bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Novel Plasmodium falciparum Hexokinase Inhibitors with Antiparasitic Activity
Authors: Davis Mindy I. , Patrick Stephen L. , Blanding Walker M. , Dwivedi Varun , Suryadi Jimmy , Golden Jennifer E. , Coussens Nathan P. , Lee Olivia W. , Shen Min , Boxer Matthew B. , Hall Matthew D. , Sharlow Elizabeth R. , Drew Mark E. , Morris James C.
Published: July 2016

Plasmodium falciparum
, the deadliest species of malaria parasites, is dependent on glycolysis for the generation of ATP during the pathogenic red blood cell stage. Hexokinase (HK) catalyzes the first step in glycolysis, transferring the γ-phosphoryl group of ATP to glucose to yield glucose-6-phosphate. Here, we describe the validation of a high-throughput assay for screening small-molecule collections to identify inhibitors of the
P. falciparum
HK (PfHK). The assay, which employed an ADP-Glo reporter system in a 1,536-well-plate format, was robust with a signal-to-background ratio of 3.4 ± 1.2, a coefficient of variation of 6.8% ± 2.9%, and a Z′-factor of 0.75 ± 0.08. Using this assay, we screened 57,654 molecules from multiple small-molecule collections. Confirmed hits were resolved into four clusters on the basis of structural relatedness. Multiple singleton hits were also identified. The most potent inhibitors had 50% inhibitory concentrations as low as ∼1 μM, and several were found to have low-micromolar 50% effective concentrations against asexual intraerythrocytic-stage
P. falciparum
parasites. These molecules additionally demonstrated limited toxicity against a panel of mammalian cells. The identification of PfHK inhibitors with antiparasitic activity using this validated screening assay is encouraging, as it justifies additional HTS campaigns with more structurally amenable libraries for the identification of potential leads for future therapeutic development.
Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients
Authors: Modongo Chawangwa , Pasipanodya Jotam G. , Magazi Beki T. , Srivastava Shashikant , Zetola Nicola M. , Williams Scott M. , Sirugo Giorgio , Gumbo Tawanda
Published: July 2016

Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC
0–24
). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (
C
max
), AUC
0–24
, and trough concentrations. The primary node for failure had two competing variables,
C
max
of <67 mg/liter and AUC
0–24
of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R
2
= 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin
C
max
of ≥67 mg/liter versus 3/15 (20%) in those with a
C
max
of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin
C
max
and AUC
0–24
below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.
Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala
Authors: Ihara Fumiaki , Nishimura Maki , Muroi Yoshikage , Mahmoud Motamed Elsayed , Yokoyama Naoaki , Nagamune Kisaburo , Nishikawa Yoshifumi
Published: July 2016

Chronic infection with
Toxoplasma gondii
becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that
T. gondii
infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by
T. gondii
infection, we analyzed the parasite load and histopathological changes.
T. gondii
infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that
T. gondii
infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during
T. gondii
infection.
Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens
Authors: Li Lin-Xi , Benoun Joseph M. , Weiskopf Kipp , Garcia K. Christopher , McSorley Stephen J.
Published: July 2016

Salmonellainfection profoundly affects host erythroid development, but the mechanisms responsible for this effect remain poorly understood. We monitored the impact ofSalmonellainfection on erythroid development and found that systemic infection induced anemia, splenomegaly, elevated erythropoietin (EPO) levels, and extramedullary erythropoiesis in a process independent ofSalmonellapathogenicity island 2 (SPI2) or flagellin. The circulating EPO level was also constitutively higher in mice lacking the expression of signal-regulatory protein α (SIRPα). The expression level of EPO mRNA was elevated in the kidney and liver but not increased in the spleens of infected mice despite the presence of extramedullary erythropoiesis in this tissue. In contrast to data from a previous report, mice lacking EPO receptor (EPOR) expression on nonerythroid cells (EPOR rescued) had bacterial loads similar to those of wild-type mice followingSalmonellainfection. Indeed, treatment to reduce splenic erythroblasts and mature red blood cells correlated with elevated bacterial burdens, implying that extramedullary erythropoiesis benefits the host. Together, these findings emphasize the profound effect ofSalmonellainfection on erythroid development and suggest that the modulation of erythroid development has both positive and negative consequences for host immunity.
The Microbiota Contributes to CD8+T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis
Authors: Keselman Aleksander , Li Erqiu , Maloney Jenny , Singer Steven M.
Published: July 2016

