bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic value of targeted next-generation sequencing in patients with suspected pancreatic or periampullary cancer
Authors: Sibinga Mulder Babs G , Mieog J Sven D , Farina Sarasqueta Arantza , Handgraaf Henricus JM , Vasen Hans F A , Swijnenburg Rutger-Jan , Luelmo Saskia A C , Feshtali Shirin , Inderson Akin , Vahrmeijer Alexander L , Bonsing Bert A , Wezel Tom van , Morreau Hans
Published: August 2017

Aims

Radiological imaging and morphological assessment of cytology material have limitations for preoperative classification of pancreatic or periampullary lesions, often resulting in surgical resection without definitive diagnosis. Our prospective study aims to define the diagnostic value of targeted next-generation sequencing (NGS) of DNA from cytology material.

Methods

Patients with a suspect pancreatic or periampullary lesion underwent standard diagnostic evaluation including preoperative morphological cytology assessment. Treatment options for suspect lesions were surgical exploration with possible resection, follow-up or palliation. The cytology samples were analysed with NGS, in which 50 genes were sequenced for the presence of pathogenic variants. The NGS results were integrated with the clinical information during multidisciplinary team meetings, and changes in the treatment plan were scored. Diagnostic accuracy of NGS analysis (malignancy vs benign disease) was calculated.

Results

NGS results of the cytology samples were confirmed in the resection specimens of the first 10 included patients. The integration of the NGS results led to a change in treatment plan in 7 out of 70 patients (from exploration to follow-up, n=4; from follow-up to exploration and resection, n=2; from palliation to resection, n=1). In four patients, the NGS results were contradictory, but did not affect the treatment plan. In the remaining 59 patients, NGS analysis supported the initial treatment plan. The diagnostic accuracy of NGS analysis was 94% (sensitivity=93%; specificity=100%).

Conclusions

NGS can change the treatment plan in a significant portion of patients with suspect pancreatic or periampullary lesions. Application of NGS can optimise treatment selection and diminish unnecessary surgeries.
What is the ethics of ageing?
Authors: Wareham Christopher Simon
Published: August 2017

Applied ethics is home to numerous productive subfields such as procreative ethics, intergenerational ethics and environmental ethics. By contrast, there is far less ethical work on ageing, and there is no boundary work that attempts to set the scope for ‘ageing ethics’ or the ‘ethics of ageing’. Yet ageing is a fundamental aspect of life; arguably even more fundamental and ubiquitous than procreation. To remedy this situation, I examine conceptions of what the ethics of ageing might mean and argue that these conceptions fail to capture the requirements of the desired subfield. The key reasons for this are, first, that they view ageing as something that happens only when one is old, thereby ignoring the fact that ageing is a process to which we are all subject, and second that the ageing person is treated as an object in ethical discourse rather than as its subject. In response to these shortcomings I put forward a better conception, one which places the ageing person at the centre of ethical analysis, has relevance not just for the elderly and provides a rich yet workable scope. While clarifying and justifying the conceptual boundaries of the subfield, the proposed scope pleasingly broadens the ethics of ageing beyond common negative associations with ageing.
Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators
Authors: Lerro Catherine C , Beane Freeman Laura E , DellaValle Curt T , Kibriya Muhammad G , Aschebrook-Kilfoy Briseis , Jasmine Farzana , Koutros Stella , Parks Christine G , Sandler Dale P , Alavanja Michael C R , Hofmann Jonathan N , Ward Mary H
Published: August 2017

Objectives

Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators.

Methods

Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-<4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models.

Results

Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01).

Conclusions

Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.
Leading order analysis of twist-3 space- and time-like cut vertices in QCD
Authors: Belitsky A. V.
Published: August 2017

We review the recent theoretical progress in the construction and solution of the evolution equations which govern the scale dependence for the twist-3 structure and fragmentation functions of the nucleon.
Design of an ultrabroadband visible metamaterial absorber based on three-dimensional metallic nanostructures
Authors: Luo Hao , Cheng Yong Zhi
Published: August 2017

We present the design and numerical simulations of an ultrabroadband visible metamaterial absorber (MMA) with polarization-insensitive and wide-angle based on three-dimensional (3D) metallic nanostructure. Distinct from previous designs, the proposed visible MMA only consisted of structured 3D metallic film constructed with an assembly of four vertical split-rings (FVSR) structure. For the optimized design of our MMA, the absorbance of over 90% with a relative bandwidth of 94.8% can be obtained. Further simulation results indicate that our design is polarization-insensitive and also operated well in a wide range of incident angles for both TE and TM modes. In addition, the designed visible MMA design can tolerate some geometric parameters errors in fabrication. Thus, the proposed visible MMA can be potential application in the photodetectors, thermal imaging, photoelectrochemical, and solar energy harvesting devices.
Performance of terahertz metamaterials as high-sensitivity sensor
Authors: He Yanan , Zhang Bo , Shen Jingling
Published: August 2017

