bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory vs. helper CD4+T-cell ratios and the progression of HIV/AIDS disease
Authors: Ndifon Wilfred , Dushoff Jonathan , Coombs Daniel
Published: June 2014

The causes of individual variability in the length of time between human immunodeficiency virus (HIV) infection and the development of AIDS are incompletely understood. Here, we present a novel hypothesis: that the relative magnitude of responses to HIV mediated by CD4+T regulatory (Treg) cells vs. CD4+T effector (Teff) cells is a critical determinant of variability in AIDS progression rates. We use a simple mathematical model to show that this hypothesis can plausibly explain three qualitatively different outcomes of HIV infection – fast or slow progression to AIDS, and long-term non-progression to AIDS – based on individual variation in underlying T-cell response. This hypothesis also provides a unifying explanation for various other empirical observations, suggesting in particular that both aging and certain dual infections increase the rate of AIDS progression because they increase the strength of the Treg cell response. We discuss potential therapeutic implications of our results.
Long-term balancing selection inLAD1maintains a missense trans-species polymorphism in humans, chimpanzees and bonobos
Authors: Teixeira João C. , de Filippo Cesare , Weihmann Antje , Meneu Juan R. , Racimo Fernando , Dannemann Michael , Nickel Birgit , Fischer Anne , Halbwax Michel , Andre Claudine , Atencia Rebeca , Meyer Matthias , Parra Genís , Pääbo Svante , Andrés Aida M.
Published: June 2014

Balancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in theHomo-Panclade. We sequenced the exome of 20 humans, 20 chimpanzees and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 million years of independent evolution. While the majority of these trSNPs were found in three genes of the MHC cluster, we also uncovered one coding trSNP (rs12088790) in the geneLAD1. All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here we focus on the trSNP inLAD1, a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression ofLAD1.
Reconstructing subclonal composition and evolution from whole genome sequencing of tumors
Authors: Deshwar Amit G. , Vembu Shankar , Yung Christina K. , Jang Gun Ho , Stein Lincoln , Morris Quaid
Published: June 2014

Tumors often contain multiple, genetically distinct subpopulations of cancerous cells. These so-called subclonal populations are defined by distinct somatic mutations that include point mutations such as single nucleotide variants and small indels - collectively called simple somatic mutations (SSMs) - as well as larger structural changes that result in copy number variations (CNVs). In some cases, the genotype and prevalence of these subpopulations can be reconstructed based on high-throughput, short-read sequencing of DNA in one or more tumor samples. To date, no automated SSM-based subclonal reconstructions have been attempted on WGS data; and CNV-based reconstructions are limited to tumors with two or fewer cancerous subclonal populations and with a small number of CNVs.

We describe a new automated method, PhyloWGS, that can be applied to WGS data from one or more tumor samples to perform subclonal reconstruction based on both CNVs and SSMs. PhyloWGS successfully recovers the composition of mixtures of a highly rearranged TGCA cell line when a CNV-based method fails. On WGS data with average read depth of 40 from five time-series chronic lymphocytic leukemia samples, PhyloWGS recovers the same tumor phylogeny previously reconstructed using deep targeted resequencing. To further explore the limits of WGS-based subclonal reconstruction, we ran PhyloWGS on simulated data: PhyloWGS can reliably reconstruct as many as three cancerous subpopulations based on 30-50x coverage WGS data from a single tumor sample with 10’s to 1000’s of SSMs per subpopulation. At least five cancerous subpopulations can be reconstructed if provided with read depths of 200 or more.

PhyloWGS is the first automated method that can be applied to WGS tumor data that accurately reconstructs the frequency, genotype and phylogeny of the subclonal populations based on both SSMs and CNVs. It also provides a principled, automated approach to combining overlapping SSM and CNV data. By demonstrating the utility of PhyloWGS on medium depth WGS data, including from examples with highly rearranged chromosomes, we have greatly expanded the range of tumors for which subclonal reconstruction is possible.
Subdigital adhesive pad morphology varies in relation to structural habitat use in the Namib Day Gecko
Authors: Collins Clint E. , Russell Anthony P. , Higham Timothy E.
Published: June 2014

Morphological features that lead to increased locomotor performance, such as faster sprint speed, are thought to evolve in concert with habitat use. The latter depends on available habitat structure and how the animal moves within that habitat. Thus, this behavioural variation will impact how natural selection acts on locomotion and morphology.

