bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporation of log odds of positive lymph nodes into the AJCC TNM classification improves prediction of survival in oral cancer
Authors: Lee C.‐C. , Lin Y.‐S. , Kang B.‐H. , Chang K.‐P. , Chi C.‐C. , Lin M.‐Y. , Su H.‐H. , Chang T.‐S. , Chen H.‐C. , Chen P.‐C. , Huang W.‐L. , Huang C.‐I. , Chou P. , Yang C.‐C.
Published: December 2016

Objectives

To assess the prognostic performance of a new N classification that incorporates the log odds of positive lymph nodes (LODDS) into the routinely used pathological N classification for oral squamous cell carcinoma (OSCC) patients.

Design

Retrospective cohort study utilising LODDS into pN category was performed, and the AJCC TNM stage and T‐New N‐M stage were compared with respect to 5‐year disease‐specific survival (DSS) rates. The discriminability was evaluated from the linear trend chi‐square test, Akaike information criterion (AIC) and Harrell's c‐statistic.

Setting

Medical centrer in Taiwan.

Participants

A total of 463 patients received primary surgery and neck dissection between 2004 and 2013 for OSCC.

Main outcome measures

The discriminability for 5‐year DSS rates.

Results

The median follow‐up period was 54 months, the mean patient age was 54 ± 11 years and 428 patients (92.4%) were male. The patients with higher LODDS had worse 5‐year DSS rates. Incorporation of LODDS into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for 5‐year DSS with a lower AIC (1883 versus 1897), and higher prediction accuracy (Harrell's c‐statistic: 0.768 versus 0.764).

Conclusions

By utilising a merger of the LODDS and pN classifications to create a new N classification has better discriminatory and predictive ability than pathological TNM staging and could help identify high‐risk patients for intense adjuvant therapy.
3,3′‐Dinitrophenolsulphonephthalein: an acid–base indicator dye with unusual properties
Authors: Mchedlov‐Petrossyan Nikolay O. , Laguta Anna N. , Shekhovtsov Sergey V. , Eltsov Sergey V. , Cheipesh Tatyana A. , Omelchenko Irina V. , Shishkin Oleg V.
Published: December 2016

This paper is devoted to the phenolsulphonephthalein nitro derivative 3,3′‐dinitrophenolsulphonephthalein, also called nitrophenol violet (NPV). The neutral molecular form, H2R, was isolated as a sultonic tautomer, and an X‐ray crystal structure analysis was carried out. UV‐vis absorption spectra in methanol, DMSO, acetonitrile, and water at different pH values were ascribed to the molecular and anionic (H2R, HR−, and R2−) species. Whereas the pKa values of this acid–base indicator (HR− R2− + H+) in water and DMSO are close to those of 3,3′,5,5′‐tetrabromophenolsulphonephthalein (or bromophenol blue), replacing the four Br atoms with two NO2 groups results in a pronounced tendency to carbinol formation. In weakly acidic aqueous media, the HR− anion slowly converts into the colourless carbinol H2ROH−. The latter is transformed to the orange carbocation only in concentrated (70–94 wt%) sulphuric acid. The formation of H2ROH− is atypical for the common sulphonephthalein indicators and should be ascribed to the enhanced positive charge density on the nodal carbon atom. The reaction mechanism and kinetic equation explaining this pH‐dependent process are proposed, in addition to a kinetic study of the common process R2− + HO− → ROH3− in the alkaline region. The numerical characterisation of the protolytic processes obtained for NPV is also helpful in gaining a better understanding of the properties of previously studied 3,3′,5,5′‐tetranitrophenolsulphonephthalein, which is much less accessible for a quantitative description.
Geometry, landmarks and the cerebral hemispheres: 2D spatial reorientation in split‐brain patients
Authors: Prete Giulia , Fabri Mara , Foschi Nicoletta , Tommasi Luca
Published: December 2016