A high-sensitivity sensor based on the resonant transmission characteristics of terahertz (THz) metamaterials was investigated, with the proposal and fabrication of rectangular bar arrays of THz metamaterials exhibiting a period of 180 [Formula: see text] on a 25 [Formula: see text] thick flexible polyimide. Varying the size of the metamaterial structure revealed that the length of the rectangular unit modulated the resonant frequency, which was verified by both experiment and simulation. The sensing characteristics upon varying the surrounding media in the sample were tested by simulation and experiment. Changing the surrounding medium from that of air to that of alcohol or oil produced resonant frequency redshifts of 80 GHz or 150 GHz, respectively, which indicates that the sensor possessed a high sensitivity of 667 GHz per unit of refractive index. Finally, the influence of the sample substrate thickness on the sensor sensitivity was investigated by simulation. It may be a reference for future sensor design.
Solid-state reaction synthesis for mixed-phase Eu3+-doped bismuth molybdate and its luminescence properties
Authors: Liang Danyang , Ding Yu , Wang Nan , Cai Xiaomeng , Li Jia , Han Linyu , Wang Shiqi , Han Yuanyuan , Jia Guang , Wang Liyong
Published: August 2017

A method for mixed-phase bismuth molybdate doped with Eu[Formula: see text] ions was developed by solid-state reaction assisting with polyvinyl alcohol (PVA). The results of powder X-ray diffraction showed a mixed-phase structure and the microscopical characterization technology revealed the formation process with the addition of PVA. As a structure inducer, the PVA molecules played a vital role in the formation of phase structure. The as-obtained Eu[Formula: see text]-doped bismuth molybdates were also characterized by using different spectroscopic techniques including FTIR and photoluminescence (PL). The results show that doping concentration, PVA addition and calcination temperature affect photoluminescence properties remarkably.
A new method to identify influential nodes based on combining of existing centrality measures
Authors: Fei Liguo , Mo Hongming , Deng Yong
Published: August 2017

How to identify influential nodes in complex networks continues to be an open issue. A number of centrality measures have been presented to address this problem. However, these studies focus only on a centrality measure and each centrality measure has its own shortcomings and limitations. To solve the above problems, in this paper, a novel method is proposed to identify influential nodes based on combining of the existing centrality measures. Because information flow spreads in different ways in different networks, in the specific network, the appropriate centrality measures should be selected to calculate the ranking of nodes. Then, an interval can be generated for the ranking of each node, which includes the upper limit and lower limit obtained from different centrality measures. Next, the final ranking of each node can be determined based on the median of the interval. In order to illustrate the effectiveness of the proposed method, four experiments are conducted to identify vital nodes simulations on four real networks, and the superiority of the method can be demonstrated by the results of comparison experiments.
Factors Influencing Outcome in the Management of Scaphoid Non-union and Comparison of Matti Russe and Interpositional Grafting Techniques
Authors: Kiran Manish , Persaud Ian , Jariwala Arpit , Wigderowitz Carlos
Published: August 2017

Background: Scaphoid non-union is often caused due to missed fractures, inadequate or inappropriate management. Matti-Russe and interpositional grafting techniques are used in the treatment of non-union. There are very few studies in literature that compare the outcomes of these techniques. The aim of our study was to analyse the factors influencing outcome in the management of scaphoid non-union and to compare the results of the Matti Russe procedure with interpositional grafting techniques.

Methods: Fifty scaphoid non-unions with a mean follow-up of 39.9 ± 5.5 months were included in this retrospective study. Demographic parameters, treatment, functional and radiological outcomes were recorded. The influence of demographic and treatment factors on union in this cohort was statistically analysed.

Results: Union was achieved in 76% of cases. Good to excellent results were achieved in 84% of patients. There was no significant difference in union rates, deformity correction achieved and period of immobilisation between the MR and IG techniques. The occurrence of arthritic changes correlated with the time interval between injury and surgery (p = 0.002).

Conclusions: The most important factor that influences the outcome is the time period between the occurrence of the fracture and surgery for non-union. The Matti-Russe procedure can achieve comparable results to interpositional grafting techniques with a shorter period of immobilisation than previously thought to be required. We believe that the presence of a deformity is not a contraindication for the procedure.
Animal Models for Tendon Repair Experiments: A Comparison of Pig, Sheep and Human Deep Flexor Tendons in Zone II
Authors: Peltz Tim Sebastian , Hoffman Stuart William , Scougall Peter James , Gianoutsos Mark Peter , Savage Robert , Oliver Rema Antoinette , Walsh William Robert
Published: August 2017

Background: This laboratory study compared pig, sheep and human deep flexor tendons in regards to their biomechanical comparability.