Quantifying the interplay between escape behaviour and locomotor morphology across habitats that vary in structural composition could reveal how selection acts on locomotion at local levels. Substrate features, such as incline and topographical variation, are likely key drivers of morphological and functional disparity among terrestrial animals. We investigated the impact of habitat variation and escape behaviour on morphology, including the adhesive system, of Rhoptropus afer, a diurnal and cursorial gecko from Namibia. Substrate incline and topographical variation are likely important for this pad‐bearing gecko due to the trade‐off between adhering and sprinting (i.e. using adhesion results in decreased sprint speed).

We corroborate the hypothesis that the adhesive system exhibits the greatest degree of reduction in populations that utilize the flattest terrain during an escape. Our findings suggest that the adhesive apparatus is detrimental to rapid locomotion on relatively horizontal surfaces and may thus be counterproductive to the evasion of predators in such situations. A broad scale analysis of geckos would determine whether diversity of adhesive morphology is driven primarily by habitat use.

Phenotypic plasticity of the adhesive system and interspecific competition are plausible candidates for driving our results. However, it is unclear whether the differences we observed have a genetic basis. Future work should focus on how variation of the adhesive system impacts downstream locomotor components such as kinematics and mechanics and how the integration of these traits is related to habitat use.
Κ‐CN gene polymorphism in Nili‐ravi buffalo, Achai and Sahiwal cattle of Pakistan
Authors: ghafoor Abdul , Riaz Muhammad N , Zahur Aamer B , Abbas Nasir , Yousaf Muhammad , Shah Abdullah , Ishaq Rafaqat , Suleman Muhammad
Published: June 2014

Kappa‐casein (κ‐CN) is the subtype of casein protein, an important constituent of bovine milk protein. The current study was undertaken to investigate the genetic polymorphism in κ‐CN gene of Nili‐ravi buffalo, Achai and Sahiwal cattle of Pakistan using polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) technique. The Nili‐ravi buffalo was found to be monomorphic (genotype BB only) for κ‐CN gene. Achai cattle were polymorphic for κ‐CN (having three genotypes AA, AB and BB) with a frequency of 0.70, 0.18 and 0.12, respectively, while in Sahiwal cattle, both the genotypes AA and AB were found with genotypic frequencies of 0.92 and 0.08, respectively. The presence of genotype BB in Achai cattle is surprising as it is absent in most of the cattle breeds worldwide.
Stereoscopy and Scanning Electron Microscopy of Brazil Nut (Bertholletia excelsa H.B.K.) Shell, Brown Skin, and Edible Part: Part One—Healthy Nut
Authors: Scussel Vildes M. , Manfio Daniel , Savi Geovana D. , Moecke Elisa H.S.
Published: June 2014

In this article, tissue layers and cells characteristics of the Brazil nut (Bertholletia excelsa H.B.K.) shell (tegument), brown skin (testae), and edible part (cotyledons) were identified by stereoscopy (SM) and scanning electron microscopies (SEM). (a) The shell (a lignin rich, protective wall) varies in thickness throughout the nut structure and comprises different tissue types (total 3)/texture (hard/mid‐hard/soft), layers (2 to 5), colors (light to dark brown and white to cream), cell shape (amorphous/flattened on both surfaces; polygonal and cylindrical with thick, porous primary and secondary wall in cross‐section), and vascular distribution (helically and polyedrical thickened vessels at soft tissue and locule/channel structures). These variations are observed either in the shell faces, face corners, nut tips, or locule in testae. (b) The brown skin (shell nut part linked to both the shell and edible part) is made of flattened irregular‐shaped parenchymal cells distributed in several layers with more flexible fibrous, thinner wall tissue than shell. It has both rough and smooth shiny texture on the upper and lower surfaces, respectively. However, the nut (c) edible part, that is the nut storage tissue, shows several different tissue/cell layers starting from epidermis (double/triple cells sequence of round and palisade shapes) layer–the endosperm tissue. The parenchymal tissues show cells of irregular shape with small and larger sizes distributed in regular and randomly layers, respectively, separated by a short meristem tissue layer. The cortex cells increase in size as they approach the cotyledons junction. The Brazil nut part's tissue layers and cells were identified by the SM and SEM microscopy methods applied, which provides knowledge for further understanding of nut alterations that may occur either in the forest or during the factory processing.
Extrinsic Attributes That Influence Parents’ Purchase of Chocolate Milk for Their Children
Authors: Li Xiaomeng E. , Lopetcharat Kannapon , Drake MaryAnne
Published: June 2014