Giardia duodenalisis a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8+T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8+αβ T cells in the small intestinal lamina propria, this increase was absent in antibiotic-treated mice. Infection also led to increased numbers of CD4+αβ T cells in the lamina propria and activation of T cell receptor γδ-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8+T cells express gamma interferon (IFN-γ) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8+T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8+T cells and γδ T cells duringGiardiainfections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8+T cell activation in giardiasis.
Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms
Authors: Chumbler Nicole M. , Farrow Melissa A. , Lapierre Lynne A. , Franklin Jeffrey L. , Lacy D. Borden
Published: July 2016

As the major cause of antibiotic-associated diarrhea,
Clostridium difficile
is a serious problem in health care facilities worldwide.
C. difficile
produces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators.
Identification and Regulation of Genes for Cobalamin Transport in the Cyanobacterium Synechococcus sp. Strain PCC 7002
Authors: Pérez Adam A. , Rodionov Dmitry A. , Bryant Donald A.
Published: July 2016

The cyanobacterium
Synechococcus
sp. strain PCC 7002 is a cobalamin auxotroph and utilizes this coenzyme solely for the synthesis of
l
-methionine by methionine synthase (MetH).
Synechococcus
sp. strain PCC 7002 is unable to synthesize cobalamin
de novo
, and because of the large size of this tetrapyrrole, an active-transport system must exist for cobalamin uptake. Surprisingly, no cobalamin transport system was identified in the initial annotation of the genome of this organism. With more sophisticated
in silico
prediction tools, a
btuB
-
cpdA
-
btuC
-
btuF
operon encoding components putatively required for a B
12
uptake (
btu
) system was identified. The expression of these genes was predicted to be controlled by a cobalamin riboswitch. Global transcriptional profiling by high-throughput RNA sequencing of a cobalamin-independent form of
Synechococcus
sp. strain PCC 7002 grown in the absence or presence of cobalamin confirmed regulation of the
btu
operon by cobalamin. Pérez et al. (A. A. Pérez, Z. Liu, D. A. Rodionov, Z. Li, and D. A. Bryant, J Bacteriol 198:2743–2752, 2016,
http://dx.doi.org/10.1128/JB.00475-16
) developed a cobalamin-dependent yellow fluorescent protein reporter system in a
Synechococcus
sp. strain PCC 7002 variant that had been genetically modified to allow cobalamin-independent growth. This reporter system was exploited to validate components of the
btu
uptake system by assessing the ability of targeted mutants to transport cobalamin. The
btuB
promoter and a variant counterpart mutated in an essential element of the predicted cobalamin riboswitch were fused to a
yfp
reporter. The combined data indicate that the
btuB
-
cpdA
-
btuF
-
btuC
operon in this cyanobacterium is transcriptionally regulated by a cobalamin riboswitch.

IMPORTANCE
With a cobalamin-regulated reporter system for expression of yellow fluorescent protein, genes previously misidentified as encoding subunits of a siderophore transporter were shown to encode components of cobalamin uptake in the cyanobacterium
Synechococcus
sp. strain PCC 7002. This study demonstrates the importance of experimental validation of
in silico
predictions and provides a general scheme for
in vivo
verification of similar cobalamin transport systems. A putative cobalamin riboswitch was identified in
Synechococcus
sp. strain PCC 7002. This riboswitch acts as a potential transcriptional attenuator of the
btu
operon that encodes the components of the cobalamin active-transport system.
Abnormal appearance of the umbilicus: an indicator of urachal anomalies
Authors: Espírito Santo Rita , Alcafache Margarida , Almeida Sofia Rodrigues , Tavares Ana
Published: July 2016