Methods: To investigate the relevant biomechanical properties for tendon repair experiments, the tendons resistance to cheese-wiring (suture drag/splitting) was assessed. Cheese-wiring of a suture through a tendon is an essential factor for repair gapping and failure in a tendon repair.

Results: Biomechanical testing showed that forces required to pulling a uniform suture loop through sheep or pig tendons in Zone II were higher than in human tendons. At time point zero of testing these differences did not reach statistical significance, but differences became more pronounced when forces were measured beyond initial cheese-wiring (2 mm, 5 mm and 10 mm). The stronger resistance to cheese-wiring was more pronounced in the pig tendons. Also regarding size and histology, sheep tendons were more comparable to human tendons than pig tendons.

Conclusions: Differences in tendon bio-properties should be kept in mind when comparing and interpreting the results of laboratory tendon experiments.
Vascularized Spare Parts Reconstruction of Hand Gunshot Injury
Authors: Patrick Nathan , Payatakes Alexander
Published: August 2017

Reconstruction of extensive traumatic bone and soft tissue deficits in the hand often presents a significant challenge. We present a case of a gunshot wound managed with a resourceful “vascularized spare parts” reconstruction in which a single compromised digit provided two separate vascularized tissue transfers. A rarely reported pedicled phalanx restored osseous stability, a digital fillet flap achieved soft tissue coverage, and the flexor tendons reanimated the hand. An excellent functional and cosmetic result was obtained and the patient was able to return to manual labor within six months of injury.
The Hand of Sabazios: Evidence of Dupuytren’s Disease in Antiquity and the Origin of the Hand of Benediction
Authors: Zdilla Matthew J.
Published: August 2017

Dupuytren’s disease gained its eponym from the surgeon Baron Guillaume Dupuytren (1777-1835). However, the terms “Cline’s contracture” and “Cooper’s contracture,” named after the two surgeons who proposed the treatment for the palmar contractures prior to Dupuytren, have also been used to describe the disease. In addition to the eponyms attributed to these three surgeons, a number of other appellations with interesting provenance exist for Dupuytren’s disease including the “Curse of the MacCrimmons,” “Celtic hand,” “Viking’s disease,” and the “Hand of Benediction.” These terms all have interesting provenance; however, contention exists with regard to the appropriateness of their coinage. Of these terms, the “Hand of Benediction” is based upon the oldest history, supposedly thought to be a result of an early Pope afflicted with Dupuytren’s disease. This report suggests that Dupuytren’s disease was recorded in history prior Christianity, the Vikings, as well as Dupuytren, Cline, and Cooper. Nearly 100 votive “Hand of Sabazios” artifacts from Antiquity appear to document Dupuytren’s disease via sculpture. The report posits that Dupuytren’s disease may have been represented by the “Hand of Sabazios,” subsequently inspiring the “Hand of Benediction” and “Hand of God” that has permeated Christian art and culture for thousands of years.
Karyotype Variability in Plant-Pathogenic Fungi
Authors: Mehrabi Rahim , Mirzadi Gohari Amir , Kema Gert H.J.
Published: August 2017

Recent advances in genetic and molecular technologies gradually paved the way for the transition from traditional fungal karyotyping to more comprehensive chromosome biology studies. Extensive chromosomal polymorphisms largely resulting from chromosomal rearrangements (CRs) are widely documented in fungal genomes. These extraordinary CRs in fungi generate substantial genome plasticity compared to other eukaryotic organisms. Here, we review the most recent findings on fungal CRs and their underlying mechanisms and discuss the functional consequences of CRs for adaptation, fungal evolution, host range, and pathogenicity of fungal plant pathogens in the context of chromosome biology. In addition to a complement of permanent chromosomes called core chromosomes, the genomes of many fungal pathogens comprise distinct unstable chromosomes called dispensable chromosomes (DCs) that also contribute to chromosome polymorphisms. Compared to the core chromosomes, the structural features of DCs usually differ for gene density, GC content, housekeeping genes, and recombination frequency. Despite their dispensability for normal growth and development, DCs have important biological roles with respect to pathogenicity in some fungi but not in others. Therefore, their evolutionary origin is also reviewed in relation to overall fungal physiology and pathogenicity.
The relationship between lymphangion chain length and maximum pressure generation established through in vivo imaging and computational modeling
Authors: Razavi Mohammad S. , Nelson Tyler S. , Nepiyushchikh Zhanna , Gleason Rudolph L. , Dixon J. Brandon
Published: August 2017

