bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased hip circumference in individuals with metabolic syndrome affects serum nesfatin-1 levels
Authors: Tekin Tuba , Çiçek Betül , Konyalıgil Nurefşan , Güntürk İnayet , Yazıcı Cevat , Karaca Züleyha , Ünlüsavuran Meltem
Published: December 2019

Background

This case–control study was conducted to investigate the relationship between serum nesfatin-1 levels and nutritional status and blood parameters in patients diagnosed with metabolic syndrome.

Methods

Thirty patients (case) diagnosed with metabolic syndrome according to National Cholesterol Education Program-Adult Treatment Panel III criteria were included. Thirty healthy subjects (control) matched with patients with metabolic syndrome in terms of age, gender and body mass index were included. Three-day food consumption records were obtained. Anthropometric indices were measured and body composition was determined by bioelectrical impedance method. Biochemical parameters and serum nesfatin-1 levels were measured after 8 hours of fasting.

Results

Serum nesfatin-1 levels were 0.245±0.272 ng/mL in the case group and 0.528±0.987 ng/mL in the control group (p>0.05). There was a positive significant correlation between serum nesfatin-1 levels and body weight, waist and hip circumferences in the case group (p<0.05). Each unit increase in hip circumference measurement affects the levels of nesfatin by 0.014 times. In the control group, there was a positive significant correlation between body weight and serum nesfatin-1 levels (p<0.05). A significant correlation was detected between HbA1c and serum nesfatin-1 levels in the case group (p<0.05). A significant relationship was detected between dietary fibre intake and the serum nesfatin-1 levels in the case group (p<0.05).

Conclusions

Anthropometric indices and blood parameters were correlated with serum nesfatin-1 levels in patients with metabolic syndrome. More clinical trials may be performed to establish the relationship between serum nesfatin-1 levels and nutritional status.
Initial validation of the electronic form of the Michigan Body Map
Authors: Hassett Afton L , Pierce Jennifer , Goesling Jenna , Fritsch Laura , Bakshi Rishi R , Kohns David J , Brummett Chad M
Published: December 2019

Background

The Michigan Body Map (MBM) was developed to assess pain location in a reliable and valid manner; however, electronic formats have not been validated. This study had two aims: (1) initial validation of the electronic form of the MBM (eMBM) and (2) preliminary test of assessing pain severity within body zones.

Methods

For the first aim, 68 participants with chronic pain completed paper and electronic forms of the MBM, then underwent scripted interviews to assess preferences among body maps and verbal confirmation of pain locations. For the second aim, a subset of the participants (n=40) completed the Brief Pain Inventory (BPI) pain severity subscale, as well as the eMBM again and endorsed pain severity using additional screens showing body zones that contained areas in which pain was endorsed.

Results

There were few discrepancies between MBM, eMBM and verbal report (1.9% and 1.6%, respectively), and no difference between forms in perceived ability to indicate areas of pain or ease of completion. Patients accurately indicated their bodily pain on both maps, with 84% and 87% reporting one or no errors on MBM and eMBM, respectively. Participants also reported no preference for which version best-depicted areas of pain or best distinguished left from right. Lastly, the most preferred measure was eMBM with pain severity zones, followed by eMBM without zones, followed by the BPI pain severity subscale.

Conclusions

These data support the validity of the eMBM for patients with chronic pain. Further, an expanded form of the eMBM that assesses pain severity was preferred by most participants.
The effects of hydrogen peroxide on mortality, escape response, and oxygen consumption of Calanus spp.
Authors: Escobar-Lux Rosa H. , Fields David M. , Browman Howard I. , Shema Steven D. , Bjelland Reidun M. , Agnalt Ann-Lisbeth , Skiftesvik Anne Berit , Samuelsen Ole B. , Durif Caroline M.F.
Published: December 2019

Hydrogen peroxide (H2O2), a pesticide used in salmonid aquaculture, is released directly into the environment where nontarget organisms are at risk of exposure. We determined threshold concentrations for mortality of Calanus spp., the dominant zooplankton species in the North Atlantic, and assessed sublethal effects, focusing on the escape response and oxygen consumption rates (OCRs) as behavioral and physiological assays. One-hour exposure to 170 mg·L−1 (i.e., 10% of the recommended H2O2 treatment) was lethal to copepodite stage V (92% mortality) and adult females (100% mortality). The acute median lethal concentration (1h-LC50) was 214.1 (150.67–277.4) and 48.6 (44.9–52.2) mg·L−1 for copepodite V and adults, respectively. The 25-h LC50 was 77.1 (57.9–96.2) and 30.63 (25.4–35.8) mg·L−1 for copepodite V and adults, respectively. At concentrations of 0.5% and 1% of the recommended treatment level, Calanus spp. showed a decrease in escape performance and lower OCRs with increased concentration. At H2O2 concentrations of 5% of the recommended treatment levels (85 mg·L−1), exposed copepods showed no escape reaction response. These results suggest that sublethal concentrations of H2O2 will increase the risk of predation for Calanus spp. Furthermore, this study provides supporting evidence that theoretical “safe” values, traditionally used for predicting toxicity thresholds, underestimate the impact of H2O2 on the physiological condition of nontarget crustaceans.
(No) Wigner Theorem for C*-algebras
Authors: Landsman Klaas , Rang Kitty
Published: December 2019