The urachus is an intra-abdominal fibrous remnant of the allantois. The non-involution of the allantois can result in urachal anomalies. The abnormal appearance of the umbilicus may be a sign of such anomalies. We have observed 3 cases of term neonates with atypical appearance of the umbilical stump, all of which manifested urachal anomalies, as documented by ultrasound scan. These appearances are rarely described in the literature, and seem to regress at around 2 months. Therefore, it is important that healthcare professionals should be aware of the possible implications of atypical umbilical stumps, evaluate each case accordingly and, if an urachal anomaly is diagnosed, refer the patient to a paediatric surgery centre, as such malformations carry an underlying risk of infection or malignancy.
Impact of physical function impairment and multimorbidity on mortality among community-living older persons with sarcopaenia: results from theilSIRENTEprospective cohort study
Authors: Landi Francesco , Calvani Riccardo , Tosato Matteo , Martone Anna Maria , Bernabei Roberto , Onder Graziano , Marzetti Emanuele
Published: July 2016

Objective

Sarcopaenia and physical function impairment may have a greater effect on survival than other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of sarcopaenia on all-cause mortality and the interaction among muscle loss, physical function impairment and multimorbidity on mortality risk over 10 years in older community-dwellers.

Design

Prospective cohort study.

Setting

Population-based study.

Participants

All persons aged 80+ years living in the community in the Sirente geographic area (L'Aquila, Italy) (n=364). Participants were categorised in the sarcopaenic or non-sarcopaenic group based on the European Working Group on Sarcopenia in Older People criteria.

Primary and secondary outcome measures

(1) All-cause mortality over 10 years according to the presence of sarcopaenia and (2) impact of physical function impairment, assessed using the Short Physical Performance Battery (SPPB), and multimorbidity on 10-year mortality risk in persons with sarcopaenia.

Results

Sarcopaenia was identified in 103 participants (29.1%). A total of 253 deaths were recorded over 10 years: 90 among sarcopaenic participants (87.4%) and 162 among non-sarcopaenic persons (65.1%; p<0.001). Participants with sarcopaenia had a higher risk of death than those without sarcopaenia (HR=2.15; 95% CI 1.02 to 4.54). When examining the effect of sarcopaenia and physical function impairment on mortality, participants with low physical performance levels showed greater mortality. Conversely, the mortality risk was unaffected by multimorbidity.

Conclusions

Our findings show that physical function impairment, but not multimorbidity, is predictive of mortality in older community-dwellers with sarcopaenia. Hence, in sarcopaenic older persons, interventions against functional decline may be more effective at preventing or postponing negative health outcomes than those targeting multimorbidity.
Official government statistics of road traffic deaths in India under-represent pedestrians and motorised two wheeler riders
Authors: Bhalla Kavi , Khurana Nidhi , Bose Dipan , Navaratne Kumari Vinodhani , Tiwari Geetam , Mohan Dinesh
Published: July 2016

Background

Reliable data on traffic deaths are important for planning road safety programmes and evaluating progress. Although pedestrians comprise approximately 40% of traffic deaths in low-income and middle-income countries, official government statistics in India suggest that pedestrians comprise less than 10% of deaths.

Objective

To assess the accuracy of official tabulations of traffic deaths among various road users in India.

Method

We reviewed police first information reports (FIRs) of traffic deaths in one district (Belgaum) in 2013 and 2014 and extracted information about crash victims. We validated the FIRs by linking with case files from four police stations in the district. Finally, we compared the information on types of road users killed based on FIRs with the district's official tabulations.

Results

We found that the distribution of deaths by types of road users reported in official tabulations differed substantially from the underlying police reports. While official tabulations reported that only 9% of deaths in 2013 were pedestrians and 37% were riders of motorised two wheelers, FIRs showed that these groups accounted for 21% and 49% of deaths, respectively.

Discussion

Official tabulations of traffic deaths in India do not correctly represent the types of roads users killed. Until the Indian National Crime Records Bureau has corrected the process of generating statistical tabulations from police reports, data on the types of road users killed in India should not be used for research and policy. In the interim, researchers and policy makers who need such information should extract it from police case files.
Republished: Paradoxical cerebral air embolism causing large vessel occlusion treated with endovascular aspiration
Authors: Belton Patrick J , Nanda Ashish , Alqadri Syeda L , Khakh Gurpreet S , Chandrasekaran Premkumar Nattanmai , Newey Christopher , Humphries William E
Published: July 2016