The intrinsic contraction of collecting lymphatic vessels serves as a pumping system to propel lymph against hydrostatic pressure gradients as it returns interstitial fluid to the venous circulation. In the present study, we proposed and validated that the maximum opposing outflow pressure along a chain of lymphangions at which flow can be achieved increases with the length of chain. Using minimally invasive near-infrared imaging to measure the effective pumping pressure at various locations in the rat tail, we demonstrated increases in pumping pressure along the length of the tail. Computational simulations based on a microstructurally motivated model of a chain of lymphangions informed from biaxial testing of isolated vessels was used to provide insights into the pumping mechanisms responsible for the pressure increases observed in vivo. These models suggest that the number of lymphangions in the chain and smooth muscle cell force generation play a significant role in determining the maximum outflow pressure, whereas the frequency of contraction has no effect. In vivo administration of nitric oxide attenuated lymphatic contraction, subsequently lowering the effective pumping pressure. Computational simulations suggest that the reduction in contractile strength of smooth muscle cells in the presence of nitric oxide can account for the reductions in outflow pressure observed along the lymphangion chain in vivo. Thus, combining modeling with multiple measurements of lymphatic pumping pressure provides a method for approximating intrinsic lymphatic muscle activity noninvasively in vivo while also providing insights into factors that determine the extent that a lymphangion chain can transport fluid against an adverse pressure gradient.

NEW & NOTEWORTHY Here, we report the first minimally invasive in vivo measurements of the relationship between lymphangion chain length and lymphatic pumping pressure. We also provide the first in vivo validation of lumped parameter models of lymphangion chains previously developed through data obtained from isolated vessel testing.
Platelet-derived growth factor receptor-α and Ras-related C3 botulinum toxin substrate-1 regulate mechano-responsiveness of lung fibroblasts
Authors: McGowan Stephen E. , McCoy Diann M.
Published: August 2017

Platelet-derived growth factor (PDGF)-A, which only signals through PDGF-receptor-α (PDGFR-α), is required for secondary alveolar septal formation. Although PDGFR-α distinguishes mesenchymal progenitor cells during the saccular stage, PDGFR-α-expressing alveolar cells persist through adulthood. PDGF-A sustains proliferation, limits apoptosis, and maintains α-smooth muscle actin (α-SMA)-containing alveolar cells, which congregate at the alveolar entry ring at postnatal day (P)12. PDGFR-α-expressing, α-SMA-containing alveolar cells redistribute in the elongating septum, suggesting that they migrate to the alveolar entry rings, where mechanical tension is higher. We hypothesized that PDGFR-α and Ras-related C3 botulinum toxin substrate 1(Rac1) are required for mechanosensitive myofibroblast migration. Spreading of PDGFR-α-deficient lung fibroblasts was insensitive to increased rigidity, and their migration was not reduced by Rac1-guanine exchange factor (GEF)-inhibition. PDGFR-α-expressing fibroblasts migrated toward stiffer regions within two-dimensional substrates by increasing migrational persistence (durotaxis). Using a Förster resonance energy transfer (FRET) biosensor for Rac1-GTP, we observed that PDGFR-α was required for fibroblast Rac1 responsiveness to stiffness within a three-dimensional collagen substrate, which by itself increased Rac1-FRET. Rho-GTPase stabilized, whereas Rac1-GTPase increased the turnover of focal adhesions. Under conditions that increased Rac1-GTP, PDGFR-α signaled through both phosphoinositide-3-kinase (PIK) or Src to engage the Rac1 GEF dedicator of cytokinesis-1 (Dock180) and p21-activated-kinase interacting exchange factor-β (βPIX). In cooperation with collagen fibers, these signaling pathways may guide fibroblasts toward the more rigid alveolar entry ring during secondary septation. Because emphysema and interstitial fibrosis disrupt the parenchymal mechanical continuum, understanding how mechanical factors regulate fibroblast migration could elicit strategies for alveolar repair and regeneration.
Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae
Authors: Londino James David , Lazrak Ahmed , Collawn James F. , Bebok Zsuzsanna , Harrod Kevin S. , Matalon Sadis
Published: August 2017

The cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial sodium channels (ENaC) are located in the apical membranes of airway and alveolar epithelial cells. These transporters play an important role in the regulation of lung fluid balance across airway and alveolar epithelia by being the conduits for chloride (Cl−) and bicarbonate ([Formula: see text]) secretion and sodium (Na+) ion absorption, respectively. The functional role of these channels in the respiratory tract is to maintain the optimum volume and ionic composition of the bronchial periciliary fluid (PCL) and alveolar lining fluid (ALF) layers. The PCL is required for proper mucociliary clearance of pathogens and debris, and the ALF is necessary for surfactant homeostasis and optimum gas exchange. Dysregulation of ion transport may lead to mucus accumulation, bacterial infections, inflammation, pulmonary edema, and compromised respiratory function. Influenza (or flu) in mammals is caused by influenza A and B viruses. Symptoms include dry cough, sore throat, and is often followed by secondary bacterial infections, accumulation of fluid in the alveolar spaces and acute lung injury. The underlying mechanisms of flu symptoms are not fully understood. This review summarizes our present knowledge of how influenza virus infections alter airway and alveolar epithelial cell CFTR and ENaC function in vivo and in vitro and the role of these changes in influenza pathogenesis.
Active sleep unmasks apnea and delayed arousal in infant rat pups lacking central serotonin
Authors: Young Jacob O. , Geurts Aron , Hodges Matthew R. , Cummings Kevin J.
Published: August 2017