A right‐hemispheric superiority in spatial encoding based on geometric cues has been largely documented in a variety of species, together with a left‐hemispheric specialization for encoding based on landmarks. In humans, hemispheric asymmetries for spatial encoding have been little explored. In this study, we compared a patient with a complete callosal resection (D.D.C.) and a patient with a wide callosal resection saving the splenium (A.P.), with healthy participants. In two 2D versions of the ‘reorientation task’, participants were asked to find the target corner of a rectangle‐shaped environment, by exploiting either geometric information alone or the combination of geometric and landmark information. In Experiment 1, the landmark consisted of a coloured side of the rectangle; in Experiment 2, this cue was replaced by a coloured disc located inside the rectangle. In both experiments, the rectangular shape ensured the geometric cue. D.D.C. was always unable to recall the target, whereas A.P. correctly solved the task when only the geometric information was available, without difference with respect to the controls. Importantly, the performance of A.P. did not differ from controls’ when the right hemisphere was tested with the landmark cues (the task being carried out using the left hand), whereas when the left hemisphere was tested (right‐hand session) his performance was worse than controls’ with the coloured side of the space, but it was better than controls’ with the coloured disc. The results are discussed comparing them with data collected on other species, and with theories of spatial processing.
Origin and evolutionary implications of introns from analysis of cellulose synthase gene
Authors: Bhattachan Punit , Dong Bo
Published: December 2016

Spliceosomal introns are present in diverse eukaryotic but not prokaryotic genes. However, their evolutionary origin is still arguable. Here, we address this question through an analysis of the cellulose synthase gene, which is present only in urochordate among the animal lineages due to horizontal transfer from a bacterial ancestor in the distant past. We hypothesize that this gene in urochordate contains primordial intron positions and attempted to find them by comparisons with the plant cellulose synthase gene intron positions. However, we could not find distinct conservation of intron positions; therefore, we believe that there was only random insertion of introns in the urochordate cellulose synthase gene. In addition, the protosplice site tendency to conserved phase zero intron positions in urochordates is only 54%, compared with 76% in plants. This shows independent origins of introns in the cellulose synthase gene of urochordates and plants during eukaryotic evolution. Therefore, we concluded that intron origin is a eukaryotic invention.
Oxygen isotope characteristics of chondrules from the Yamato‐82094 ungrouped carbonaceous chondrite: Further evidence for common O‐isotope environments sampled among carbonaceous chondrites
Authors: Tenner T. J. , Kimura M. , Kita N. T.
Published: December 2016

High‐precision secondary ion mass spectrometry (SIMS) was employed to investigate oxygen three isotopes of phenocrysts in 35 chondrules from the Yamato (Y) 82094 ungrouped 3.2 carbonaceous chondrite. Twenty‐one of 21 chondrules have multiple homogeneous pyroxene data (∆17O 3SD analytical uncertainty: 0.7‰); 17 of 17 chondrules have multiple homogeneous pyroxene and plagioclase data. Twenty‐one of 25 chondrules have one or more olivine data matching coexisting pyroxene data. Such homogeneous phenocrysts (1) are interpreted to have crystallized from the final chondrule melt, defining host O‐isotope ratios; and (2) suggest efficient O‐isotope exchange between ambient gas and chondrule melt during formation. Host values plot within 0.7‰ of the primitive chondrule mineral (PCM) line. Seventeen chondrules have relict olivine and/or spinel, with some δ17O and δ18O values approaching −40‰, similar to CAI or AOA‐like precursors. Regarding host chondrule data, 22 of 34 have Mg#s of 98.8–99.5 and ∆17O of −3.9‰ to −6.1‰, consistent with most Acfer 094, CO, CR, and CV chondrite chondrules, and suggesting a common reduced O‐isotope reservoir devoid of 16O‐poor H2O. Six Y‐82094 chondrules have ∆17O near −2.5‰, with Mg#s of 64–97, consistent with lower Mg# chondrules from Acfer 094, CO, CR, and CV chondrites; their signatures suggest precursors consisting of those forming Mg# ~99, ∆17O: −5‰ ± 1‰ chondrules plus 16O‐poor H2O, at high dust enrichments. Three type II chondrules plot slightly above the PCM line, near the terrestrial fractionation line (∆17O: ~+0.1‰). Their O‐isotopes and olivine chemistry are like LL3 type II chondrules, suggesting they sampled ordinary chondrite‐like chondrule precursors. Finally, three Mg# >99 chondrules have ∆17O of −6.7‰ to −8.1‰, potentially due to 16O‐rich refractory precursor components. The predominance of Mg# ~99, ∆17O: −5‰ ± 1‰ chondrules and a high chondrule‐to‐matrix ratio suggests bulk Y‐82094 characteristics are closely related to anhydrous dust sampled by most carbonaceous chondrite chondrules.
Dynamics of volume‐averaged intracellular Ca2+ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations
Authors: Lin Kun‐Han , Taschenberger Holger , Neher Erwin
Published: December 2016

Key points

The intracellular concentration of free calcium ions ([Ca2+]i) in a nerve terminal controls both transmitter release and synaptic plasticity.