The consumption of milk is essential for children's heath; and flavored milk, especially chocolate milk, is often purchased to increase children's milk consumption. However, the sugar content of chocolate milk has raised health concerns. As such, it is important to understand chocolate milk extrinsic attributes that influence parents’ purchase decisions when they are purchasing chocolate milk for their children. The objective of this study was to determine the key extrinsic attributes for parents when they purchase chocolate milk for their children. An online survey with a conjoint analysis design, emotions questions, and Kano questionnaire that focused on chocolate milk was conducted targeting parents. Three hundred and twelve parents participated in the survey. Parents reported positive emotions including good, good natured, happy, loving, and satisfied when purchasing chocolate milk for their kids. Three segments of parents were identified with subtle but distinct differences in their key preferences for chocolate milk attributes for their children. Type of sweetener was the primary driver of choice for purchasing chocolate milk for children followed by fat content. Among sweetener types, natural noncaloric/nonnutritive sweeteners or sucrose were preferred over artificial sweeteners, and reduced fat was preferred over full fat or skim milk. Kano results revealed that reduced fat and sugar with an all natural label and added vitamins, minerals, and protein were attractive to the majority of parents when purchasing chocolate milk for their kids.
Inbreeding depression in livestock species: review and meta‐analysis
Authors: Leroy G.
Published: June 2014

Inbreeding, by virtue of its consequence on traits of interest, is a topic of major interest for geneticists and animal breeders. Based on meta‐analysis conducted on 57 studies and seven livestock species considering a wide variety of selected traits, it was estimated that inbreeding depression corresponds to on average a decrease of 0.137 percent of the mean of a trait per 1 percent of inbreeding. The decrease was larger for production traits (reduction of 0.351%) than for other trait categories. For populations raised as purebreds, inbreeding depression may impact the economic income of breeders. There is a need for studies assessing the existence of an inbreeding purge phenomenon as well as the impact of inbreeding on adaptation capacities of livestock species. Promises brought by the development of dense genotyping as well as functional genomics will increase the capacities to improve our understanding and management of the phenomenon.
Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes
Authors: Arendt Maja , Fall Tove , Lindblad‐Toh Kerstin , Axelsson Erik
Published: June 2014

High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch‐rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed‐dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.
Chlamydia muridarum Infection Associated Host MicroRNAs in the Murine Genital Tract and Contribution to Generation of Host Immune Response
Authors: Gupta Rishein , Arkatkar Tanvi , Yu Jieh‐Juen , Wali Shradha , Haskins William E. , Chambers James P. , Murthy Ashlesh K. , Bakar Sazaly Abu , Guentzel M Neal , Arulanandam Bernard P.
Published: June 2014

Problem

Chlamydia trachomatis (CT) is the leading sexually transmitted bacterial infection in humans and is associated with reproductive tract damage. However, little is known about the involvement and regulation of microRNAs (miRs) in genital CT.

Methods

We analyzed miRs in the genital tract (GT) following C. muridarum (murine strain of CT) challenge of wild type (WT) and CD4+ T‐cell deficient (CD4−/−) C57BL/6 mice at days 6 and 12 post‐challenge.

Results

At day 6, miRs significantly downregulated in the lower GT were miR‐125b‐5p, ‐16, ‐214, ‐23b, ‐135a, ‐182, ‐183, ‐30c, and ‐30e while ‐146 and ‐451 were significantly upregulated, profiles not exhibited at day 12 post‐bacterial challenge. Significant differences in miR‐125b‐5p (+5.06‐fold change), ‐135a (+4.9), ‐183 (+7.9), and ‐182 (+3.2) were observed in C. muridarum‐infected CD4−/− compared to WT mice. In silico prediction and mass spectrometry revealed regulation of miR‐135a and ‐182 and associated proteins, that is, heat‐shock protein B1 and alpha‐2HS‐glycoprotein.

Conclusion

This study provides evidence on regulation of miRs following genital chlamydial infection suggesting a role in pathogenesis and host immunity.
A randomised controlled trial of ultrasound‐guided transversus abdominis plane block for renal transplantation
Authors: Gulyam Kuruba S. M. , Mukhtar K. , Singh S. K.
Published: June 2014

We conducted this study to evaluate the efficacy of a transversus abdominis plane block in reducing morphine requirements in the first 24 h after renal transplant surgery. We performed transversus abdominis plane injections under ultrasound guidance in 54 patients with either 20 ml levobupivacaine 0.5% (n = 27) or 20 ml saline 0.9% (n = 27). All patients received regular paracetamol and patient‐controlled analgesia postoperatively. Three participants were not studied owing to protocol violations. In the remaining 51 patients, median (IQR [range]) morphine consumption in the first 24 h was similar in both the transversus abdominis plane group (19.4 (11.7−28.6 [0.5−49.8]) mg) and the control group (16.4 (12.0−31.0 [0.0−61.7]) mg), p = 0.94. We found that use of ultrasound‐guided transversus abdominis plane block for renal transplantation did not reduce 24‐h morphine requirements.
The suprasacral parallel shift vs lumbar plexus blockade with ultrasound guidance in healthy volunteers – a randomised controlled trial
Authors: Bendtsen T. F. , Pedersen E. M. , Haroutounian S. , Søballe K. , Moriggl B. , Nikolajsen L. , Hasselstrøm J. B. , Fisker A. K. , Strid J. M. C. , Iversen B. , Børglum J.
Published: June 2014