Sudden infant death syndrome (SIDS), occurring during sleep periods, is highly associated with abnormalities within serotonin (5-HT) neurons, including reduced 5-HT. There is evidence that future SIDS cases experience more apnea and have abnormal arousal from sleep. In rodents, a loss of 5-HT neurons is associated with apnea in early life and, in adulthood, delayed arousal. As the activity of 5-HT neurons changes with vigilance state, we hypothesized that the degree of apnea and delayed arousal displayed by rat pups specifically lacking central 5-HT varies with state. Two-week-old tryptophan hydroxylase 2-deficient ( TPH2−/−) and wild-type (WT) rat pups were placed in plethysmographic chambers supplied with room air. At the onset of active (AS) or quiet (QS) sleep, separate groups of rats were exposed to hypercapnia (5% CO2) or mild hypoxia (~17% O2) or maintained in room air. Upon arousal, rats received room air. Apnea indexes and latencies to spontaneous arousal from AS and QS were determined for pups exposed only to room air. Arousal latencies were also calculated for TPH2−/− and WT pups exposed to hypoxia or hypercapnia. Compared with WT, TPH2−/− pups hypoventilated in all states but were profoundly more apneic solely in AS. TPH2−/− pups had delayed arousal in response to increasing CO2, and AS selectively delayed the arousal of TPH2−/− pups, irrespective of the gas they breathed. Thus infants who are deficient in CNS 5-HT may be at increased risk for SIDS in AS because of increased apnea and delayed arousal compared with QS.

NEW & NOTEWORTHY Sudden infant death syndrome (SIDS) occurs during sleep and is associated with central serotonin (5-HT) deficiency. We report that rat pups deficient in central 5-HT ( TPH2−/−) are profoundly more apneic in active sleep (AS) but not quiet sleep (QS). Unlike control pups, the arousal of TPH2−/− pups in air, CO2, and hypoxia was delayed in AS compared with QS. Thus for infants deficient in central 5-HT, the risk of SIDS may be higher in AS than in QS.
FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen
Authors: Barone Amy , Chi Dow-Chung , Theoret Marc R. , Chen Huanyu , He Kun , Kufrin Dubravka , Helms Whitney S. , Subramaniam Sriram , Zhao Hong , Patel Anuja , Goldberg Kirsten B. , Keegan Patricia , Pazdur Richard
Published: August 2017

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44–0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448–53. ©2017 AACR.
Inhibition of the V-ATPase by Archazolid A: A New Strategy to Inhibit EMT
Authors: Merk Henriette , Messer Philipp , Ardelt Maximilian A. , Lamb Don C. , Zahler Stefan , Müller Rolf , Vollmar Angelika M. , Pachmayr Johanna
Published: August 2017

Epithelial–mesenchymal transition (EMT) induces tumor-initiating cells (TIC), which account for tumor recurrence, metastasis, and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as a promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EMT process and inhibit TIC generation, as shown by a reduced formation of mammospheres and decreased cell motility. As an underlying mechanism, V-ATPase inhibition by Archazolid A disturbs the turnover of E-cadherin: Archazolid abrogates E-cadherin loss during EMT by interfering with its internalization and recycling. Our study elucidates V-ATPase as essential player in EMT by regulating E-cadherin turnover. Archazolid A is suggested as a promising therapeutic agent to block EMT and the generation of TICs. Mol Cancer Ther; 16(11); 2329–39. ©2017 AACR.
Early Visible Improvements during K101-03 Treatment: An Open-Label Multicenter Clinical Investigation in Patients with Onychomycosis and/or Nail Psoriasis
Authors: Piraccini Bianca Maria , Starace Michela , Toft Anders
Published: August 2017