Wigner’s Theorem states that bijections of the set [Formula: see text] of one-dimensional projections on a Hilbert space [Formula: see text] that preserve transition probabilities are induced by either a unitary or an anti-unitary operator on [Formula: see text] (which is uniquely determined up to a phase). Since elements of [Formula: see text] define pure states on the C*-algebra [Formula: see text] of all bounded operators on [Formula: see text] (though typically not producing all of them), this suggests possible generalizations to arbitrary C*-algebras. This paper is a detailed study of this problem, based on earlier results by R. V. Kadison (1965), F. W. Shultz (1982), K. Thomsen (1982), and others. Perhaps surprisingly, the sharpest known version of Wigner’s Theorem for C*-algebras (which is a variation on a result from Shultz, with considerably simplified proof) generalizes the equivalence between the hypotheses in the original theorem and those in an analogous result on (anti-)unitary implementability of Jordan automorphisms of [Formula: see text], and does not yield (anti-)unitary implementability itself, far from it: abstract existence results that do give such implementability seem arbitrary and practically useless. As such, it would be fair to say that there is no Wigner Theorem for C*-algebras.
Computation and consequences of high order amplitude- and parameter-dependent tune shifts in storage rings for high precision measurements
Authors: Weisskopf Adrian , Tarazona David , Berz Martin
Published: December 2019

Nonlinear effects of the various electric field and magnetic field components of storage rings to confine the particles and bend their trajectory can cause substantial amplitude-dependent tune shifts within the beam. Furthermore, tune shifts are often sensitive to variations of system parameters, e.g. total particle momentum offsets [Formula: see text]. Such amplitude- and parameter-dependent tune shifts influence the dynamics and stability of a beam in particle storage rings. Thus, it is critical for high precision measurements to analyze and understand these influences. On this basis, we present normal form methods for the calculation of high order amplitude and system parameter dependencies of the horizontal and vertical tunes in storage rings using the differential algebra (DA) framework within COSY INFINITY. A storage ring is simulated using COSY INFINITY to generate a DA Poincaré return map describing the transverse phase space behavior after each revolution in the storage ring. The map is expanded around the parameter-dependent closed orbit of the system before transforming the resulting map into normal form coordinates to extract the high order tune dependencies on the phase space amplitude and variation in the system parameters. As a specific example, a storage ring similar to the Storage Ring of the Muon [Formula: see text]-2 Experiment at Fermilab (E989) is investigated.
Design of quaternary quantum reversible half subtractor, full subtractor and n-qudit borrow ripple subtractor
Authors: Doshanlou Abdollah Norouzi , Haghparast Majid , Hosseinzadeh Mehdi , Reshadi Midia
Published: December 2019

In this paper, we proposed novel plans of quaternary quantum reversible half and full subtractor circuits. The subtractor element is the essential part of the ALU in the digital computational devices. Thus, the improvement of subtractor block has a significant impact on the overall system performance. According to the comparison results, the proposed quaternary quantum half and full subtractor circuits show tremendous improvement in quantum cost, hardware complexity, number of constant input and garbage output as compared to their counterparts. Moreover, for the first time, the quaternary quantum borrow ripple subtractor structure is realized using the proposed quaternary quantum half and full subtractor circuits.
25 years of development of Mn porphyrins — from mimics of superoxide dismutase enzymes to thiol signaling to clinical trials: The story of our life in the USA
Authors: Batinic-Haberle Ines , Spasojevic Ivan
Published: December 2019

We have developed Mn porphyrins (MnPs) initially as mimics of superoxide dismutase (SOD) enzymes based on structure–activity relationships. Several cationic Mn porphyrins, being substituted with cationic ortho [Formula: see text]-alkyl- or alkoxyalkylpyridyl groups in meso positions of the porphyrin ring, have been identified as potential therapeutics based on their high SOD-like activity and high bioavailability. Two of those [Mn(III) meso-tetrakis([Formula: see text]-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP[Formula: see text] (BMX-010, AEOL10113) and Mn(III) meso-tetrakis(Nn-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP[Formula: see text] (BMX-001)] are now in five Phase II clinical trials. Studies of ours, and those of others, contributed to the understanding of the diverse activities of these compounds. With biologically compatible potentials and four biologically accessible oxidation states, Mn porphyrins interact with numerous reactive species, both as oxidants and reductants. Among those reactions, their abilities to (catalytically) oxidize [Formula: see text]-glutathionylate protein thiols may perhaps be their major in vivo mode of action. Via [Formula: see text]-glutathionylation, MnPs modulate actions of signaling proteins and, in turn, cellular apoptotic and proliferative pathways. During the major part of our stay in the USA, our lives have been dedicated to Mn porphyrins. Our families and especially our son and his three babies have been our inspiration not to give up on a life often burdened with hardship. It is thus our immense pleasure to see our compounds in clinical trials. Above all, we hope that our story will inspire future researchers to persevere — women in particular.
The influence of stratigraphy and facies distribution on reservoir quality and production performance in the Triassic Skagerrak Formation of the UK and Norwegian Central North Sea
Authors: Gray E. , Hartley A. , Howell J.
Published: December 2019