Cerebral air embolism is a dreaded complication of invasive medical procedures. The mainstay of therapy for patients with cerebral air embolism has been hyperbaric oxygen therapy, high flow oxygen therapy, and anticonvulsants. We present a novel therapeutic approach for treatment of cerebral air embolism causing large vessel occlusion, using endovascular aspiration. Our patient developed a cerebral air embolism following sclerotherapy for varicose veins. This caused near total occlusion of the superior division of the M2 segment of the right middle cerebral artery. Symptoms included unilateral paralysis, unintelligible speech, and hemianopia; National Institutes of Health Stroke Scale (NIHSS) on presentation was 16. The air embolism was treated using a distal aspiration technique. Angiography following aspiration showed Thrombolysis in Cerebral Infarction 2B reperfusion. Following aspiration, the patient was re-examined; NIHSS at that time was 4. At 1 month follow-up, the modified Rankin Scale score was 1 and NIHSS was 1. Treatment of cerebral air embolism is discussed.
Concurrent physitis and portosystemic shunts in three dogs
Authors: Meehan Lucinda Jayne , Hodgkiss‐Geere Hannah , Walsh Bernard , Mellanby Richard J , Schwarz Tobias
Published: July 2016

Hepatic disease is a known risk factor for the development of bone infection in human beings. Three dogs with portosystemic shunting and concurrent physitis are presented here and an association is postulated between both disease processes. Portosystemic shunting may be a risk factor for the development of physitis in dogs. Skeletal structures should not be overlooked when reviewing diagnostic imaging studies of dogs with portosystemic shunts. Skeletal infections should be considered as a differential diagnosis in dogs with liver disease and concurrent skeletal abnormalities.
Polyethylene glycol and poly(vinyl alcohol) hydrogels treated with photo-initiated chemical vapor deposition
Authors: Javanbakht Taraneh , Bérard Ariane , Tavares Jason R.
Published: July 2016

This study was designed to determine if surface modification via photo-initiated chemical vapor deposition (PICVD) affects the physicochemical properties of polyethylene glycol (PEG) and poly(vinyl alcohol) (PVA) differently, given their different chemical structures and properties. Contact angle measurements showed that both polymers increase in surface hydrophobicity after PICVD treatment. Further, the improved hydrophobicity facilitated dispersion into nonpolar solvents. Chemical changes were concentrated near the surface, evidenced by Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) measurements, indicating namely that partial oxidation occurs during treatment. These findings were discussed in the context of the difference of the molecular structures of PEG and PVA, which, in turn, control their surface functionalization and hydrophobicity.
Computational study of the threshold energy for the 1,2-interchange of X and R (X, R = halogens, pseudohalogens, and monovalent hydrocarbon groups) on CH2XCH2R
Authors: Kim Ju-Sung , Brandt Laura M. , Heard George L. , Holmes Bert E.
Published: July 2016

Transition state geometries and threshold energies, E0, were computed for an unusual unimolecular isomerization reaction that exchanges two groups (X, R) on CH2XCH2R. An objective is to determine the most energetically feasible interchanges to guide experimental investigations. The interchanging species included halogens (F, Cl, Br) and pseudohalogens and monovalent hydrocarbons (H, SH, CH3, NH2, OH, OCF3, OCH3, CH=CH2, CH2CH3, CH2OH, C≡CH, CH2CF3, CCl3, CF3) attached to a two carbon backbone. Ground state and transition state geometries were optimized with the B3PW91 level of theory and 6-311+G(2d,p) basis set. The Br–Br interchange had the lowest E0 (141 kJ/mol), and CH3–H had the highest E0 (582 kJ/mol). In general, larger atoms or groups with lone pairs of electrons such as halogens, SH, OH, OCH3, OCF3, and NH2 tend to lower the E0 barrier for interchange, making them the most likely to be experimentally observed.
Action of a Frobenius-like group with kernel having central derived subgroup
Authors: Ercan Gülin , Güloğlu İsmail Ş.
Published: July 2016