Introduction: Onychomycosis and nail psoriasis can be embarrassing to patients, so improving the appearance of affected nails should be one of the key short-term goals of treatment. Methods: An 8-week open-label multicenter study was conducted to assess whether K101-03, a marketed topical treatment containing propylene glycol, glycerol, urea, and lactic acid, could produce rapid cosmetic improvements in affected nails. Adult patients with a big toenail or thumbnail (the “target” nail) affected by onychomycosis (n = 72) or psoriasis (n = 34) or both (n = 1) applied K101-03 to their affected nails once a day for 8 weeks. During and after treatment, patients rated the overall appearance of their target nail on a 4-point scale. They also assessed whether thickening, discoloration, brittleness, and softness of the target nail had improved since baseline. Adverse events (AEs) that occurred between the first application of K101-03 and the end of treatment were recorded and categorized according to severity and relationship to K101-03. Results: After 8 weeks of K101-03 treatment, 92.2% of patients (95% confidence interval [CI] 87.06-97.40) reported at least some improvement in the target nail. After 1 week of treatment, 78.3% of patients with onychomycosis (95% CI 68.53-87.99) reported at least some improvement in the target nail, and 55.1% of them reported that discoloration of their target nail had improved. Three patients reported a total of 5 AEs, none of which were judged to be related to K101-03. Conclusions: In summary, K101-03 was well tolerated in patients with onychomycosis or nail psoriasis and rapidly improved their nails.
Resection of Locally Advanced Pancreatic Neoplasms after Neoadjuvant Chemotherapy with Nab-Paclitaxel and Gemcitabine following FOLFIRINOX Failure
Authors: Hahn Sarah , Ayav Ahmet , Lopez Anthony
Published: August 2017

The incidence of pancreatic cancer has dramatically increased over the past years, but the prognosis has not improved. Between 30 and 40% of tumors are considered locally advanced, essentially due to vascular involvement. In recent years, new chemotherapy protocols with high response rates have been developed. FOLFIRINOX seems to be an interesting option in this situation, but hematologic toxicity could be an obstacle to its prescription. Nab-paclitaxel and gemcitabine offer significant response rates with a reasonable safety profile. We report here a single-center experience of 2 cases with a locally advanced pancreatic cancer initially considered unresectable, progressive after first-line neoadjuvant FOLFIRINOX chemotherapy, and then treated with second-line nab-paclitaxel/gemcitabine chemotherapy.
Ischemic Colitis Associated with Paclitaxel and Carboplatin Combination
Authors: Elsayed Ahmed Gamal , Srivastava Roma , Pacioles Toni , Limjoco Teresa , Tirona Maria Tria
Published: August 2017

A 62-year-old white female with a history of early-stage triple-negative breast cancer on a combination of carboplatin and paclitaxel in the adjuvant setting presented with lower gastrointestinal bleeding. She tolerated 4 cycles of dose-dense adriamycin/cyclophosphamide with no major symptoms. After 6 cycles of weekly paclitaxel in combination with carboplatin every 3 weeks, she presented with diarrhea and lower gastrointestinal bleeding. Colonosopic examination showed erythema and inflammation in the splenic flexure, descending colon, and sigmoid colon consistent with ischemic colitis. Pathology favored the same diagnosis. She was treated conservatively with intravenous fluids and bowel rest. Chemotherapy was held for 2 weeks and resumed after recovery without carboplatin. She was able to tolerate the remaining 6 cycles of paclitaxel with no recurrence of her symptoms.
Chronic Rejection of Cardiac Allografts Is Associated With Increased Lymphatic Flow and Cellular Trafficking
Authors: Edwards Lindsey A. , Nowocin Anna K. , Jafari Nazila V. , Meader Lucy L. , Brown Kathryn , Sarde Aurélien , Lam Carolyn , Murray Alex , Wong Wilson
Published: August 2017

Background:

Cardiac transplantation is an excellent treatment for end-stage heart disease. However, rejection of the donor graft, in particular, by chronic rejection leading to cardiac allograft vasculopathy, remains a major cause of graft loss. The lymphatic system plays a crucial role in the alloimmune response, facilitating trafficking of antigen-presenting cells to draining lymph nodes. The encounter of antigen-presenting cells with T lymphocytes in secondary lymphoid organs is essential for the initiation of alloimmunity. Donor lymphatic vessels are not anastomosed to that of the recipient during transplantation. The pathophysiology of lymphatic disruption is unknown, and whether this disruption enhances or hinders the alloimmune responses is unclear. Although histological analysis of lymphatic vessels in donor grafts can yield information on the structure of the lymphatics, the function following cardiac transplantation is poorly understood.

Methods:

Using single-photon emission computed tomography/computed tomography lymphoscintigraphy, we quantified the lymphatic flow index following heterotrophic cardiac transplantation in a murine model of chronic rejection.

Results:

Ten weeks following transplantation of a minor antigen (HY) sex-mismatched heart graft, the lymphatic flow index was significantly increased in comparison with sex-matched controls. Furthermore, the enhanced lymphatic flow index correlated with an increase in donor cells in the mediastinal draining lymph nodes; increased lymphatic vessel area; and graft infiltration of CD4
+
, CD8
+
T cells, and CD68
+
macrophages.