Stratigraphy, depositional facies and proximal-distal position within a depositional system are identified as controls on reservoir quality and dynamic reservoir performance in the Triassic, fluvial-dominated, Skagerrak Formation reservoirs of the UK and Norwegian Central North Sea. Core sedimentological analysis from across the basin links decreasing trends of channel facies proportion and channel package thickness with increasing floodplain and splay facies proportions and their respective package thicknesses. These trends are considered to represent the proximal to distal transitions of distributive fluvial systems. Depositional facies are shown to strongly control static and theoretical dynamic reservoir quality using porosity–permeability cross-plots and stratigraphically modified Lorenz plots using conventional core plug data. This linkage of stratigraphy, depositional system position, facies proportions and package thicknesses with static and theoretical dynamic reservoir performance is used to predict pressure-depletion profiles in various settings of Triassic reservoirs of the Central North Sea beyond major areas of well and field control in UK Quads 22 and 30.
The importance of surface ruptures and fault damage zones in earthquake hazard assessment: a review and new suggestions
Authors: Jin Kwangmin , Kim Young-Seog
Published: December 2019

Large earthquakes (M
W
>
c.
6) generate surface ruptures and strong ground motions, resulting in extensive property damage and loss of lives. The earthquake damage and causality levels depend, for example, on the earthquake magnitude, seismic wave characteristics, the distance from the epicentre, the depth of earthquake and the foundation of related area . However, these factors cannot all be known for future earthquakes, because the exact times and locations of earthquakes cannot be predicted with the current technology. Thus, it is only possible to prepare for earthquakes by implementing anti-seismic design codes based on the local geological conditions. With accurate information about the locations of active faults or potential surface ruptures and deformation patterns, earthquake-prone areas could be avoided during site selection, especially for important facilities such as nuclear power plants and high-level radioactive waste disposal facilities. In this study, we investigated several factors for earthquake hazard estimation, focusing on the fault damage zones and respect distances. Fault damage zones around faults are mainly controlled by fault types, tip modes, exposed locations and slip senses along the fault. The characteristics of geological faults and earthquake ruptures show asymmetrical displacements and damage patterns, making it difficult to estimate respect distances and surface deformations. Therefore, both the respect distance and fault damage zone should be considered when identifying safe regions. This information will facilitate earthquake hazard assessment and appropriate site selection to reduce earthquake hazards in earthquake-prone areas.
Evidence of giant earthquakes and tsunamis of the seventeenth-century type along the southern Kuril subduction zone, eastern Hokkaido, northern Japan: a review
Authors: Nanayama Futoshi
Published: December 2019

Large earthquakes of magnitude 7–8 occur at intervals of about 70–100 years in the southern Kuril Trench off eastern Hokkaido, northern Japan. However, especially large giant earthquakes (M
w
c.
8.8) have recurred at 300–500 year intervals, and the most recent of these was in the early seventeenth century. Surveys on the Pacific coast of eastern Hokkaido have documented field evidence that includes sharp contacts of peat and mud layers, indicative of coseismic coastal uplift, and large tsunami sand layers. Several proposed fault models of the seventeenth-century giant earthquake have been tested with numerical tsunami simulations. The best of these models incorporates a multi-segment interplate earthquake (M
w
8.8) with large slip near the trench axis. The seventeenth-century giant earthquake and the 1611 Keicho Sanriku tsunami appear to have had different sources because varve counts from Lake Harutori suggest that the seventeenth-century giant earthquake occurred at
c.
1637. Moreover, a consideration of regional tectonics suggests that convergence of the Kuril forearc sliver controls the current topography of eastern Hokkaido. Further progress in understanding the seismicity of this region will benefit from the combined insights of both geologists and seismologists.
Decreased atrioventricular plane displacement after acute myocardial infarction yields a concomitant decrease in stroke volume
Authors: Berg J. , Jablonowski R. , Nordlund D. , Kopic S. , Bidhult S. , Xanthis C. G. , Saeed M. , Solem K. , Arheden H. , Carlsson M.
Published: December 2019