A finite group [Formula: see text] is said to be Frobenius-like if it has a nontrivial nilpotent normal subgroup [Formula: see text] with a nontrivial complement [Formula: see text] such that [Formula: see text] for all nonidentity elements [Formula: see text]. Suppose that a finite group [Formula: see text] admits a Frobenius-like group of automorphisms [Formula: see text] of coprime order with [Formula: see text] In case where [Formula: see text] we prove that the groups [Formula: see text] and [Formula: see text] have the same nilpotent length under certain additional assumptions.
Third-order nonlinear optical properties of a novel series of D-π-A pyrene-aldehyde derivatives
Authors: Wang Xiangke , Wang Dong , Gao Hong , Yang Zhou , Cao Hui , Yang Huai , He Wanli , Wang Huihui , Gu Jianming , Hu Huiying
Published: July 2016

A series of mono-substituted pyrene derivatives having a pyrene mesogenic core and aldehyde group peripherals were designed and synthesized, which had typical D-[Formula: see text]-A structures. Photophysical properties of the compounds were characterized by UV/Vis spectroscopy and the third-order nonlinearities of the compounds were studied by “open aperture” and “closed aperture” [Formula: see text]-scan techniques. Both of the compounds showed typical nonlinear absorptions and refractions, and the third-order nonlinear susceptibilities have been found to be very high in all cases. The significant nonlinear optical response combined with the possibility to further modify it, by changing the electron acceptor and the electron-donor groups, suggests that these systems can prove to be important candidates for a variety of photonic/optoelectronic applications.
Polarization angular-resolved transmission spectroscopy of opal films
Authors: Muldarisnur M. , Marlow F.
Published: July 2016

In this paper, we investigated the angular behavior of light transmission through opal films over a broad range of wavelengths and angles. The opal films were prepared using the capillary deposition method (CDM). The observation of many well-defined diffraction peaks indicates that the CDM results in opal films with high quality. Peaks overlapping at normal incidence split when samples are rotated. The angular shift of these peaks was found to satisfy the kinematical diffraction theory very well. Furthermore, the variation of intensity with incident angle can be interpreted in terms of a simplified dynamical diffraction theory. Moreover, the presence of two differently oriented domains in CDM-made opal films is essential in discussing the measured spectra. These domains can be assigned to parallel microscopic stripes of ABC and ACB type fcc structures. Angular-resolved spectroscopy with polarized incident light shows interesting polarization dependence of light propagation inside opals.
Discrete solitons in an array of linear waveguides with a nonlinear 𝒫𝒯-symmetric defect
Authors: Chen Guihua , Wang Hongcheng , Fan Lixian , Liu Yan
Published: July 2016

A one-dimensional linear waveguide array with a parity-time[Formula: see text]([Formula: see text])-symmetric defect, which is represented by a pair of waveguides carrying equal amount of nonlinear gain and loss, is considered. Compared to the system with linear [Formula: see text]-symmetric defect, a different instability of solitons is exhibited in this model, in which the unstable fundamental discrete solitons suffer either decay or blowup. The effect of nonlinear [Formula: see text]-symmetry on the stability of fundamental solitons is investigated numerically by obtaining the stability region of the solitons. The region has a finite threshold of total power as the coupling within the defect is less than the counterpart of other linear waveguides, while the threshold is absent as the coupling within the defect is larger than the one between other linear waveguides. The stability region is intensely enlarged by the increase of the coupling strength within the defect, and descends exponentially with the increase of the total power.
Commentary on “Biophysical Economics” and Evolving Areas
Authors: Flomenbom Ophir , Coban Gul Unal , Adigüzel Yekbun
Published: July 2016

In this Issue, papers in the area of socio-econo-physics and biophysical economics are presented. We have recently introduced socio-econo-physics and biophysical economics in Biophysical Reviews and Letters (BRL), yet saw 3 to 4 relevant papers just in these most recent three quarters. In this commentary, we therefore would like to elaborate on the topics of socio-econo-physics and biophysical economics and to introduce these concepts to the readers of BRL and the biophysical community of science, with the purpose of supporting many more publications here in BRL, in this evolving area.
Determination of an unknown source term for an inverse source problem of the time-fractional equation
Authors: Khorshidi Meisam Noei , Yousefi Sohrab Ali , Firoozjaee Mohammad Arab
Published: July 2016