Surgical anaesthesia with haemodynamic stability and opioid‐free analgesia in fragile patients can theoretically be provided with lumbosacral plexus blockade. We compared a novel ultrasound‐guided suprasacral technique for blockade of the lumbar plexus and the lumbosacral trunk with ultrasound‐guided blockade of the lumbar plexus. The objective was to investigate whether the suprasacral technique is equally effective for anaesthesia of the terminal lumbar plexus nerves compared with a lumbar plexus block, and more effective for anaesthesia of the lumbosacral trunk. Twenty volunteers were included in a randomised crossover trial comparing the new suprasacral with a lumbar plexus block. The primary outcome was sensory dermatome anaesthesia of L2–S1. Secondary outcomes were peri‐neural analgesic spread estimated with magnetic resonance imaging, sensory blockade of dermatomes L2–S3, motor blockade, volunteer discomfort, arterial blood pressure change, block performance time, lidocaine pharmacokinetics and complications. Only one volunteer in the suprasacral group had sensory blockade of all dermatomes L2–S1. Epidural spread was verified by magnetic resonance imaging in seven of the 34 trials (two suprasacral and five lumbar plexus blocks). Success rates of the sensory and motor blockade were 88–100% for the major lumbar plexus nerves with the suprasacral technique, and 59–88% with the lumbar plexus block (p > 0.05). Success rate of motor blockade was 50% for the lumbosacral trunk with the suprasacral technique and zero with the lumbar plexus block (p < 0.05). Both techniques are effective for blockade of the terminal nerves of the lumbar plexus. The suprasacral parallel shift technique is 50% effective for blockade of the lumbosacral trunk.
The outer mantle epithelium of Haliotis tuberculata (Gastropoda Haliotidae): an ultrastructural and histochemical study using lectins
Authors: Álvarez Nogal Rafael , Molist García Pilar
Published: June 2014

The mantle of molluscs has been the subject of many studies as it is the organ that forms the shell. Microscopic studies in particular focus on the outer mantle epithelium, but few studies address this epithelium in a histochemical way. In this study, the outer mantle epithelium in adult specimens of Haliotis tuberculata is studied, that is, in specimens involved in maintaining and repairing the shell rather than in generating it. The epithelial cells are studied by scanning (SEM) and transmission electron microscopy (TEM), and by histochemical techniques, including the use of lectins for their biochemical characterization. The epithelium is composed of pigmented epidermal cells with small microvilli and junctional complexes. It furthermore contains a few ciliated cells, as well as two types of secretory cells which differ in the ultrastructural appearance of their secretory granules and their glycoconjugate content. Histochemical study shows secretory cells containing sulphated glycoconjugates such as glycosaminoglycans or mucins rich in N‐acetylgalactosamine and N‐glycoproteins rich in fucose. Furthermore, the apical regions of the epidermal cells are positive for lectins that label fucose, mannose and N‐acetylglucosamine. The role of epithelial cells in the synthesis of structural components of the shell is discussed.
Effects of Antihypertensive and Triglyceride‐lowering Agents on Hepatic Copper Concentrations in Rats with Fatty Liver Disease
Authors: Ackerman Zvi , Skarzinski Galina , Grozovski Maria , Oron‐Herman Mor , Sela Ben‐Ami
Published: June 2014

Copper deficiency had been suggested to link between fructose‐enriched diet (FED) and the development of non‐alcoholic fatty liver disease (NAFLD). In this study, we characterized changes in hepatic copper concentrations and hepatic oxidative milieu, in rats with the metabolic syndrome and NAFLD as a result of FED with pharmacological manipulations to reduce blood pressure or plasma triglycerides. Changes in plasma and hepatic copper concentrations were correlated with changes observed in the immunohistochemical hepatic expression of copper–zinc–superoxide dismutase (CuZnSOD; SOD1), metallothionein (MT) and nitrotyrosine (NITT). FED administration was associated with a 2.2‐fold reduction in hepatic copper concentrations, a decrease in the hepatic SOD1 expression, disappearance of the hepatic MT expression and increase in the hepatic NITT expression. Bezafibrate administration restored the hepatic copper concentrations and the hepatic SOD1 expression to levels that were observed in the control rats. A significant positive correlation between hepatic copper concentrations and the values of hepatic SOD1 expression of each animal included in this study was found. Administration of either captopril or bezafibrate increased hepatic MT expression, however, to levels that were lower than those observed in the control group. Administration of either amlodipine, or captopril or bezafibrate to the FED rats, had no effect on hepatic NITT expression. NAFLD development in FED rats is associated with a decrease in hepatic copper concentrations that is associated with a decrease in the hepatic SOD1 expression. Bezafibrate administration increases hepatic copper concentrations and restores the hepatic SOD1 expression.
Current regimens and novel agents for mantle cell lymphoma
Authors: Chen Yiming , Wang Michael , Romaguera Jorge
Published: June 2014