The rapid triggering of transmitter release depends on the local micro‐ or nanodomain of highly elevated [Ca2+]i in the vicinity of open voltage‐gated Ca2+ channels, whereas short‐term synaptic plasticity is often controlled by global changes in residual [Ca2+]i, averaged over the whole nerve terminal volume.

Here we describe dynamic changes of such global [Ca2+]i in the calyx of Held – a giant mammalian glutamatergic nerve terminal, which is particularly suited for biophysical studies.

We provide quantitative data on Ca2+ inflow, Ca2+ buffering and Ca2+ clearance.

These data allow us to predict changes in [Ca2+]i in the nerve terminal in response to a wide range of stimulus protocols at high temporal resolution and provide a basis for the modelling of short‐term plasticity of glutamatergic synapses.

Many aspects of short‐term synaptic plasticity (STP) are controlled by relatively slow changes in the presynaptic intracellular concentration of free calcium ions ([Ca2+]i) that occur in the time range of a few milliseconds to several seconds. In nerve terminals, [Ca2+]i equilibrates diffusionally during such slow changes, such that the globally measured, residual [Ca2+]i that persists after the collapse of local domains is often the appropriate parameter governing STP. Here, we study activity‐dependent dynamic changes in global [Ca2+]i at the rat calyx of Held nerve terminal in acute brainstem slices using patch‐clamp and microfluorimetry. We use low concentrations of a low‐affinity Ca2+ indicator dye (100 μm Fura‐6F) in order not to overwhelm endogenous Ca2+ buffers. We first study voltage‐clamped terminals, dialysed with pipette solutions containing minimal amounts of Ca2+ buffers, to determine Ca2+ binding properties of endogenous fixed buffers as well as the mechanisms of Ca2+ clearance. Subsequently, we use pipette solutions including 500 μm EGTA to determine the Ca2+ binding kinetics of this chelator. We provide a formalism and parameters that allow us to predict [Ca2+]i changes in calyx nerve terminals in response to a wide range of stimulus protocols. Unexpectedly, the Ca2+ affinity of EGTA under the conditions of our measurements was substantially lower (KD = 543 ± 51 nm) than measured in vitro, mainly as a consequence of a higher than previously assumed dissociation rate constant (2.38 ± 0.20 s−1), which we need to postulate in order to model the measured presynaptic [Ca2+]i transients.
A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis
Authors: Fofana Mariam O. , Shrestha Sourya , Knight Gwenan M. , Cohen Ted , White Richard G. , Cobelens Frank , Dowdy David W.
Published: December 2016

Several infectious diseases of global importance—e.g., HIV infection and tuberculosis (TB)—require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the
de novo
emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of
Mycobacterium tuberculosis
transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB—defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)—exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.
Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults
Authors: Griffin M. Pamela , Khan Anis A. , Esser Mark T. , Jensen Kathryn , Takas Therese , Kankam Martin K. , Villafana Tonya , Dubovsky Filip
Published: December 2016

Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (
n
= 102) or placebo (
n
= 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.)
Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
Authors: Castro María del Mar , Gomez Maria Adelaida , Kip Anke E. , Cossio Alexandra , Ortiz Eduardo , Navas Adriana , Dorlo Thomas P. C. , Saravia Nancy Gore
Published: December 2016

An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up.
Leishmania
(
Viannia
)
panamensis
predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments (
P
< 0.01).
Leishmania
persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination.
In vitro
miltefosine susceptibility was similar for
Leishmania
strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.)
Tet38 Efflux Pump Affects Staphylococcus aureus Internalization by Epithelial Cells through Interaction with CD36 and Contributes to Bacterial Escape from Acidic and Nonacidic Phagolysosomes
Authors: Truong-Bolduc Q. C. , Khan N. S. , Vyas J. M. , Hooper D. C.
Published: December 2016