In this paper, we consider an inverse source problem for a time-fractional equation with variable coefficients in a general bounded domain. The fractional derivative in the problem is in the Caputo sense. Transforming time-fractional inverse problems into optimization problem and using polynomial basis functions, we obtain the system of algebraic equation. Then, we solve the system of nonlinear algebraic equation using Mathematica7 and we have the coefficients of polynomial expansion. We extensively discuss the convergence of the method. Illustrative examples are included to demonstrate the validity and applicability of the new technique.
New Inner Product Quasilinear Spaces on Interval Numbers
Authors: Bozkurt Hacer , Yilmaz Yılmaz
Published: July 2016

Primarily we examine the new example of quasilinear spaces, namely, “IRninterval space.” We obtain some new theorems and results related to this new quasilinear space. After giving some new notions of quasilinear dependence-independence and basis on quasilinear functional analysis, we obtain some results onIRninterval space related to these concepts. Secondly, we presentIs,Ic0,Il∞, andIl2quasilinear spaces and we research some algebraic properties of these spaces. We obtain some new results and provide an important contribution to the improvement of quasilinear functional analysis.
Riesz Transform Characterization of Weighted Hardy Spaces Associated with Schrödinger Operators
Authors: Zhu Hua
Published: July 2016

We characterize the weighted local Hardy spaceshρ1(ω)related to the critical radius functionρand weightsω∈A1ρ,∞(Rn)by localized Riesz transformsR^j; in addition, we give a characterization of weighted Hardy spacesHL1(ω)via Riesz transforms associated with Schrödinger operatorL, whereL=-Δ+Vis a Schrödinger operator onRn(n≥3) andVis a nonnegative function satisfying the reverse Hölder inequality.
On the Synchronization of Two Eccentric Rotors with Common Rotational Axis: Theory and Experiment
Authors: Chen Xiaozhe , Kong Xiangxi , Zhang Xueliang , Li Lingxuan , Wen Bangchun
Published: July 2016

We study synchronization of two eccentric rotors (ERs) with common rotational axis in the vibration system of the far-resonant spatial motion. We deduce the dimensionless coupling equation of two ERs with applying the average method of small parameters. We convert the synchronization problem into the existence and stability of solving the zero solutions for the dimensionless coupling equations. By introducing the synchronization torque and the difference between the residual torques of two motors, we obtain the synchronization condition that two ERs achieve the synchronized motion. We derive the stability condition of the synchronized motion, which satisfies Routh-Hurwitz criterion. We discuss numerically the choosing motion feature of the vibration system, which indicates that the vibration system has two steady motion modes. The synchronization torque forces the phase difference to approachπwhen the structural parameters of the vibration system satisfy the condition of the spatial cone motion, and the synchronization torque drives the phase difference to approach zero when those satisfy the condition of the spatial circle motion. Finally, through the comparison and analysis of experimental data, the structural parameters of the vibration system satisfying the above two conditions can guarantee the synchronization stability for two ERs.
Implications of the Bystander and Abscopal Effects of Radiation Therapy
Authors: Verma Vivek , Lin Steven H.
Published: July 2016

Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763–5. ©2016 AACR.

See related article by Siva et al., p. 4817
Abstract 1003: Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase
Authors: Ma Kin Fai , Lo Jessica , Lau Eunice Yuen-Ting , Copland John A. , Ng Irene Oi-Lin , Lee Terence Kin-Wah
Published: July 2016

Hepatocellular carcinoma is one of the most lethal cancers in the world. Most of the patients are diagnosed at advanced stage, and they receive sorafenib as their treatment modality. However, sorafenib can only extend patients’ survival to a median of 3-4 months. Hence, there is an urgent need to identify a new therapeutic target for treatment of this disease. Increasing evidence showed that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments. Identification of the signalling pathways that maintain the functions of T-ICs provides potential targets for treatment of HCC. For this purpose, we cultured serial passages of hepatospheres combined with chemotherapeutic regimens as a strategy to enrich liver T-IC population. Using cDNA microarray, we found upregulation of several key enzymes in lipogenesis in enriched T-IC population, among which Stearoyl CoA desaturase-1 (SCD1), the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was the most significant. In HCC clinical samples, 62% (36/58) was found to be overexpressed (> 2-fold) when compared with non-tumor counterparts and patients with SCD1 overexpression had shorter disease free survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, drug resistance and expression of liver T-IC markers. SCD1 was found critical in survival of T-ICs, as enriched T-IC population are more sensitive to the inhibition of SCD1 compared to adherent lineages. Interestingly, SCD1 was found to be upregulated in sorafenib-resistant HCC cells. Pharmacological inhibition of SCD1 by A939572 not only suppressed self-renewal ability but also consistently enhanced the sensitivity towards sorafenib. Using a patient-derived xenograft model, we found that a new inhibitor against SCD1 demonstrated significant growth suppressive effect. By comparing the genetic profiles between SCD1 knockdown cells and control cells by RNA sequencing analysis, we found that upregulation of ER stress signature genes may be the potential downstream targets of SCD1 to maintain the properties of T-ICs. In conclusion, we demonstrated the crucial role of SCD1 in maintenance of liver T-ICs, and targeting SCD1 in combination with sorafenib might be a novel therapeutic regimen against HCC.

