays in the arrival time of the contrast agent were noted in 8 of the 14 patients. In the other 6 patients, no color changes were observed in the tumor, or red and/or yellow increase, suggesting a decrease in blood flow velocity between images 2 and 4 wk after the treatment and those before the treatment. Dynamic CT could be performed 4-8 wk after the treatment in 13 of the 14 patients. Median differences in the MT were 1.13 s and 1.015 s, 2 and 4 wk after the treatment, respectively, in the 8 patients who showed stable disease (SD)/partial response (PR) on dynamic CT. Median differences in the MT were -0.39 s and -0.95 s, 2 and 4 wk after the treatment, respectively, in the 5 patients who showed progressive disease (PD). Differences in the median MT between SD/PR and PD groups were significant 2 and 4 wk after the treatment with P = 0.019 and P = 0.028, respectively. CONCLUSION AtPI by CEUS using Sonazoid is suggested to be useful for evaluating early responses to sorafenib.
Face recognition using m-MSD and SVD with single training image

Maximum scatter difference (MSD) has been widely used in face recognition for feature extraction. However, its advantage will decrease when each object has only one training sample because the intra-class variations cannot be statistically measured in this case. To address the problem, a novel method based on m-MSD and SVD is proposed in this paper. A facial image is decomposed by the SVD algorithm, so one image can be transformed into several approximate images by reconstructing method with different number of singular values. That is to say, the number of training sample for each object is increased by singular value decomposition algorithm. Thus, the MSD algorithm can be applied to extract the discriminant features. Experiment results based on FERET and ORL face database show that the proposed method is efficient and it can achieve higher recognition rate than several existing algorithms.