Acute myocardial infarction (AMI) can progress to heart failure, which has a poor prognosis. Normally, 60% of stroke volume (SV) is attributed to the longitudinal ventricular shortening and lengthening evident in the atrioventricular plane displacement (AVPD) during the cardiac cycle, but there is no information on how the relationship changes between SV and AVPD before and after AMI. Therefore, the aim of this study was to determine how SV depends on AVPD before and after AMI in two swine models. Serial cardiac magnetic resonance imaging was carried out before and 1–2 h after AMI in a microembolization model ( n = 12) and an ischemia-reperfusion model ( n = 14). A subset of pigs ( n = 7) were additionally imaged at 24 h and at 7 days. Cine and late gadolinium enhancement images were analyzed for cardiac function, AVPD measurements and infarct size estimation, respectively. AVPD decreased ( P < 0.05) in all myocardial regions after AMI, with a concomitant SV decrease ( P < 0.001). The ischemia-reperfusion model affected SV to a higher degree and had a larger AVPD decrease than the microembolization model (−29 ± 14% vs. −15 ± 18%; P < 0.05). Wall thickening decreased in infarcted areas ( P < 0.001), and A-wave AVPD remained unchanged ( P = 0.93) whereas E-wave AVPD decreased ( P < 0.001) after AMI. We conclude that AVPD is coupled to SV independent of infarct type but likely to a greater degree in ischemia-reperfusion infarcts compared with microembolization infarcts. AMI reduces diastolic early filling AVPD but not AVPD from atrial contraction. These findings shed light on the physiological significance of atrioventricular plane motion when assessing acute and subacute myocardial infarction.

NEW & NOTEWORTHY The link between cardiac longitudinal motion, measured as atrioventricular plane displacement (AVPD), and stroke volume (SV) is investigated in swine after acute myocardial infarction (AMI). This cardiac magnetic resonance study demonstrates a close coupling between AVPD and SV before and after AMI in an experimental setting and demonstrates that this connection is present in ischemia-reperfusion and microembolization infarcts, acutely and during the first week. Furthermore, AVPD is equally and persistently depressed in infarcted and remote myocardium after AMI.
Biochemical Charcterization of Some Taro (Colocasia esculentaL. Schott) Germplasm in Ghana
Authors: Boampong R. , Aboagye L. M. , Nyadanu D. , Essilfie M. E. , Adu Amoah R.
Published: December 2019

Corms of eighteen (18) genotypes comprising twelve (12) introduced and six (6) local genotypes were studied for their nutrient quality to provide information on their nutrient characteristics for a holistic development of the crop. The crop is known for its edible corms and leaves. Corms are boiled before eating and take a short time to cook as their carbohydrate structure is not complex. The leaves are eaten as vegetables. The crops were planted at Nobewam in the Ejisu-Juaben Municipality in the Ashanti Region of Ghana using the Randomized Complete Block Design (RCBD). The biochemical or nutritional analysis was done at Crop and Soil Sciences laboratory at Kwame Nkrumah University of Science and Technology (KNUST). Data were collected on the chemical and mineral compositions of the genotypes (corms). Variations were observed in both chemical and mineral characteristics. Carbohydrate content of the genotypes ranged from 62% to 76%; protein ranged from 13% to 25%; fibre ranged from 1% to 2%; calcium ranged from 0.29% to 0.72% and iron content ranged from 0.18 mg/100 g to 1.18 mg/100 g. Significant differencesP<0.05were observed in both chemical and mineral traits, indicating a higher degree of variability in the genotypes. SignificantP<0.01and positive correlations were observed between protein and energy levels; magnesium and iron; magnesium and calcium; and potassium and ash. The Principal Component Analysis (PCA) showed that the first component (PC1) accounted for 96% of variation. Some genotypes including; BL/SM/10, BL/SM/132, KA/019, SAO/020, BL/SM/151, BL/SM/80, BL/SM/116, BL/SM/16, and KA/035 possess desirable nutrient levels such as protein, fibre, carbohydrate, and iron which could be exploited for further development of taro in Ghana.
An Interactive Model of Target and Context for Aspect-Level Sentiment Classification
Authors: Han Hu , Liu Guoli , Dang Jianwu
Published: December 2019

Aspect-level sentiment classification aims to identify the sentiment polarity of a review expressed toward a target. In recent years, neural network-based methods have achieved success in aspect-level sentiment classification, and these methods fall into two types: the first takes the target information into account for context modelling, and the second models the context without considering the target information. It is concluded that the former is better than the latter. However, most of the target-related models just focus on the impact of the target on context modelling, while ignoring the role of context in target modelling. In this study, we introduce an interactive neural network model named LT-T-TR, which divided a review into three parts: the left context with target phrase, the target phrase, and the right context with target phrase. And the interaction between the left/right context and the target phrase is utilized by an attention mechanism to learn the representations of the left/right context and the target phrase separately. As a result, the most important words in the left/right context or in the target phrase are captured, and the results on laptop and restaurant datasets demonstrate that our model outperforms the state-of-the-art methods.
Low Grade Islet but Marked Exocrine Pancreas Inflammation in an Adult with Autoimmune Pre-Diabetes
Authors: Nomoto Hiroshi , Gurlo Tatyana , Rosenberger Madeline , Girgis Mark D. , Dry Sarah , Butler Peter C.
Published: December 2019