We previously reported that the Tet38 efflux pump is involved in internalization of
Staphylococcus aureus
by A549 lung epithelial cells. A lack of
tet38
reduced bacterial uptake by A549 cells to 36% of that of the parental strain RN6390. Using invasion assays coupled with confocal microscopy imaging, we studied the host cell receptor(s) responsible for bacterial uptake via interaction with Tet38. We also assessed the ability of
S. aureus
to survive following alkalinization of the phagolysosomes by chloroquine. Antibody to the scavenger receptor CD36 reduced the internalization of
S. aureus
RN6390 by A549 cells, but the dependence on CD36 was reduced in QT7
tet38
, suggesting that an interaction between Tet38 and CD36 contributed to
S. aureus
internalization. Following fusion of the
S. aureus
-associated endosomes with lysosomes, alkalinization of the acidic environment with chloroquine led to a rapid increase in the number of
S. aureus
RN6390 bacteria in the cytosol, followed by a decrease shortly thereafter. This effect of chloroquine was not seen in the absence of intact Tet38 in mutant QT7. These data taken together suggest that Tet38 plays a role both in bacterial internalization via interaction with CD36 and in bacterial escape from the phagolysosomes.
Storage filters upland suspended sediment signals delivered from watersheds
Authors: Pizzuto James , Keeler Jeremy , Skalak Katherine , Karwan Diana
Published: December 2016

Climate change, tectonics, and humans create long- and short-term temporal variations in the supply of suspended sediment to rivers. These signals, generated in upland erosional areas, are filtered by alluvial storage before reaching the basin outlet. We quantified this filter using a random walk model driven by sediment budget data, a power-law distributed probability density function (PDF) to determine how long sediment remains stored, and a constant downstream drift velocity during transport of 157 km/yr. For 25 km of transport, few particles are stored, and the median travel time is 0.2 yr. For 1000 km of transport, nearly all particles are stored, and the median travel time is 2.5 m.y. Both travel-time distributions are power laws. The 1000 km travel-time distribution was then used to filter sinusoidal input signals with periods of 10 yr and 104 yr. The 10 yr signal is delayed by 12.5 times its input period, damped by a factor of 380, and is output as a power law. The 104 yr signal is delayed by 0.15 times its input period, damped by a factor of 3, and the output signal retains its sinusoidal input form (but with a power-law “tail”). Delivery time scales for these two signals are controlled by storage; in-channel transport time is insignificant, and low-frequency signals are transmitted with greater fidelity than high-frequency signals. These signal modifications are essential to consider when evaluating watershed restoration schemes designed to control sediment loading, and where source-area geomorphic processes are inferred from the geologic record.
Rh glycoprotein immunoreactivity in the skin and its role in extrabranchial ammonia excretion by the sea lamprey (Petromyzonmarinus) in fresh water
Authors: Blair S.D. , Wilkie M.P. , Edwards S.L.
Published: December 2016

Aquatic organisms employ various strategies to excrete ammonia across the gills, skin, and (or) renal routes. During three different stages of their life cycle, we hypothesized that the basal vertebrate sea lamprey (Petromyzon marinus L., 1758) used the skin as a route for ammonia excretion. Measurements of ammonia excretion using divided flux chambers revealed that extrabranchial sites (skin plus renal) of ammonia excretion were quantitatively more important in larval sea lampreys, but following metamorphosis, the gills became the dominant route of excretion in juvenile sea lampreys. Despite the greater relative importance of the skin in the larval stage, Rh glycoprotein isoforms Rhbg, Rhcg1, and Rhcg2 were detected in the skin in all three sea lamprey life stages examined, but the patterns of expression were dependent on the life stage. We conclude that, during the relatively sedentary filter-feeding larval stage, extrabranchial routes play an equally important role as the gill in facilitating ammonia excretion. However, the gills by virtue of their extensive branchial vasculature become the dominant route of ammonia excretion following metamorphosis because of the need to offload greater amounts of ammonia arising from higher rates of basal ammonia production and the potential to excrete higher amounts of ammonia following ingestion of protein-rich blood in the parasitic stage.
First-principles study on the dielectric and transport properties of the LiNbO3-type CdPbO3
Authors: Zhang Jing , Ke San Huang , Rowlands Derwyn A.
Published: December 2016