Conclusions:

Chronic rejection results in increased lymphatic flow from the donor graft to draining lymph nodes, which may be a factor in promoting cellular trafficking, alloimmunity, and cardiac allograft vasculopathy.
Ectopy on a Single 12‐Lead ECG, Incident Cardiac Myopathy, and Death in the Community
Authors: Nguyen Kaylin T. , Vittinghoff Eric , Dewland Thomas A. , Dukes Jonathan W. , Soliman Elsayed Z. , Stein Phyllis K. , Gottdiener John S. , Alonso Alvaro , Chen Lin Y. , Psaty Bruce M. , Heckbert Susan R. , Marcus Gregory M.
Published: August 2017

Background

Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12‐lead
ECG
is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12‐lead
ECG
would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.

Methods and Results

We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the
CHS
, multivariable analyses revealed that a baseline 12‐lead
ECG
premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95%
CI,
1.3–2.0;
P
<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95%
CI
, 1.0–1.6;
P
=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95%
CI,
1.1–1.5;
P
=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95%
CI,
1.0–1.3;
P
=0.044). Similarly statistically significant results for each analysis were also observed in
ARIC
.

Conclusions

Based on a single standard
ECG
, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.
Temporal Anticipation Based on Memory
Authors: Cravo André M. , Rohenkohl Gustavo , Santos Karin Moreira , Nobre Anna C.
Published: August 2017

The fundamental role that our long-term memories play in guiding perception is increasingly recognized, but the functional and neural mechanisms are just beginning to be explored. Although experimental approaches are being developed to investigate the influence of long-term memories on perception, these remain mostly static and neglect their temporal and dynamic nature. Here, we show that our long-term memories can guide attention proactively and dynamically based on learned temporal associations. Across two experiments, we found that detection and discrimination of targets appearing within previously learned contexts are enhanced when the timing of target appearance matches the learned temporal contingency. Neural markers of temporal preparation revealed that the learned temporal associations trigger specific temporal predictions. Our findings emphasize the ecological role that memories play in predicting and preparing perception of anticipated events, calling for revision of the usual conceptualization of contextual associative memory as a reflective and retroactive function.
Nonnegative Matrix Factorization with Rank Regularization and Hard Constraint
Authors: Shang Ronghua , Liu Chiyang , Meng Yang , Jiao Licheng , Stolkin Rustam
Published: August 2017

Nonnegative matrix factorization (NMF) is well known to be an effective tool for dimensionality reduction in problems involving big data. For this reason, it frequently appears in many areas of scientific and engineering literature. This letter proposes a novel semisupervised NMF algorithm for overcoming a variety of problems associated with NMF algorithms, including poor use of prior information, negative impact on manifold structure of the sparse constraint, and inaccurate graph construction. Our proposed algorithm, nonnegative matrix factorization with rank regularization and hard constraint (NMFRC), incorporates label information into data representation as a hard constraint, which makes full use of prior information. NMFRC also measures pairwise similarity according to geodesic distance rather than Euclidean distance. This results in more accurate measurement of pairwise relationships, resulting in more effective manifold information. Furthermore, NMFRC adopts rank constraint instead of norm constraints for regularization to balance the sparseness and smoothness of data. In this way, the new data representation is more representative and has better interpretability. Experiments on real data sets suggest that NMFRC outperforms four other state-of-the-art algorithms in terms of clustering accuracy.
Constrained ERM Learning of Canonical Correlation Analysis: A Least Squares Perspective
Authors: Cai Jia , Sun Hongwei
Published: August 2017

Canonical correlation analysis (CCA) is a useful tool in detecting the latent relationship between two sets of multivariate variables. In theoretical analysis of CCA, a regularization technique is utilized to investigate the consistency of its analysis. This letter addresses the consistency property of CCA from a least squares view. We construct a constrained empirical risk minimization framework of CCA and apply a two-stage randomized Kaczmarz method to solve it. In the first stage, we remove the noise, and in the second stage, we compute the canonical weight vectors. Rigorous theoretical consistency is addressed. The statistical consistency of this novel scenario is extended to the kernel version of it. Moreover, experiments on both synthetic and real-world data sets demonstrate the effectiveness and efficiency of the proposed algorithms.
Active Inference, Curiosity and Insight
Authors: Friston Karl J. , Lin Marco , Frith Christopher D. , Pezzulo Giovanni , Hobson J. Allan , Ondobaka Sasha
Published: August 2017