Mantle cell lymphoma is a heterogeneous subtype of non‐Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol‐4,5‐bisphosphate 3‐kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.
Properties of hypothesis testing techniques and (Bayesian) model selection for exploration‐based and theory‐based (order‐restricted) hypotheses
Authors: Kuiper Rebecca M. , Nederhoff Tim , Klugkist Irene
Published: June 2014

In this paper, the performance of six types of techniques for comparisons of means is examined. These six emerge from the distinction between the method employed (hypothesis testing, model selection using information criteria, or Bayesian model selection) and the set of hypotheses that is investigated (a classical, exploration‐based set of hypotheses containing equality constraints on the means, or a theory‐based limited set of hypotheses with equality and/or order restrictions). A simulation study is conducted to examine the performance of these techniques. We demonstrate that, if one has specific, a priori specified hypotheses, confirmation (i.e., investigating theory‐based hypotheses) has advantages over exploration (i.e., examining all possible equality‐constrained hypotheses). Furthermore, examining reasonable order‐restricted hypotheses has more power to detect the true effect/non‐null hypothesis than evaluating only equality restrictions. Additionally, when investigating more than one theory‐based hypothesis, model selection is preferred over hypothesis testing. Because of the first two results, we further examine the techniques that are able to evaluate order restrictions in a confirmatory fashion by examining their performance when the homogeneity of variance assumption is violated. Results show that the techniques are robust to heterogeneity when the sample sizes are equal. When the sample sizes are unequal, the performance is affected by heterogeneity. The size and direction of the deviations from the baseline, where there is no heterogeneity, depend on the effect size (of the means) and on the trend in the group variances with respect to the ordering of the group sizes. Importantly, the deviations are less pronounced when the group variances and sizes exhibit the same trend (e.g., are both increasing with group number).
Platelets promote osteosarcoma cell growth through activation of the platelet‐derived growth factor receptor‐Akt signaling axis
Authors: Takagi Satoshi , Takemoto Ai , Takami Miho , Oh‐hara Tomoko , Fujita Naoya
Published: June 2014

The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation‐inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor‐platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma‐platelet interactions induce the release of platelet‐derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co‐culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho‐antibody arrays revealed that co‐culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma‐platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated‐PDGFR and ‐Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet‐induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma‐platelet interactions may eradicate osteosarcomas.
Survival benefit from S‐1 as compared to Fluorouracil in Asian patients with advanced gastrointestinal cancer: A meta‐analysis
Authors: Cao Chunxiang , Zhang Xunlei , Kuang Meng , Gu Dongying , He Mingliang , Chen Jinfei , Tang Cuiju
Published: June 2014

Whether S‐1 could replace 5‐Fluorouracil (5‐Fu) or not in the treatment of advanced gastrointestinal (GI) cancer (including advanced gastric cancer [AGS] and metastatic colorectal cancer [mCRC]) in Asian patients has been controversial. This meta‐analysis was performed to compare the activity, efficacy and toxicity of S‐1‐based versus 5‐Fu‐based chemotherapy in those Asian patients. Randomized controlled trials (RCTs) were identified by electronic search of Pubmed. Relevant abstracts were manually searched to identify relevant trials. A total of 2182 patients from eight RCTs were included, and our results demonstrated that S‐1‐based chemotherapy significantly improved overall survival (OS) (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77–1.00) and overall response rate (ORR) (odds ratio [OR], 1.72; 95% CI, 1.09–2.70), but no significant progression‐free survival (PFS) benefit was found between arms (HR, 0.87; 95% CI, 0.72–1.06). Subgroup analyses revealed that S‐1‐based chemotherapy significantly improved OS and ORR in subgroups of patients with non‐platinum containing regimens (P = 0.041; P = 0.034) and patients with no prior chemotherapy history (P = 0.025; P = 0.016). Statistically significant improvements of PFS and ORR in the S‐1‐based chemotherapy were observed in the subgroup of patients with AGC (P < 0.001; P = 0.005). S‐1‐based chemotherapy was characterized by significantly higher incidences of diarrhea, fatigue and thrombocytopenia, and a lower incidence of nausea. This analysis provided strong evidence for survival benefits of S‐1, and S‐1‐based chemotherapy could be considered to replace 5‐Fu‐based therapy for the treatment of advanced GI cancer in Asian patients.
Meta‐analysis comparing higher and lower dose radiotherapy for palliation in locally advanced lung cancer
Authors: Ma Jie‐Tao , Zheng Jia‐He , Han Cheng‐Bo , Guo Qi‐Yong
Published: June 2014