Using first-principles calculation method, we have investigated the zone-center phonon modes, dielectric and transport properties of the LiNbO3-type CdPbO3. The results show that the relatively large peaks of infrared (IR) and Raman spectra mainly come from the [Formula: see text] and [Formula: see text] modes, respectively. The dielectric constant calculations reveal that this compound is positive uniaxial crystal and has the large dielectric constants. By investigating the electric transport properties using gold as electrode, the interesting negative differential resistance (NDR) effect can be observed, which reveals this compound should have important application in semiconducting electronic devices.
Quantum interferometric power and the role of nonclassical correlations in quantum metrology for a special class of two-qubit states
Authors: El Hadfi H. , Ait Taleb Y. , Daoud M.
Published: December 2016

We analyze the effects of quantum correlations on the parameter precision in an interferometric configuration. As probe states, we consider a class of two-qubit states for which the analytical expression of the quantum interferometric power, quantifying the quantum correlations, is explicitly derived. Also, we give and analyze the local quantum Fisher information, which evaluates the sensitivity of the probe state to the phase shift, for some relevant local Hamiltonians. The discord-like quantum correlations based on the notion of quantum interferometric power are compared with the original quantum discord based on von Neumann entropy. We also examine the significance of quantum correlations in enhancing the precision of the phase estimation. Our study corroborates the recent series of investigations focusing on the role of quantum correlations other than entanglement on the efficiency of quantum metrology protocols.
Addressing the uncertainties in autonomous driving
Authors: Macfarlane Jane , Stroila Matei
Published: December 2016

Autonomous driving is a highly complex sensing and control problem. Today's vehicles may include many different compositions of sensor sets including the newer more sophisticated sensors like radar, cameras, and lidar. Each sensor in the car provides specific information about the environment at varying levels and has an inherent uncertainty and accuracy measure. Beyond the sensors needed for perception, the control system needs some basic measure of its position in space and its surrounding reality that can be conflated with the perceived local space. The inherent challenges of map building introduce its own set of uncertainties. As such, the map itself can be regarded as a very complex sensor with multiple levels of uncertainty and measures of accuracy. The algorithms used to integrate this information will have to manage the propagation of their inaccuracies, fuse information to reduce the uncertainties and, in the end, offer levels of confidence in the produced representations that can be then used for safe navigation decisions and actions.
My Career as a Theoretical Physicist—So Far
Authors: Langer J.S.
Published: December 2016

Theoretical physics and the institutions that support it have changed greatly during my career. In this article, I recount some of my most memorable experiences as a physicist, first as a graduate student with Rudolf Peierls at the University of Birmingham in England and later as a colleague of Walter Kohn at the Institute for Theoretical Physics in Santa Barbara, California. I use this account to illustrate some of the changes that have occurred in my field and also as a rationale for asserting that theoretical physics has an increasingly vital role to play in modern science.
The Varied Roles of Notch in Cancer
Authors: Aster Jon C. , Pear Warren S. , Blacklow Stephen C.
Published: December 2016

Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.
Necroptosis: Mechanisms and Relevance to Disease
Authors: Galluzzi Lorenzo , Kepp Oliver , Chan Francis Ka-Ming , Kroemer Guido
Published: December 2016

Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.
The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer
Authors: Affo Silvia , Yu Le-Xing , Schwabe Robert F.
Published: December 2016

Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix–associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.
Humanized Mouse Models of Clinical Disease
Authors: Walsh Nicole C. , Kenney Laurie L. , Jangalwe Sonal , Aryee Ken-Edwin , Greiner Dale L. , Brehm Michael A. , Shultz Leonard D.
Published: December 2016

Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice, have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft-versus-host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly personalized medicine in the clinic. This review discusses recent progress in the development and use of humanized mice and highlights their utility for the study of human diseases.
The Pathogenesis of Ebola Virus Disease
Authors: Baseler Laura , Chertow Daniel S. , Johnson Karl M. , Feldmann Heinz , Morens David M.
Published: December 2016