There is unexplained deficit in size and function of the exocrine pancreas in type 1 diabetes (T1D). We obtained pancreas from an individual with pre-T1D obtained at surgery and addressed the question, what is the relative inflammation in the exocrine and endocrine pancreas in pre-T1D in the absence of the potential confounding changes at autopsy or in brain dead organ donors. Pancreas was removed surgically from a 36 year woman for benign neuroendocrine tumors (NET). The patient had gestational diabetes at age 29 and has a 23 year old sister with T1D. Pre-operative fasting glucose of 109 mg/dl and HbA1C 5.8% revealed prediabetes with an anti-GAD 1,144 (5–250 U/ml) together with family history implying pre-T1D. There was patchy low grade immune infiltration in some, but not all, islets that met criteria for autoimmune insulitis. The exocrine pancreas showed more abundant inflammation with areas of chronic pancreatitis and acinar to ductal metaplasia, and with other areas of atrophy and fatty infiltration. In pre-T1D inflammation may be more prominent in the exocrine than the endocrine pancreas, calling into question the sequence of events and assumed islet centric basis of autoimmunity leading to T1D.
Modeling a Simulation for Sociotechnical Resilience
Authors: Tantri Fredy , Amir Sulfikar
Published: December 2019

This paper proposes a conceptual model to simulate the response of sociotechnical systems to crisis. The model draws on a concept of “sociotechnical resilience” as the theoretical framework, which underscores the hybrid nature of sociotechnical systems. Revolving around the notion of transformability, the concept considers sociotechnical resilience to be constitutive of three fundamental attributes, namely, informational relations, sociomaterial structures, and anticipatory practices. Our model aims to capture the complex interactions within a sociotechnical system during a recovery process by incorporating these core attributes in the operational units embedded in a multilevel directed acyclic graph, information networks, and recovery strategies. Furthermore, the model emphasizes specifically the role of informational configuration during a disruption. We introduce two recovery strategies in our simulation, namely, random recovery and informed recovery. The former represents the unprepared responses to crisis, while the latter incorporates the reporting process to support the command centre in making optimum decisions. The simulation results suggest the importance of system flexibility to allow structural reconfiguration at the organizational level. Our proposed model complements the theoretical principles of sociotechnical resilience while laying a practical foundation of sociotechnical modeling for resilience enhancement in real‐world settings.
Evolution Law of Overburden Longitudinal Connected Fissures in a Shallowly Buried Coal Face with Thin Bedrock
Authors: Jia Housheng , Pan Kun , Wang Luyao , Liu Shaowei , Fu Mengxiong , Ji Xiang
Published: December 2019

Longitudinal connected fissures in a shallowly buried coal face with thin bedrock are the main factor causing sand‐burst accidents, water‐burst accidents, and abnormal increases in water inflow. To understand the evolution of longitudinal connected fissures and propose method for controlling such fissures, 3‐1 Coal of the Jinjie Coal Mine in Shendong Coal Group, China, was used as a case study. Physical simulation, numerical simulation, field measurements, and other measures were carried out to analyze thoroughly the opening and closure of fissures. At the same time, the stage characteristics of fissures evolution process are also obtained. The results indicate that when periodic weighting occurs, a longitudinal connected fissure starts to open. As the coal face moves on, the fissure expands gradually with the dynamic changes in horizontal force and rock dislocation; when the expansion reaches its limit, the key rock falls and the longitudinal connected fissure rapidly closes. With the advent of the next periodic weighting, the longitudinal connected fissure compacts further and the next longitudinal connected fissure appears. The formation of longitudinal connected fissures is described with reference to three factors: the advancement speed of the coal face, the holding power of the hydraulic support, and the filling degree of the goaf area, all of which can be easily controlled by engineering means. This study provides a basis for control of sand‐burst accidents, water‐burst accidents, and abnormal increase in water inflow in a shallow coal face with thin bedrock.
Cell Adhesiveness Serves as a Biophysical Marker for Metastatic Potential
Authors: Beri Pranjali , Popravko Anna , Yeoman Benjamin , Kumar Aditya , Chen Kevin , Hodzic Enio , Chiang Alyssa , Banisadr Afsheen , Placone Jesse K. , Carter Hannah , Fraley Stephanie I. , Katira Parag , Engler Adam J.
Published: December 2019