The purpose of this meta‐analysis was to compare higher dose (≥30 Gy) and lower dose (<30 Gy) radiotherapy (RT) on palliation of symptoms and survival in patients with locally advanced lung cancer. A search of PubMed and Google Scholar was conducted on 10 June 2013 using combinations of the search terms: radiotherapy, non‐small‐cell lung carcinoma, palliative, supportive, symptom relief. Inclusion criteria were: (i) palliative thoracic RT; (ii) randomized controlled trial; (iii) English language; and (iv) compared outcomes between higher dose (≥30 Gy) and lower dose (<30 Gy) RT. The primary outcome was palliation of symptoms (cough, chest pain, hemoptysis), and 1‐ and 2‐year overall survival. Tests of heterogeneity, sensitivity, and publication bias were performed. Five randomized controlled trials with a total of 1730 patients with lung cancer were included in the meta‐analysis. There were 925 patients treated with a higher RT dose (≥30 Gy) and 805 treated with a lower RT dose (<30 Gy). The combined odds ratios (ORs) indicated no significant difference in palliation of cough, chest pain, and hemoptysis between the higher dose and lower dose RT groups (combined ORs = 0.88, 1.83, 1.39, respectively). The 1‐ and 2‐year OS rates were similar between the high and low dose RT groups (combined ORs = 1.09 and 1.38, respectively). This meta‐analysis indicates that high dose (≥30 Gy) and lower dose (<30 Gy) RT provide similar symptom palliation and 1‐ and 2‐year OS in patients with locally advanced lung cancer.
Clinical outcome of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly in the rituximab era
Authors: Sato Ai , Nakamura Naoya , Kojima Minoru , Ohmachi Ken , Carreras Joaquim , Kikuti Yara Yukie , Numata Hiroki , Ohgiya Daisuke , Tazume Kei , Amaki Jun , Moriuchi Makiko , Miyamoto Mitsuki , Aoyama Yasuyuki , Kawai Hidetsugu , Ichiki Akifumi , Hara Ryujiro , Kawada Hiroshi , Ogawa Yoshiaki , Ando Kiyoshi
Published: June 2014

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.
Deflection of vascular endothelial growth factor action by SS18–SSX and composite vascular endothelial growth factor‐ and chemokine (C‐X‐C motif) receptor 4‐targeted therapy in synovial sarcoma
Authors: Wakamatsu Toru , Naka Norifumi , Sasagawa Satoru , Tanaka Takaaki , Takenaka Satoshi , Araki Nobuhito , Ueda Takafumi , Nishizawa Yasuko , Yoshikawa Hideki , Itoh Kazuyuki
Published: June 2014

Synovial sarcoma (SS) is a malignant soft‐tissue tumor characterized by the recurrent chromosomal translocation SS18–SSX. Vascular endothelial growth factor (VEGF)‐targeting anti‐angiogenic therapy has been approved for soft‐tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS18–SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18–SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18–SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C‐X‐C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18–SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS.
Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer
Authors: Matsuda Yoko , Yoshimura Hisashi , Suzuki Taeko , Uchida Eiji , Naito Zenya , Ishiwata Toshiyuki
Published: June 2014