Citation Format: Kin Fai Ma, Jessica Lo, Eunice Yuen-Ting Lau, John A. Copland, Irene Oi-Lin Ng, Terence Kin-Wah Lee. Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1003.
Abstract 1053: Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy
Authors: li zhenfei , Alyamani Mohammad , Sharifi Nima
Published: July 2016

Prostate cancer is the most diagnosed cancer in men and Abiraterone is used for castration resistant prostate cancer therapy by suppressing androgen production. In patients, abiraterone is converted to D4A, a novel metabolite with more potent anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is further metabolized by the related steroidogenic enzymes to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial with patients taking abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted by dutasteride, while D4A concentrations rise, effectively blocking production of a tumor promoting metabolite and permitting D4A accumulation. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine tuning abiraterone metabolism to optimize therapy.

Citation Format: zhenfei li, Mohammad Alyamani, Nima Sharifi. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1053.
Abstract 1068: The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance
Authors: Piovan Claudia , D’Ippolito Elvira , Plantamura Ilaria , Casalini Patrizia , Tagliabue Elda , Iorio Marilena V.
Published: July 2016

HER2, member of HER family, is overexpressed in up to 30% of breast cancers and often associated to a more aggressive phenotype, resistance to chemotherapeutic agents and increased risk of metastasis. Anti-HER2 targeted therapies significantly increased the overall survival of HER2 breast cancer patients, however tumor cells frequently develop alternative resistance mechanisms and the molecular bases of this phenomenon are still far to be fully elucidated. A crucial issue is then represented by the urgent need of biomarkers able to predict the response to treatment, and certainly of new therapeutic tools to counteract the resistance mechanisms. The oncosuppressive role of miR-205 in the pathogenesis of breast cancer has been demonstrated, as well as a possible cross-regulation between miR-205 and HER signaling. MiR-205 is in fact negatively regulated by HER2 and is involved in the regulation of HER2-mediated proliferation by directly targeting HER3, preferential partner of HER2. We have investigated miR-205 role on trastuzumab resistance by using human HER2 overexpressing breast cancer cell lines and patient-derived xenograft (PDX) models. Here we show that HER3 silencing, either mediated by miR-205 or by a siRNA specific against HER3, is able to improve the responsiveness to Trastuzumab, reducing tumor cell growth and colony formation capability. This effect is mediated by impairment of Akt-mediated pathway.Combination of Trastuzumab treatment and in vivo delivery of miR-205-conjugated lipid nanoparticles in PDX models is currently on going. Finally, expression analysis of miR-205 in breast cancer patients treated in adjuvant with trastuzumab has provided new insights about its possible role as predictive biomarker of response. In summary, here we show that miR-205 improves the responsiveness to Trastuzumab treatment at least partially though HER3 silencing, and associated to outcome of patients treated in adjuvant setting, thus representing a potential adjuvant tool and predictive biomarker.