Tumors are heterogeneous and composed of cells with different dissemination abilities. Despite significant effort, there is no universal biological marker that serves as a metric for metastatic potential of solid tumors. Common to disseminating cells from such tumors, however, is the need to modulate their adhesion as they detach from the tumor and migrate through stroma to intravasate. Adhesion strength is heterogeneous even among cancer cells within a given population, and using a parallel plate flow chamber, we separated and sorted these populations into weakly and strongly adherent groups; when cultured under stromal conditions, this adhesion phenotype was stable over multiple days, sorting cycles, and common across all epithelial tumor lines investigated. Weakly adherent cells displayed increased migration in both two-dimensional and three-dimensional migration assays; this was maintained for several days in culture. Subpopulations did not show differences in expression of proteins involved in the focal adhesion complex but did exhibit intrinsic focal adhesion assembly as well as contractile differences that resulted from differential expression of genes involved in microtubules, cytoskeleton linkages, and motor activity. In human breast tumors, expression of genes associated with the weakly adherent population resulted in worse progression-free and disease-free intervals. These data suggest that adhesion strength could potentially serve as a stable marker for migration and metastatic potential within a given tumor population and that the fraction of weakly adherent cells present within a tumor could act as a physical marker for metastatic potential.

Significance:

Cancer cells exhibit heterogeneity in adhesivity, which can be used to predict metastatic potential.
NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer
Authors: Nacarelli Timothy , Fukumoto Takeshi , Zundell Joseph A. , Fatkhutdinov Nail , Jean Stephanie , Cadungog Mark G. , Borowsky Mark E. , Zhang Rugang
Published: December 2019

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs.

Significance:

This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.
Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis
Authors: Liu Sijia , González-Prieto Román , Zhang Mengdi , Geurink Paul P. , Kooij Raymond , Iyengar Prasanna Vasudevan , van Dinther Maarten , Bos Erik , Zhang Xiaobing , Le Dévédec Sylvia E. , van de Water Bob , Koning Roman I. , Zhu Hong-Jian , Mesker Wilma E. , Vertegaal Alfred C.O. , Ovaa Huib , Zhang Long , Martens John W.M. , ten Dijke Peter
Published: December 2019

Purpose:

Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly active DUBs in TNBC may lead to novel therapies.

Experimental Design:

Using DUB activity probes, we profiled global DUB activities in 52 breast cancer cell lines and 52 patients' tumor tissues. To validate our findings in vivo, we employed both zebrafish and murine breast cancer xenograft models. Cellular and molecular mechanisms were elucidated using in vivo and in vitro biochemical methods. A specific inhibitor was synthesized, and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.

Results:

Two DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling–induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in sera of patients with TNBC, and highly enriched in sera exosomes as well as TNBC cell–conditioned media. UCHL1-enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.

Conclusions:

Our DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment.
Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312)
Authors: Cole Kristina A. , Pal Sharmistha , Kudgus Rachel A. , Ijaz Heba , Liu Xiaowei , Minard Charles G. , Pawel Bruce R. , Maris John M. , Haas-Kogan Daphne A. , Voss Stephan D. , Berg Stacey L. , Reid Joel M. , Fox Elizabeth , Weigel Brenda J.
Published: December 2019

Purpose:

Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.

Patients and Methods:

Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.

Results:

Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.

Conclusions:

Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
Taxifolin Inhibits Neurosteroidogenic Rat Steroid 5α-Reductase 1 and 3α-Hydroxysteroid Dehydrogenase
Authors: Su Ying , Zhu Qiqi , Hong Xie , Ge Ren-Shan
Published: December 2019

Aims: Taxifolin, a flavonoid, has several pharmacological activities. Taxifolin inhibits some steroid biosynthetic enzymes, suggesting that it might inhibit neurosteroid synthesis. Here, we investigated effects of taxifolin on rat neurosteroidogenic enzymes, steroid 5α-reductase 1 ­(SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RDH2). Methods: SRD5A1, AKR1C9, and RDH2 were expressed in COS-1 cells and the direct effects of taxifolin on these enzymes and the mode of action were determined using steroid substrates and thin chromatography separation-coupled radiometric scanning. Results: The half maximal inhibitory concentration values of taxifolin on SRD5A1 and AKR1C9 were 100 and 1.01 mol/L. Taxifolin did not inhibit RDH2 even at as high as 100 mol/L. Taxifolin competitively inhibited rat AKR1C9 against steroid dihydrotestosterone (DHT), and docking analysis revealed that taxifolin bound to the steroid binding site of rat AKR1C9 with similar free energy with the substrate DHT. Conclusion: Taxifolin is a potent inhibitor of rat AKR1C9 and moderate inhibitor of rat SRD5A1, thereby controlling the rate of neurosteroid biosynthesis.
Outcomes among Patients Treated with Renal Replacement Therapy during Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study
Authors: Dado David N. , Ainsworth Craig R. , Thomas Sarah B. , Huang Benjamin , Piper Lydia C. , Sams Valerie G. , Batchinsky Andriy , Morrow Benjamin D. , Basel Anthony P. , Walter Robert J. , Mason Phillip E. , Chung Kevin K.
Published: December 2019