The alternative splicing of the extracellular domain of fibroblast growth factor receptor (FGFR)‐2 generates the IIIb and IIIc isoforms. Expression of FGFR‐2 IIIb correlates with vascular endothelial growth factor‐A (VEGF‐A) expression and venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR‐2 IIIc expression correlates with faster development of liver metastasis after surgery, and increased proliferation rates and invasion of the cancer. In this study, we analyzed the expression and roles of total FGFR‐2 (both isoforms) to determine the effectiveness of FGFR‐2‐targeting therapy for PDAC. Immunohistochemically, FGFR‐2 was highly expressed in 25/48 (52.1%) PDAC cases, and correlated with advanced stage cancer. In FISH analysis, FGFR2 was amplified in 3/7 PDAC cell lines. We stably transfected an FGFR‐2 shRNA targeting the IIIb and IIIc isoforms into FGFR2‐amplified PDAC cells. The proliferation rates, migration, and invasion of FGFR‐2‐shRNA‐transfected cells were lower than those of control cells in vitro. In response to FGF‐2, FGFR‐2‐shRNA‐transfected cells showed decreased phosphorylation of ERK compared with control cells. The FGFR‐2‐shRNA‐transfected cells also expressed lower levels of vascular endothelial growth factor‐A than control cells, and formed smaller s.c. tumors in nude mice. These findings suggest that FGFR‐2 is a therapeutic target for inhibition in PDAC.
Safely targeting cancer stem cells via selective catenin coactivator antagonism
Authors: Lenz Heinz‐Josef , Kahn Michael
Published: June 2014

Throughout our life, long‐lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self‐renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG‐001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI‐724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.
Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non‐small cell lung cancer
Authors: Ichinose Junji , Watanabe Kousuke , Sano Atsushi , Nagase Takahide , Nakajima Jun , Fukayama Masashi , Yatomi Yutaka , Ohishi Nobuya , Takai Daiya
Published: June 2014

Alternative polyadenylation (APA), which induces shortening of the 3′UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA‐mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3′UTR shortening in lung cancer, using the package of the Bioconductor for probe‐level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT‐PCR in 147 clinical specimens of non‐small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA‐related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA‐mediated gene regulation.
A prospective, randomized study on hepatotoxicity of anastrozole compared with tamoxifen in women with breast cancer
Authors: Lin Ying , Liu Jianlun , Zhang Xiaohua , Li Li , Hu Rui , Liu Jian , Deng Yongchuan , Chen Dedian , Zhao Yangbing , Sun Shengrong , Ma Rong , Zhao Ying , Liu Jinping , Zhang Yang , Wang Xijing , Li Yafen , He Pingqing , Li Enxiao , Xu Zheli , Wu Yaqun , Tong Zhongsheng , Wang Xiaojia , Huang Tao , Liang Zhongxiao , Wang Shui , Su Fengxi , Lu Yunfei , Zhang Helong , Feng Guosheng , Wang Shenming
Published: June 2014

Tamoxifen and anastrozole are widely used as adjuvant treatment for early stage breast cancer, but their hepatotoxicity is not fully defined. We aimed to compare hepatotoxicity of anastrozole with tamoxifen in the adjuvant setting in postmenopausal breast cancer patients. Three hundred and fifty‐three Chinese postmenopausal women with hormone receptor‐positive early breast cancer were randomized to anastrozole or tamoxifen after optimal primary therapy. The primary end‐point was fatty liver disease, defined as a liver–spleen ratio <0.9 as determined using a computed tomography scan. The secondary end‐points included abnormal liver function and treatment failure during the 3‐year follow up. The cumulative incidence of fatty liver disease after 3 years was lower in the anastrozole arm than that of tamoxifen (14.6% vs 41.1%, P < 0.0001; relative risk, 0.30; 95% CI, 0.21–0.45). However, there was no difference in the cumulative incidence of abnormal liver function (24.6% vs 24.7%, P = 0.61). Interestingly, a higher treatment failure rate was observed in the tamoxifen arm compared with anastrozole and median times to treatment failure were 15.1 months and 37.1 months, respectively (P < 0.0001; HR, 0.27; 95% CI, 0.20–0.37). The most commonly reported adverse events were ‘reproductive system disorders’ in the tamoxifen group (17.1%), and ‘musculoskeletal disorders’ in the anastrozole group (14.6%). Postmenopausal women with hormone receptor‐positive breast cancer receiving adjuvant anastrozole displayed less fatty liver disease, suggesting that this drug had a more favorable hepatic safety profile than tamoxifen and may be preferred for patients with potential hepatic dysfunction.
Comparative evaluation of the combined application of titanium implants and calcium phosphate bone substitutes in a rabbit model
Authors: Alsayed Arwa , Anil Sukumaran , Jansen John A. , van den Beucken Jeroen J. J. P.
Published: June 2014

Objectives

To study the healing of defects around titanium implants filled with biphasic calcium phosphates (BCP).

Material and methods

Forty custom‐made, titanium implants (Ti) with a diameter of 5 mm, and length of 8 mm, with two‐sided gaps, were fabricated and installed in the femoral condyle of 20 rabbits. Following a randomization protocol, implants were alternately installed in one condyle without BCP bone substitute material (Ti) in the gaps and in the contralateral condyle gaps were filled with BCP bone substitute material (Ti+BCP). The implants were retrieved after 4 and 12 weeks of healing, after which histological and histomorphometrical analyses were done to assess the percentage of bone implant contact (BIC), the percentage of bone area (BA) and the percentage of particle area (PA) within the region of interest (ROI); the rectangular area joining the two arms of the L‐shaped implant was considered as the ROI.