This article offers a formal account of curiosity and insight in terms of active (Bayesian) inference. It deals with the dual problem of inferring states of the world and learning its statistical structure. In contrast to current trends in machine learning (e.g., deep learning), we focus on how people attain insight and understanding using just a handful of observations, which are solicited through curious behavior. We use simulations of abstract rule learning and approximate Bayesian inference to show that minimizing (expected) variational free energy leads to active sampling of novel contingencies. This epistemic behavior closes explanatory gaps in generative models of the world, thereby reducing uncertainty and satisfying curiosity. We then move from epistemic learning to model selection or structure learning to show how abductive processes emerge when agents test plausible hypotheses about symmetries (i.e., invariances or rules) in their generative models. The ensuing Bayesian model reduction evinces mechanisms associated with sleep and has all the hallmarks of “aha” moments. This formulation moves toward a computational account of consciousness in the pre-Cartesian sense of sharable knowledge (i.e., con: “together”; scire: “to know”).
Infinite von Mises–Fisher Mixture Modeling of Whole Brain fMRI Data
Authors: Røge Rasmus E. , Madsen Kristoffer H. , Schmidt Mikkel N. , Mørup Morten
Published: August 2017

Cluster analysis of functional magnetic resonance imaging (fMRI) data is often performed using gaussian mixture models, but when the time series are standardized such that the data reside on a hypersphere, this modeling assumption is questionable. The consequences of ignoring the underlying spherical manifold are rarely analyzed, in part due to the computational challenges imposed by directional statistics. In this letter, we discuss a Bayesian von Mises–Fisher (vMF) mixture model for data on the unit hypersphere and present an efficient inference procedure based on collapsed Markov chain Monte Carlo sampling. Comparing the vMF and gaussian mixture models on synthetic data, we demonstrate that the vMF model has a slight advantage inferring the true underlying clustering when compared to gaussian-based models on data generated from both a mixture of vMFs and a mixture of gaussians subsequently normalized. Thus, when performing model selection, the two models are not in agreement. Analyzing multisubject whole brain resting-state fMRI data from healthy adult subjects, we find that the vMF mixture model is considerably more reliable than the gaussian mixture model when comparing solutions across models trained on different groups of subjects, and again we find that the two models disagree on the optimal number of components. The analysis indicates that the fMRI data support more than a thousand clusters, and we confirm this is not a result of overfitting by demonstrating better prediction on data from held-out subjects. Our results highlight the utility of using directional statistics to model standardized fMRI data and demonstrate that whole brain segmentation of fMRI data requires a very large number of functional units in order to adequately account for the discernible statistical patterns in the data.
A Robust Regression Framework with Laplace Kernel-Induced Loss
Authors: Yang Liming , Ren Zhuo , Wang Yidan , Dong Hongwei
Published: August 2017

This work proposes a robust regression framework with nonconvex loss function. Two regression formulations are presented based on the Laplace kernel-induced loss (LK-loss). Moreover, we illustrate that the LK-loss function is a nice approximation for the zero-norm. However, nonconvexity of the LK-loss makes it difficult to optimize. A continuous optimization method is developed to solve the proposed framework. The problems are formulated as DC (difference of convex functions) programming. The corresponding DC algorithms (DCAs) converge linearly. Furthermore, the proposed algorithms are applied directly to determine the hardness of licorice seeds using near-infrared spectral data with noisy input. Experiments in eight spectral regions show that the proposed methods improve generalization compared with the traditional support vector regressions (SVR), especially in high-frequency regions. Experiments on several benchmark data sets demonstrate that the proposed methods achieve better results than the traditional regression methods in most of data sets we have considered.
New records of Cyanobacterial morphotypes with Leptolyngbya indica sp. nov. from terrestrial biofilms of the Lower Gangetic Plain, India
Authors: DEBNATH MANOJIT , SINGH TARKESHWAR , BHADURY PUNYASLOKE
Published: August 2017

Macroscopic cyanobacterial biofilms were collected from alluvial plain soils and estuarine mangrove soils representing the Lower Gangetic Plains of South East Asia (India). The composition of the biofilms was investigated using light microscopy and field emission scanning electron microscopy of collected samples. In this study four simple trichal non-heterocytous morphotypes were found to be unique. Out of four, three morphotypes clearly showed differences with respect to described taxa as based on most recent taxonomic classification and possibly represent new report from the Indian subcontinent. One morphotype was successfully established under culture conditions and described as Leptolyngbya indica sp. nov. isolated from the alluvial arsenic affected rice field soil. This study provides vital information on morphotypic diversity of Cyanobacteria from specific biotopes which can contribute key information on their biogeography and potential application in green remediation.
Resurrection and epitypification of Butia poni (Arecaceae), a neglected palm micro-endemic in the grasslands of Misiones, Argentina
Authors: PAZ DEBLE LEONARDO , KELLER HECTOR A. , ALVES FABIANO DA SILVA
Published: August 2017

A lectotype is designated here for Cocos poni, a species first proposed by Hauman in Las Palmeras de la Flora Argentina and currently treated as a synonym of Butia yatay or B. paraguayensis. Collections were made in the locality designated by Hauman based on his photos and description, and an epitype for this species is also designated here. Butia poni is recognized as a distinct species. This paper includes a description, photos, relationships, geographic distribution, and conservation assessment for Butia poni.