Background: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities used in critically ill patients suffering organ failure and metabolic derangements. Although the effects of CRRT have been extensively studied, the impact of simultaneous CRRT and ECMO is less well described. The purpose of this study is to evaluate the incidence and the impact of CRRT on outcomes of patients receiving ECMO. Methods: A single center, retrospective chart review was conducted for patients receiving ECMO therapy over a 6-year period. Patients who underwent combined ECMO and CRRT were compared to those who underwent ECMO alone. Intergroup ­statistical comparisons were performed using Wilcoxon/Kruskal-Wallis and chi-square tests. Logistic regression was performed to identify independent risk factors for mortality. Results: The demographic and clinical data of 92 patients who underwent ECMO at our center were reviewed including primary diagnosis, indications for and mode of ECMO support, illness severity, oxygenation index, vasopressor requirement, and presence of acute kidney injury. In those patients that required ECMO with CRRT, we reviewed urine output prior to initiation, modality used, prescribed dose, net fluid balance after 72 h, requirement of renal replacement therapy (RRT) at discharge, and use of diuretics prior to RRT initiation. Our primary endpoint was survival to hospital discharge. During the study period, 48 patients required the combination of ECMO with CRRT. Twenty-nine of these patients survived to hospital discharge. Of the 29 survivors, 6 were dialysis dependent at hospital discharge. The mortality rate was 39.5% with combined ECMO/CRRT compared to 31.4% among those receiving ECMO alone (p = 0.074). Of those receiving combined therapy, nonsurvivors were more likely to have a significantly positive net fluid balance at 72 h (p = 0.001). A multivariate linear regression analysis showed net positive fluid balance and increased age were independently associated with mortality. Conclusions: Use of CRRT is prevalent among patients undergoing ECMO, with over 50% of our patient population receiving combination therapy. Fluid balance appears to be an important variable associated with outcomes in this cohort. Rates of renal recovery and overall survival were higher compared to previously published reports among those requiring combined ECMO/CRRT.
Association of the STAT6 rs3024974 (C/T) Polymorphism with IgE-Mediated Food Sensitization among West Bengal Population in India
Authors: Laha Arghya , Ghosh Amlan , Moitra Saibal , Saha Ishita , Kumar Saha Goutam , Bhattacharya Srijit , Podder Sanjoy
Published: December 2019

Introduction: Genetic polymorphisms associated with IgE-mediated food sensitization have been a robust area of research for decades. A genome-wide search for susceptible loci regulating the IgE response (atopy) identified the candidate gene STAT6, which is important in the context of food allergic manifestations. Objective: The present study was designed to investigate the sensitization of West Bengal population against some common allergenic food items and to study the role of the STAT6 gene polymorphism in elevating food-specific IgE levels among sensitized individuals. Methods: Skin prick test was performed for 6 food items among 501 patients (126 children, 85 adolescents, and 290 adults)from West Bengal, India. Among them, 165 patients were selected for measurement of total IgE and food-specific IgE levels along with 165 controls. Finally, the STAT6 (rs3024974 (C/T) polymorphism was genotyped in 139 cases and control subjects. Results: Shrimp was identified as a dominant food allergen in adolescents and adults, whereas milk sensitization was highest in children. Food-sensitized patients with onset during childhood had significantly higher total IgE levels compared to patients with onset during adulthood (p < 0.00001). The frequency of the rs3024974 CC genotype in both cases and control subjects (55.40 and 46.76%, respectively) was higher than that of CT or TT. Patients with childhood onset bearing the CC genotype had significantly higher specific IgE levels in comparison to those with adult onset (p = 0.001). Conclusion: Food sensitization has a genetic background and the rs3024974 polymorphism is associated with susceptibility and reaction severity in food-sensitized patients in West Bengal population in India.
Pseudodicentric Chromosome Originating from Autosomes 9 and 21 in a Male Patient with Oligozoospermia
Authors: Beaumont Marion , Tucker Elena J. , Mary Laura , Launay Erika , Lurton Yann , Pimentel Céline , Rollier Paul , Akloul Linda , Beneteau Claire , Chevallier-Bordeau Solène , Neyroud Anne-Sophie , Pichon Olivier , Ravel Célia , Odent Sylvie , Belaud-Rotureau Marc-Antoine , Jaillard Sylvie
Published: December 2019

Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient.
Expediente
Authors: Magri Dirceu
Published: December 2019