Citation Format: Claudia Piovan, Elvira D’Ippolito, Ilaria Plantamura, Patrizia Casalini, Elda Tagliabue, Marilena V. Iorio. The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1068.
Abstract 1087: Circulating microRNAs as metastasis biomarkers in oral cavity and oropharyngeal squamous cell carcinomas
Authors: Andreghetto Flavia Maziero , de Souza Mariana Barbosa , Moyses Raquel Ajub , Toporcov Tatiana Natasha , Nunes Fabio Daumas , de Carvalho Marcos Brasilino , Severino Patricia
Published: July 2016

MicroRNAs are small non-coding RNA molecules with roles in gene expression regulation and implications in cancer initiation and progression. Cell-free microRNAs detected in body fluids, and in particular in plasma, are of clinical interest due to their possible use as biomarkers. Despite the fact that their reliable quantification depends on several technical parameters, there is great clinical interest in this approach due to its simplicity and low risk to the patient. Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide, with survival rates of about 50% in 5 years. Tobacco and alcohol consumption are the most important risk factors and, currently, the presence of cervical lymph node metastases remain the strongest prognostic factor for this cancer type. In this study we identified plasma microRNAs associated with squamous cell carcinomas of the oral cavity and oropharynx as well as with the presence of cervical lymph node metastases. We evaluated the expression of 179 microRNAs in plasma from 45 patients (28 presenting cervical lymph node metastases at diagnosis and 17 with no lymph node metastasis) and 15 healthy controls. Samples were matched according to age, sex, drinking and smoking habits. Among microRNAs mostly expressed in tumor samples, some had been already detected in oral squamous cell carcinoma tissues, such as miR-210, while others, such as miR-573, are still poorly studied. Comparisons between oral and oropharyngeal carcinomas yielded several differences, in accordance with molecular distinctions between these cancer types. MicroRNAs possibly involved in the metastatic process were identified when comparing plasma samples from individuals presenting lymph node metastasis at diagnosis and plasma from patients who were metastasis-free. Among these molecules, miR-192 and miR-574 were identified as more expressed in plasma from individuals with metastatic oropharyngeal cancer. We conclude that plasma microRNAs associated with specific clinical conditions or cancer sub-sites may help in the diagnosis and prognosis assessment of head and neck squamous cell carcinomas.

Citation Format: Flavia Maziero Andreghetto, Mariana Barbosa de Souza, Raquel Ajub Moyses, Tatiana Natasha Toporcov, Fabio Daumas Nunes, Marcos Brasilino de Carvalho, Patricia Severino. Circulating microRNAs as metastasis biomarkers in oral cavity and oropharyngeal squamous cell carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1087.
Abstract 1165: TRPM8 is avidly targeted for degradation in prostate cancer
Authors: Asuthkar Swapna , Zakharian Eleonora
Published: July 2016

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing receptor and a hallmark Ca2+ channel of the prostate epithelium. The TRPM8 mRNA is overexpressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Thus, androgens, which are at the crossroads of several signaling pathways, appear to be associated with TRPM8-mediated Ca2+ signaling. Although, TRPM8 mRNA levels are upregulated during prostate cancer progression, this upregulation is not adequately translated to the TRPM8 protein levels. We identified that the lower TRPM8 protein abundance and activation in LNCaP cells is associated with increased ubiquitination and loss of TRPM8 from the plasma membrane (PM). The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of the initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the PM of LNCaP cells. Our data indicate that PMTRPM8 plays a protective role in prostate cancer progression accompanied by enhanced activation of p53 and Caspase-9. In addition, we found that the promoter region of trpm8 possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. Our findings support previous studies that suggest the fine balance between AR and p53 expression that regulates androgen-dependent growth of prostate cancer. Thus, we hypothesize that TRPM8 activity significantly contributes to anti-tumor defense mechanism and may serve as a novel therapeutic target in prostate cancer.

Citation Format: Swapna Asuthkar, Eleonora Zakharian. TRPM8 is avidly targeted for degradation in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1165.
Abstract 117: Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas
Authors: Johnson Nathalie , Assouline Sarit , Alcaide Miguel , Mohajeri Arezoo , Greenwood Celia , Riazalhosseini Yasser , Mann Koren , Morin Ryan
Published: July 2016

Purpose: Relapsed or refractory diffuse large B cell lymphoma (rrDLBCL) is fatal in 90% of patients and yet little is known about its biology.

Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.

Results: Based on the a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3, CCND3, NFKBIZ and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.

Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL.  

Citation Format: Nathalie Johnson, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Celia Greenwood, Yasser Riazalhosseini, Koren Mann, Ryan Morin. Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 117.