For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations.
Burden of Placental Malaria among Pregnant Women Who Use or Do Not Use Intermittent Preventive Treatment at Mulago Hospital, Kampala
Authors: Odongo Charles Okot , Odida Michael , Wabinga Henry , Obua Celestino , Byamugisha Josaphat
Published: December 2016

Intermittent preventive treatment of malaria in pregnancy with sulphadoxine-pyrimethamine (SP-IPTp) is widely used to reduce the incidence of adverse pregnancy outcomes. As a monitor for continued effectiveness of this intervention amidst SP resistance, we aimed to assess malaria burden among pregnant women who use or do not use SP-IPTp. In a descriptive cohort study at Mulago Hospital, Kampala, 87 women who received two supervised doses of SP-IPTp were followed up until delivery. Controls were pregnant women presenting in early labour without history of SP-IPTp. Histopathological investigation for placental malaria (PM) was performed using the Bulmer classification criterion. Thirty-eight of the 87 women returned for delivery and 33 placentas were successfully collected and processed along with 33 placentas from SP nonusers. Overall, 12% (4/33) of the users had evidence of PM compared to 48% (16/33) of nonusers. Among nonusers, 17/33, 8/33, 2/33, and 6/33 had no placental infection, active infection, active-chronic infection, and past-chronic infection, respectively. Among users, respective proportions were 29/33, 2/33, 0/33, and 2/33. No difference in birth weights was apparent between the two groups, probably due to a higher proportion of infections occurring later in pregnancy. Histological evidence here suggests that SP continues to offer substantial benefit as IPTp.
Fiber-Reinforced Polymer-Packaged Optical Fiber Bragg Grating Strain Sensors for Infrastructures under Harsh Environment
Authors: Zhou Zhi , Wang Zhenzhen , Shao Lian
Published: December 2016

Optical fiber Bragg grating (FBG) has been recognized as an outstanding high-performance local monitoring sensor and is largely applied in structural health monitoring (SHM). This paper proposes a series of fiber-reinforced polymer- (FRP-) packaged optical fiber Bragg grating strain sensors to completely meet the requirements of rough civil engineering infrastructures, and their sensing performance under normal environment and harsh environment is experimentally investigated. It is experimentally and theoretically proved that FRP-packaged FBG strain sensors maintain excellent sensing performance as the bare FBG sensor under a harsh environment, and their durability is significantly enhanced due to the FRP materials. These FRP-packaged FBG strain sensors are successfully applied in the SHM system of Aizhai Bridge.
Research on a Novel Kernel Based Grey Prediction Model and Its Applications
Authors: Ma Xin
Published: December 2016

The discrete grey prediction models have attracted considerable interest of research due to its effectiveness to improve the modelling accuracy of the traditional grey prediction models. The autoregressive GM(1,1)model, abbreviated as ARGM(1,1), is a novel discrete grey model which is easy to use and accurate in prediction of approximate nonhomogeneous exponential time series. However, the ARGM(1,1)is essentially a linear model; thus, its applicability is still limited. In this paper a novel kernel based ARGM(1,1)model is proposed, abbreviated as KARGM(1,1). The KARGM(1,1)has a nonlinear function which can be expressed by a kernel function using the kernel method, and its modelling procedures are presented in details. Two case studies of predicting the monthly gas well production are carried out with the real world production data. The results of KARGM(1,1)model are compared to the existing discrete univariate grey prediction models, including ARGM(1,1), NDGM(1,1,k), DGM(1,1), and NGBMOP, and it is shown that the KARGM(1,1)outperforms the other four models.
Quantification of Warfarin in Dried Rat Plasma Spots by High-Performance Liquid Chromatography with Tandem Mass Spectrometry
Authors: Chernonosov Alexander
Published: December 2016