Não consta resumo.
Contracepção permanente por inserção de dispositivo intratubário sob a perspectiva da Lei n. 9.263/1996
Authors: Miranda Margarida Araújo Barbosa , Evangelista Danielle Rosa , Miranda Wellington Gomes
Published: December 2019

Estudo transversal, de abordagem quantitativa e caráter descritivo, que objetivou analisar o fluxo de encaminhamento das mulheres ao serviço de referência em esterilização por meio de inserção do dispositivo intratubário contracepção permanente, no contexto da legislação vigente em planejamento reprodutivo. População composta por 32 mulheres, residentes em Palmas (Tocantins) e submetidas à inserção do dispositivo intratubário em serviço público de referência estadual. Os dados foram coletados de junho a outubro de 2017 em entrevista semiestrutura e analisados no programa Stata, versão 14.0. As variáveis categóricas foram descritas por meio de proporção e as contínuas, por média e desvio-padrão. O perfil sociodemográfico mostrou mulheres com 35,2±2,9 anos de idade, maioria com parceria fixa e parda, ensino médio como nível de escolaridade predominante e ocupando funções variadas. A média do número de filhos foi de 2,8±1,1. A média do tempo de espera para a inserção do dispositivo intratubário foi de 2,5 meses. Todas as mulheres inseriram o dispositivo intratubário fora do período gravídico puerperal. A média de idade das mulheres à época do procedimento foi de 31,9±3 anos. Os dados revelaram agilidade do serviço no atendimento à mulher, considerando o pouco tempo entre a manifestação da vontade e a realização do procedimento, porém respeitando o limite mínimo exigido pela legislação brasileira. Em geral, houve observância dos aspectos legais pelo serviço de referência, com exceção da notificação de esterilização. Constatou-se a necessidade de revisar o paradigma da autorização do cônjuge para a realização do procedimento, ante a violação dos direitos sexuais e reprodutivos.
Reclamatórias em saúde recebidas pelo Ministério Público do Estado do Paraná: um estudo do CAOP de Proteção à Saúde Pública
Authors: Aragão Suéllyn Mattos de , Silva André Luis Cândido da , Ditterich Rafael Gomes , Kusma Solena Ziemer
Published: December 2019

O objetivo do estudo foi evidenciar os principais desafios sanitários no Estado do Paraná nos anos de 2016 e 2017, a partir da análise das denúncias realizadas junto ao Ministério Público Estadual. A proposta foi instrumentalizar gestores e usuários do sistema público para o reconhecimento e o enfrentamento das necessidades prementes em saúde. Realizou-se um estudo, documental e qualitativo, por meio da organização e análise de dados do sistema de informação do Centro de Apoio Operacional das Promotorias de Justiça de Proteção à Saúde Pública. Na categorização, adotou-se cinco classes iniciais, preconizadas pelo serviço estudado. Posteriormente, procedeu-se ao reconhecimento das categorias finais correspondentes e à formulação de conceitos norteadores com base nos fundamentos do Direito Sanitário. Os resultados demonstraram predomínio de demandas pertencentes à categoria relacionada a medicamentos, insumos e procedimentos. Destacou-se, também, a categoria referente às ocorrências de má prática profissional. A pesquisa concluiu que a principal fragilidade do Sistema Único de Saúde no Estado do Paraná, denunciada ao Ministério Público estadual, foi o provimento de medicamentos. Com a constatação de que a problemática dominante apontada pelo estudo relaciona-se ao fornecimento de fármacos e, por conseguinte, às limitações da universalidade e da integralidade do sistema público sanitário, foram debatidas as variantes imbricadas nesses preceitos: indefinição sobre os limites do dever do Estado, no que se refere ao oferecimento de serviços e produtos; extensão e pretensão da política de assistência farmacêutica do Sistema Único de Saúde;  interesses conflitantes entre Estado e mercado; desafios regulatórios; entre outros.
O julgamento do Habeas Corpus n. 143.641 a partir de uma perspectiva de direitos reprodutivos
Authors: Almeida Marina Nogueira de , Pereira Larissa Urruth
Published: December 2019

Partindo-se da premissa de que os direitos reprodutivos são efetivados a partir do direito à saúde e incluindo-os no âmbito do Direito Sanitário, este comentário de jurisprudência visa a estudar, em uma perspectiva de direitos reprodutivos, o Habeas Corpus n. 143.641, que versa sobre a maternidade e o cárcere. Inicialmente, conceituam-se os direitos reprodutivos com base sua inserção no rol dos direitos humanos. Na segunda parte, busca-se compreender a maternidade e o cárcere a partir da análise de aspectos do Código de Processo Penal e, principalmente, da jurisprudência do Habeas Corpus n. 143.641. Utiliza-se método dedutivo do estudo da doutrina jurídica para o caso. Conclui-se que a pauta dos direitos reprodutivos está presente nas discussões jurídicas brasileiras sobre maternidade e cárcere, mas seu exercício ainda não é pleno.