Results

After 4 and 12 weeks of healing, Ti+BCP showed significantly higher BIC and BA values compared to Ti. Further, the BCP particles showed a significant decrease from 4 to 12 weeks of healing. The BCP particles (PA) showed a significant reduction from 31.6 ± 11.0% at 4 weeks to 21.0 ± 7.2% at 12 weeks.

Conclusion

The addition of BCP bone substitute to fill peri‐implant gaps significantly enhanced both bone formation (~2.5‐fold) and bone to implant contact (>2‐fold) for the custom‐made titanium implants with two‐sided gaps.
Comparison between magnetic resonance imaging and rigid rectoscopy in the preoperative identification of intra‐ and extraperitoneal rectal cancer
Authors: Paparo F. , Puppo C. , Montale A. , Bacigalupo L. , Pascariello A. , Clavarezza M. , Binda C. , Rollandi G. A. , Binda G. A.
Published: June 2014

Aim

Accurate preoperative discrimination between extra‐ and intraperitoneal rectal cancer has important treatment implications. Our main objective was to compare the diagnostic performance of MRI with rigid rectoscopy (RRS) in assessing the location of rectal cancers above or below the peritoneal reflection (PR), using the findings obtained during abdominal surgery for treatment of the cancer as the reference standard. We also compared the accuracy of MRI and RRS in assessing the level of the lower border of the tumour from the anal verge.

Method

Patients with rectal carcinoma awaiting surgery underwent MRI and RRS. The MRI images were reviewed by two abdominal radiologists who determined the location of the inferior border of the tumour in relation to the PR. Receiver–operating characteristics (ROC) curve analysis was performed to determine the diagnostic performance of RRS at different cut‐off values.

Results

The sensitivity and specificity were 98.15% and 100%, respectively, for MRI, and 100% and 76.92%, respectively, for RRS at a cut‐off value of < 10 cm. The mean level of the lower border of the tumour from the anal verge was 68 ± 44.3 mm on RRS and 73.5 ± 42.4 mm on MRI (P = 0.25), with a trend towards overestimation with MRI.

Conclusion

RRS is still the main means of assessing the level of a rectal tumour from the anal verge, but MRI has value in determining the level of the tumour in relation to the PR, which cannot be seen on endoscopy.
Right Ventricular Strain in Pulmonary Arterial Hypertension: A 2D Echocardiography and Cardiac Magnetic Resonance Study
Authors: Freed Benjamin H. , Tsang Wendy , Bhave Nicole M. , Patel Amit R. , Weinert Lynn , Yamat Megan , Vicedo Beatriz Miralles , Dill Karin , Mor‐Avi Victor , Gomberg‐Maitland Mardi , Lang Roberto M.
Published: June 2014

Background

Right ventricular (RV) strain is a potentially useful prognostic marker in patients with pulmonary arterial hypertension (PAH). However, published reports regarding the accuracy of two‐dimensional echocardiography (2DE)‐derived RV strain against an independent reference in this patient population are limited. The aims of this study were: (1) to study the relationship between 2DE RV longitudinal strain and cardiovascular magnetic resonance (CMR)‐derived RV ejection fraction (RVEF) in patients with PAH; (2) to compare 2DE‐derived and CMR‐derived RV longitudinal strain in these patients; and (3) to determine the reproducibility of these measurements.

Methods

Thirty patients with PAH underwent 2DE and CMR imaging within a 2‐hour time period. 2DE RV longitudinal strain was measured from a focused RV apical four‐chamber view using speckle tracking software. CMR RV longitudinal strain was measured from short‐axis slices acquired using fast‐strain‐encoded sequence. Global peak systolic RV longitudinal strain was calculated for both 2DE and CMR.

Results

RV longitudinal strain using 2DE software correlated well with CMR‐derived RVEF (R = 0.69, P = 0.0006). There was moderate agreement when comparing 2DE to CMR RV longitudinal strain (R = 0.74, P = 0.0002; bias −1%, limits of agreement −9 to 7%). Inter‐observer variability and intra‐observer variability for RV longitudinal strain were lower for 2DE than CMR.

Conclusions

RV longitudinal strain by 2DE provides a good alternative for CMR‐derived RVEF in patients with PAH. The moderate agreement in strain measurements between 2DE and CMR suggests that further software improvements are needed before these measurements can be used interchangeably in clinical practice.