This paper presents the development and validation of a novel method for quantification of the oral anticoagulant drug warfarin in dried plasma spots (DPS) by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Blood plasma was chosen as a biological fluid to preclude the influence of the hematocrit on the results of the analysis. A 30 μL sample of rat plasma was placed onto Whatman 903 Protein Saver Card and was allowed to dry. A single DPS is sufficient for preparing eight 3.2 mm discs, each containing approximately 1.5–1.6 μL of plasma. Warfarin extraction from one 3.2 mm disc was carried out by adding 200 μL of the acetonitrile : water mixture (1 : 1, v/v) containing 10 mM NH4COOH (pH 4.0), with incubation on a shaker at 1000 rpm for 1 h at 25°C. After chromatographic separation, warfarin and coumachlor (an internal standard) were measured using negative-ion multiple-reaction monitoring with ion transitionsm/z307 → 161 for warfarin andm/z341 → 161 for the internal standard. The working range of this method is 10–10,000 ng/mL. Within this range, intra- and interday variability of precision and accuracy was <13% and recovery was 82–99%. The results indicate that the new method requires only small plasma samples and may be useful for pharmacokinetic research on warfarin.
Outcomes of Infectious versus Sterile Perforated Corneal Ulcers after Therapeutic Penetrating Keratoplasty in the United States
Authors: Rush Sloan W. , Rush Ryan B.
Published: December 2016

Purpose. To compare the long-term outcomes of infectious versus sterile perforated corneal ulcers after therapeutic penetrating keratoplasty in the United States.Methods. The charts of 45 consecutive eyes that underwent primary therapeutic penetrating keratoplasty for a perforated corneal ulcer at a single center were retrospectively reviewed. The perforated ulcers were classified as infectious or sterile and the underlying demographics, clinical features, and 36-month outcomes were compared among the two groups.Results.Mean follow-up among subjects was 38.6 (±6.9) months. Patients presenting with sterile perforated ulcers were more likely to have a peripheral perforation location (p=0.0333) and recurrence of the underlying disease condition (p=0.0321), require adjunctive surgical measures in the immediate postoperative period (p<0.0001), have reperforation after keratoplasty (p=0.0079), have worse best corrected visual acuity (p=0.0130), develop no light perception vision (p=0.0053), and require enucleation/evisceration (p=0.0252) when compared to the infectious perforated ulcer group.Conclusions. Sterile perforated corneal ulcers have a worse prognosis and may be more frequent than those caused by infectious disease in the United States compared to the developing world.
Local Buckling Analysis of T-Section Webs with Closed-Form Solutions
Authors: Liang Cheng , He Yabo , Liu Sumei
Published: December 2016

This paper reports on approaches to estimate the critical buckling loads of thin-walled T-sections with closed-form solutions. We first develop a model using energy conservation approach under the assumption that there is no correlation between the restraint coefficient and buckling half-wavelength. Secondly, we propose a numerical approach to estimate the critical buckling conditions under the more realistic torsional stiffener constraint condition. A dimensionless parameter correlated with constraint conditions is introduced through finite element (FE) analysis and data fitting technique in the numerical approach. The critical buckling coefficient and loads can be expressed as explicit functions of the dimensionless parameter. The proposed numerical approach demonstrates higher accuracy than the approach under noncorrelation assumption. Due to the explicit expression of critical buckling loads, the numerical approach presented here can be easily used in the design, analysis, and precision manufacture of T-section webs.
Serum Cytokine Profiles in Children with Crohn’s Disease
Authors: Vasilyeva Ekaterina , Abdulkhakov Sayar , Cherepnev Georgi , Martynova Ekaterina , Mayanskaya Irina , Valeeva Alina , Abdulkhakov Rustam , Safina Dilyara , Khaiboullina Svetlana , Rizvanov Albert
Published: December 2016

Crohn’s disease (CD) is a chronic inflammatory bowel disease that can be diagnosed at any age. There are two major patient groups based on diagnosis of this disease, before or after the age of 20 (juvenile/adolescent or adult), with disease progression in adults usually milder than in juvenile CD patients. Immune mechanisms have been suggested to play an important role in CD pathogenesis, with cytokines governing the development of the immune response. Upregulation of inflammatory cytokines in serum of juvenile and adult CD patients has been documented; still little is known about age-dependent differences in serum cytokine profiles of CD patients. We applied multiplex technology to analyze serum levels of 12 cytokines in juveniles and adults. We show that during the acute stage of the disease all CD patients have high serum levels of CXCL10, which remains upregulated during remission. Increased serum levels of TNF-αand IL-6 during the acute stage was characteristic of juvenile CD patients, whereas adult CD patients had upregulated levels of GM-CSF and IFN-γ. Taken together, these results demonstrate age-dependent differences in cytokine profiles, which may affect the pathogenesis of CD in patients at different ages of disease onset.
Long-Term Trend of Climate Change and Drought Assessment in the Horn of Africa
Authors: Ghebrezgabher Mihretab G. , Yang Taibao , Yang Xuemei
Published: December 2016

Climate change due to global warming is a world concern, particularly in Africa. In this study, precipitation and temperature variables are taken as a proxy to assess and quantify the long-term climate change and drought in the Horn of Africa (HOA) (1930–2014). We adapted a simple linear regression and interpolation to analyze, respectively, the trend and spatial distribution of the mean annual precipitation and temperature. In addition, standardized precipitation evapotranspiration index (SPEI) was applied to evaluate the drought condition of the HOA. The results revealed that statistically the trend of precipitation decreased insignificantly; the trend of temperature was observed to drop very significantly between 1930 and 1969, but it was dramatically elevated very significantly from 1970 to 2014. The SPEI showed that the HOA experienced from mild to moderate drought throughout the study period with severe to extreme drought in some regions, particularly in 1943, 1984, 1991, and 2009. The drought was a very serious environmental problem in the HOA in the last 85 years. Thus, an immediate action is required to tackle drought and hence poverty and famine in the HOA.
Stabilization of Semi-Markovian Jump Systems with Uncertain Probability Intensities and Its Extension to Quantized Control
Authors: Nguyen Ngoc Hoai An , Kim Sung Hyun , Choi Jun
Published: December 2016

This paper concentrates on the issue of stability analysis and control synthesis for semi-Markovian jump systems (S-MJSs) with uncertain probability intensities. Here, to construct a more applicable transition model for S-MJSs, the probability intensities are taken to be uncertain, and this property is totally reflected in the stabilization condition via a relaxation process established on the basis of time-varying transition rates. Moreover, an extension of the proposed approach is made to tackle the quantized control problem of S-MJSs, where the infinitesimal operator of a stochastic Lyapunov function is clearly discussed with consideration of input quantization errors.
Dual Inhibition of Key Proliferation Signaling Pathways in Triple-Negative Breast Cancer Cells by a Novel Derivative of Taiwanin A
Authors: Kuo Yueh-Hsiung , Chiang En-Pei Isabel , Chao Che-Yi , Rodriguez Raymond L. , Chou Pei-Yu , Tsai Shu-Yao , Pai Man-Hui , Tang Feng-Yao
Published: December 2016

The treatment of breast cancer cells obtained by blocking the aberrant activation of the proliferation signaling pathways PI3K/Akt/mTOR and MEK/ERK has received considerable attention in recent years. Previous studies showed that Taiwanin A inhibited the proliferation of several types of cancer cells. In this study, we report that 3,4-bis-3,4,5-trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell-cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of β-catenin, cdc2 and the cell-cycle regulatory proteins, cyclin A, cyclin D1, and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation of the Akt and ERK1/2 signaling pathways. Moreover, BTMB induced cell apoptosis through an increase in the expression of BAX, cleaved caspase-3, and cleaved PARP. Moreover, BTMB inhibited TNBC cell colony formation and sensitized TNBC cells to cisplatin, a chemotherapeutic drug. In a TNBC mouse xenograft model, BTMB significantly inhibited the growth of mammary carcinomas through decreased expression of cyclin D1. BTMB was shown to significantly suppress the growth of mammary carcinoma and therefore to have potential as an anticancer therapeutic agent. Mol Cancer Ther; 16(3); 480–93. ©2016 AACR.
Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer Patients Progressing after Docetaxel: A Prospective Single-Center Study
Authors: Cicero Giuseppe , De Luca Rossella , Dorangricchia Patrizia , Galvano Antonio , Lo Re Giuseppe , Serretta Vincenzo , Dispensa Nino , Dieli Francesco
Published: December 2016

Purpose: The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone. Methods: Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate-specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints. Results: Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (β = 0.377, p < 0.01). Conclusions: Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment.