bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal regret after treatment for low‐ and intermediate‐risk prostate cancer
Authors: Hurwitz Lauren M. , Cullen Jennifer , Kim Daniel J. , Elsamanoudi Sally , Hudak Jane , Colston Maryellen , Travis Judith , Kuo Huai‐Ching , Rice Kevin R. , Porter Christopher R. , Rosner Inger L.
Published: July 2017

BACKGROUND

Prostate cancer patients diagnosed with low‐ and intermediate‐risk disease have several treatment options. Decisional regret after treatment is a concern, especially when poor oncologic outcomes or declines in health‐related quality of life (HRQoL) occur. This study assessed determinants of longitudinal decisional regret in prostate cancer patients attending a multidisciplinary clinic and treated with radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy (BT), or active surveillance (AS).

METHODS

Patients newly diagnosed with prostate cancer at the Walter Reed National Military Medical Center who attended a multidisciplinary clinic were enrolled into a prospective study from 2006 to 2014. The Decision Regret Scale was administered at 6, 12, 24, and 36 months posttreatment. HRQoL was also assessed at regular intervals using the Expanded Prostate Cancer Index Composite and 36‐item RAND Medical Outcomes Study Short Form questionnaires. Adjusted probabilities of reporting regret were estimated via multivariable logistic regression fitted with generalized estimating equations.

RESULTS

A total of 652 patients met the inclusion criteria (395 RP, 141 EBRT, 41 BT, 75 AS). Decisional regret was consistently low after all of these treatments. In multivariable models, only African American race (odds ratio, 1.67; 95% confidence interval, 1.12‐2.47) was associated with greater regret across time. Age and control preference were marginally associated with regret. Regret scores were similar between RP patients who did and did not experience biochemical recurrence. Declines in HRQoL were weakly correlated with greater decisional regret.

CONCLUSION

In the context of a multidisciplinary clinic, decisional regret did not differ significantly between treatment groups but was greater in African Americans and those reporting poorer HRQoL. Cancer 2017;123:4252–4258. © 2017 American Cancer Society.
Prospective study of proton‐beam radiation therapy for limited‐stage small cell lung cancer
Authors: Rwigema Jean‐Claude M. , Verma Vivek , Lin Liyong , Berman Abigail T. , Levin William P. , Evans Tracey L. , Aggarwal Charu , Rengan Ramesh , Langer Corey , Cohen Roger B. , Simone Charles B.
Published: July 2017

BACKGROUND

Existing data supporting the use of proton‐beam therapy (PBT) for limited‐stage small cell lung cancer (LS‐SCLC) are limited to a single 6‐patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS‐SCLC.

METHODS

This study prospectively analyzed patients with primary, nonrecurrent LS‐SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity‐modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence‐free survival (RFS), and overall survival (OS) rates and toxicities.

RESULTS

Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45‐66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow‐up of 14 months, the 1‐/2‐year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1‐/2‐year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively.

CONCLUSIONS

In the first prospective registry study and largest analysis to date of PBT for LS‐SCLC, PBT was found to be safe with a limited incidence of high‐grade toxicities. Cancer 2017;123:4244–4251. © 2017 American Cancer Society.
Detection of Extracellular Vesicles Using Proximity Ligation Assay with Flow Cytometry Readout—ExoPLA
Authors: Löf Liza , Arngården Linda , Ebai Tonge , Landegren Ulf , Söderberg Ola , Kamali‐Moghaddam Masood
Published: July 2017

Extracellular vesicles (EVs) are continuously released by most cells, and they carry surface markers of their cells of origin. Found in all body fluids, EVs function as conveyers of cellular information, and evidence implicates them as markers of disease. These characteristics make EVs attractive diagnostic targets. However, detection and characterization of EVs is challenging due to their small size. We've established a method, called ExoPLA, that allows individual EVs to be detected and characterized at high specificity and sensitivity. Based on the in situ proximity ligation assay (in situ PLA), proximal oligonucleotide‐conjugated antibodies bound to their targets on the surfaces of the EVs allow formation of circular products that can be fluorescently labeled by rolling circle amplification. The intense fluorescent signals produced in this assay allow detection and enumeration of individual EVs by flow cytometry. We describe the procedures for ExoPLA, along with expected results and troubleshooting. © 2017 by John Wiley & Sons, Inc.
Detection and Quantification of Mitochondrial Fusion Using Imaging Flow Cytometry
Authors: Nascimento Aldo , Lannigan Joanne , Kashatus David
Published: July 2017

Mitochondria are dynamic organelles that perform several vital cellular functions. Requisite for these functions are mitochondrial fusion and fission. Despite the increasing importance of mitochondrial dynamics in a range of cellular processes, there exist limited methods for robust quantification of mitochondrial fission and fusion. Currently, the most widely used method to measure mitochondrial fusion is the polyethylene glycol (PEG) fusion assay. While this assay can provide useful information regarding fusion activity, the reliance on manual selection of rare fusion events is time consuming and may introduce selection bias. By utilizing the image‐capture features and colocalization analysis of imaging flow cytometry in combination with the PEG fusion assay, we are able to develop a high‐throughput method to detect and quantify mitochondrial fusion activity. © 2017 by John Wiley & Sons, Inc.
How Osmolytes Counteract Pressure Denaturation on a Molecular Scale
Authors: Shimizu Seishi , Smith Paul E.
Published: July 2017

Life in the deep sea exposes enzymes to high hydrostatic pressure, which decreases their stability. For survival, deep sea organisms tend to accumulate various osmolytes, most notably trimethylamine N‐oxide used by fish, to counteract pressure denaturation. However, exactly how these osmolytes work remains unclear. Here, a rigorous statistical thermodynamics approach is used to clarify the mechanism of osmoprotection. It is shown that the weak, nonspecific, and dynamic interactions of water and osmolytes with proteins can be characterized only statistically, and that the competition between protein–osmolyte and protein–water interactions is crucial in determining conformational stability. Osmoprotection is driven by a stronger exclusion of osmolytes from the denatured protein than from the native conformation, and water distribution has no significant effect on these changes at low osmolyte concentrations.
NEBNext Direct: A Novel, Rapid, Hybridization‐Based Approach for the Capture and Library Conversion of Genomic Regions of Interest
Authors: Emerman Amy B. , Bowman Sarah K. , Barry Andrew , Henig Noa , Patel Kruti M. , Gardner Andrew F. , Hendrickson Cynthia L.
Published: July 2017

Next‐generation sequencing (NGS) is a powerful tool for genomic studies, translational research, and clinical diagnostics that enables the detection of single nucleotide polymorphisms, insertions and deletions, copy number variations, and other genetic variations. Target enrichment technologies improve the efficiency of NGS by only sequencing regions of interest, which reduces sequencing costs while increasing coverage of the selected targets. Here we present NEBNext Direct®, a hybridization‐based, target‐enrichment approach that addresses many of the shortcomings of traditional target‐enrichment methods. This approach features a simple, 7‐hr workflow that uses enzymatic removal of off‐target sequences to achieve a high specificity for regions of interest. Additionally, unique molecular identifiers are incorporated for the identification and filtering of PCR duplicates. The same protocol can be used across a wide range of input amounts, input types, and panel sizes, enabling NEBNext Direct to be broadly applicable across a wide variety of research and diagnostic needs. © 2017 by John Wiley & Sons, Inc.
Nicotine Vapor Method to Induce Nicotine Dependence in Rodents
Authors: Kallupi Marsida , George Olivier
Published: July 2017

Nicotine, the main addictive component of tobacco, induces potentiation of brain stimulation reward, increases locomotor activity, and induces conditioned place preference. Nicotine cessation produces a withdrawal syndrome that can be relieved by nicotine replacement therapy. In the last decade, the market for electronic cigarettes has flourished, especially among adolescents. The nicotine vaporizer or electronic nicotine delivery system is a battery‐operated device that allows the user to simulate the experience of tobacco smoking without inhaling smoke. The device is designed to be an alternative to conventional cigarettes that emits vaporized nicotine inhaled by the user. This report describes a procedure to vaporize nicotine in the air to produce blood nicotine levels in rodents that are clinically relevant to those that are observed in humans and produce dependence. We also describe how to construct the apparatus to deliver nicotine vapor in a stable, reliable, and consistent manner, as well as how to analyze air for nicotine content. © 2017 by John Wiley & Sons, Inc.
An Acid‐Responsive Single Trichromatic Luminescent Dye That Provides Pure White‐Light Emission
Authors: Imamura Keigo , Ueno Yoshifumi , Akimoto Seiji , Eda Kazuo , Du Yanqing , Eerdun Chaolu , Wang Meiling , Nishinaka Kumiko , Tsuda Akihiko
Published: July 2017

A novel acid‐responsive single trichromatic luminescent dye capable of emitting pure white light (WL) is reported. A newly designed p‐phenylene‐bridged bipyrrole bearing N‐alkylimino groups (1 a) specifically provides WL emission upon mixing with trifluoroacetic acid (TFA) in a CH2Cl2 solution. The emission originates from the trichromatic luminescent behavior of 1 a upon protonation of the imino groups. The blue‐light‐emitting 1 a exhibits dramatic color changes in fluorescence to orange and green upon mono‐ and diprotonation, respectively, providing a wide emission band in the range of λ=400–800 nm that provide WL when the compound is in a dynamic equilibrium between the three states. The sample also exhibits low self‐absorption of the emitted light and a high fluorescence quantum yield upon excitation with UV light.
Direct synthesis technique (DST) for complex general Chebyshev filters
Authors: Xiao Fei
Published: July 2017

Recently, we discussed the concept of direct synthesis technique (DST), in which real‐coefficient filtering polynomials containing all information of the filters to be synthesized are derived directly for realization, and they could find applications in the design of lumped‐element LC filters, active RC filters, and infinite impulse response digital filters. In this paper, another DST for complex general Chebyshev bandpass filters is discussed, which is based on a complex mapping relation and featured by complex‐coefficient filtering polynomials. It is called as complex DST in this paper. Compared with real‐coefficient filtering polynomials whose polarities are determined by the number of their zeros at zero frequency, the polarities of complex‐coefficient filtering polynomials can be easily changed by multiplying imaginary unit j. Such advantage might make their realization more flexible. The analysis shows that conventional coupling matrix could be considered as narrow‐band approximation of network matrix derived by complex DST in the normalized frequency domain. In order to demonstrate the validity of complex DST in this paper, it is applied in the design of classic parallel‐coupled microstrip bandpass filters. Compared with conventional synthesis techniques, complex DST could find out better dimensions and provide more choices for realization and synthesize both even‐order and odd‐order parallel‐coupled microstrip bandpass filters. Copyright © 2017 John Wiley & Sons, Ltd.
Robust stability analysis and improved design of phase‐locked loops with non‐monotonic nonlinearities: LMI‐based approach
Authors: Ahmad Nur Syazreen
Published: July 2017

Due to nonlinear nature of several phase detectors, linear approximation method often leads to performance degradation in many phase‐locked loops (PLLs), particularly when the phase errors are sufficiently large. A third or higher order PLL, in spite of the ability to track a wider variety of inputs and having higher operating‐frequency range, requires more design attention in order to ensure stable tracking. In this work, with the nonlinearities inserted into the system's model, suitable criteria that take into account the nonlinearities' non‐monotonicity, sector and slope bounds are employed to establish robust stability conditions. The result is applicable to any PLLs without order and type restrictions. For Type‐1 PLLs, the resulting condition can be used to search for the maximum stable loop gain, which is also linked to the lock‐in range of the system. In the later part of this work, the focus is devoted towards designing PLLs with high lock‐in range, which is performed via mixing the proposed method with H∞ synthesis. The searches for the parameters in both PLL analysis and design are expressed in terms of convex linear matrix inequalities, which are computationally tractable. To illustrate the improvement introduced via this approach, several numerical examples and simulations are included with comparisons over conventional methods. Copyright © 2017John Wiley & Sons, Ltd.
The metabolic syndrome alters the miRNA signature of porcine adipose tissue‐derived mesenchymal stem cells
Authors: Meng Yu , Eirin Alfonso , Zhu Xiang‐Yang , Tang Hui , Chanana Pritha , Lerman Amir , Van Wijnen Andre J. , Lerman Lilach O.
Published: July 2017

Autologous transplantation of mesenchymal stem cells (MSCs) is a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) and that EVs shuttle miRNAs to damaged parenchymal cells to activate an endogenous repair program. We hypothesize that comorbidities may interfere with the packaging of cargo in MSC‐derived EVs. Therefore, we examined whether metabolic syndrome (MetS) modulates the miRNA content packed within MSC‐derived EVs. MSCs were collected from swine abdominal adipose tissue after 16 weeks of lean or obese diet (n = 7 each). Next‐generation RNA sequencing of miRNAs (miRNA‐seq) was performed to identify miRNAs enriched in MSC‐derived EVs and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using gene ontology analysis. Lean‐ and MetS‐EVs were enriched in, respectively, 14 and 8 distinct miRNAs. Target genes of miRNAs enriched in MetS‐EVs were implicated in the development of MetS and its complications, including diabetes‐related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin‐like receptors), and Peptide ligand‐binding receptors. In contrast, miRNAs enriched in Lean EVs target primarily EphrinA‐EPHA and the Rho family of GTPases. MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy and limit the therapeutic use of autologous MSCs in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS. © 2017 International Society for Advancement of Cytometry
A new design of prefilter for reducing timing synchronization jitter
Authors: Chi Yonggang , Wu Fenghui , Yang Mu , Zheng Yuxi , Chen Sanbin
Published: July 2017

For high‐precision timing synchronization in feedback Gardner algorithm and different feedforward nonlinear algorithms, timing jitter reduction is the key problem, especially with a small roll‐off factor in high‐order modulation. Through the elaborate analysis about the timing jitter, this paper proposes a new prefilter design method based on finite impulse response structure. Using a suitable Kaiser window for suppressing the sidelobe energy of the proposed prefilter, this method can further decrease the complexity of filter design and eliminate most part of the pattern noise. Compared with the previous prefilter design algorithms, the approach has a better improvement in steady‐state phase jitter reduction without increasing the capture time in Gardner timing error detector. Meanwhile, with such kind of prefilter, the performance of logarithmic nonlinearity is better than that of square law nonlinearity, this is not reported in literature. Simulation results show that the residual timing jitter in both kinds of algorithms is closed to the modified Cramer‐Rao bound when the roll‐off factor is equal to 0.1 in 1024QAM.
Maximum harvested energy policy in full‐duplex relaying networks with SWIPT
Authors: Nguyen Xuan‐Xinh , Do Dinh‐Thuan
Published: July 2017

It is considered that energy scavenging is a promising way for source node transfer energy to powered constraint relay in cooperative networks with advantage of cost‐effective maintenance and flexible deployment, which so‐called simultaneous wireless information and power transfer. In this paper, relay selection for optimal wireless energy is investigated. In terms of time switching–based relaying, this paper considers the performance comparison of 3 proposed relay selection schemes, namely, (1) optimal relay selection scheme, (2) maximum harvested energy relay selection scheme, and (3) minimum self‐interference relay selection. In particular, the system performance is studied intensively with regard to outage probability and throughput over Rayleigh fading channels. We also achieve the integral form for accurate expressions and closed form for approximate expressions. Finally, these analytical expressions are proved exactness according to Monte Carlo simulation.
Reduction of wireless signals in indoor environments by using an active frequency selective wall based on spectrum sensing
Authors: Cho Sung‐Sil , Hong Ic‐Pyo
Published: July 2017

This paper presents a wireless local area network (WLAN) spectrum control system that uses active frequency selective shielding walls to selectively reduce or pass WLAN signals in the 5 GHz band indoors. The proposed system utilizes a well‐known active frequency selective structure based on a rectangular loop with PIN diodes and is thus capable of either reducing or passing the WLAN frequency by using the on/off switching of the PIN diode based on the measured electric field strength in indoor. We designed and simulated the proposed active frequency selective shielding wallpaper by using commercial electromagnetic simulation software and confirmed that the proposed structure can reduce the WLAN signal by switching the PIN diode by applying the manufactured prototype on the exterior of an experimental apparatus containing a WLAN receiver antenna that is capable of measuring the received electric field strength. Extension of the results presented herein can be applied to reduce the wireless signal to enhance the spectrum efficiency of an indoor space.
Study of the in vitro and in vivo metabolism of the tryptamine 5‐MeO‐MiPT using human liver microsomes and real case samples
Authors: Grafinger Katharina Elisabeth , Hädener Marianne , König Stefan , Weinmann Wolfgang
Published: July 2017

The synthetic tryptamine 5‐methoxy‐N‐methyl‐N‐isopropyltryptamine (5‐MeO‐MiPT) has recently been abused as a hallucinogenic drug in Germany and Switzerland. This study presents a case of 5‐MeO‐MiPT intoxication and the structural elucidation of metabolites in pooled human liver microsomes (pHLM), blood, and urine. Microsomal incubation experiments were performed using pHLM to detect and identify in vitro metabolites. In August 2016, the police encountered a naked man, agitated and with aggressive behavior on the street. Blood and urine samples were taken at the hospital and his premises were searched. The obtained blood and urine samples were analyzed for in vivo metabolites of 5‐MeO‐MiPT using liquid chromatography–high resolution tandem mass spectrometry (LC–HRMS/MS). The confiscated pills and powder samples were qualitatively analyzed using Fourier transform infrared (FTIR), gas chromatography–mass spectrometry (GC–MS), LC‐HRMS/MS, and nuclear magnetic resonance (NMR). 5‐MeO‐MiPT was identified in 2 of the seized powder samples. General unknown screening detected cocaine, cocaethylene, methylphenidate, ritalinic acid, and 5‐MeO‐MiPT in urine. Seven different in vitro phase I metabolites of 5‐MeO‐MiPT were identified. In the forensic case samples, 4 phase I metabolites could be identified in blood and 7 in urine. The 5 most abundant metabolites were formed by demethylation and hydroxylation of the parent compound. 5‐MeO‐MiPT concentrations in the blood and urine sample were found to be 160 ng/mL and 3380 ng/mL, respectively. Based on the results of this study we recommend metabolites 5‐methoxy‐N‐isopropyltryptamine (5‐MeO‐NiPT), 5‐hydroxy‐N‐methyl‐N‐isopropyltryptamine (5‐OH‐MiPT), 5‐methoxy‐N‐methyl‐N‐isopropyltryptamine‐N‐oxide (5‐MeO‐MiPT‐N‐oxide), and hydroxy‐5‐methoxy‐N‐methyl‐N‐isopropyltryptamine (OH‐5‐MeO‐MiPT) as biomarkers for the development of new methods for the detection of 5‐MeO‐MiPT consumption, as they have been present in both blood and urine samples.
Synthesis and Coordination Chemistry of a Chelating P–Sn Ligand Based on Stanna‐closo‐dodecaborate
Authors: Wütz Tobias , Diab Fatima , Wesemann Lars
Published: July 2017

Substitution at a B–H unit of the heteroborate cluster stanna‐closo‐dodecaborate [SnB11H11]2– at the upper belt of the icosahedron by one of the triarylphosphine moieties of xantphos was carried out under the catalysis of palladium acetate. The resulting coupling product is a monoanion offering two coordination sites: a low‐valent tin‐cluster vertex and a triaryl phosphine moiety. The basicity and nucleophilicity of the anion were investigated in reactions with a strong acid or an alkylating agent. Transition‐metal electrophiles like platinum halide PtCl2 or rhodium carbonyl [Rh(CO)2Cl]2 react with the bidentate ligand, with the formation of cis‐coordination products.
Reversible Small‐Molecule Interactions with Coordinatively Unsaturated Metal Centers Held in Metallathiaborane Clusters
Authors: Bould Jonathan , Passarelli Vincenzo , Oro Luis A. , Macías Ramón
Published: July 2017

The metallathiaboranes [8,8‐(dppe)‐nido‐8,7‐NiSB9H11] [1, dppe = bis(diphenylphosphanyl)ethane], [7‐Et‐8,8‐(dppe)‐nido‐8,7‐NiSB9H10] (2), [9‐Et‐8,8‐(dppe)‐nido‐8,7‐NiSB9H10] (3) and [2,2‐(dppe)‐closo‐2,1‐NiSB8H8] (4) are isolated from the reactions between Cs[arachno‐SB9H12], Li[BHEt3] and [NiCl2(dppe)] at low temperature in yields of 30, 1, 0.1 and <1 %, respectively. The arachno‐nickellathiadecaborane [6,6‐(dppe)‐arachno‐6,9‐NiSB8H10] (5) is isolated from the reaction between [(N,N,N′,N′‐tetramethylnaphthalene‐1,8‐diamine)H][SB8H11], Li[BHEt3] and [NiCl2(dppe)] at low temperature (75 % yield). Compound 1 reversibly takes up NH3 in solution, and the characterization of the resulting compound is discussed. Compound 5 shows no interactions with ammonia but does reversibly take up CO to give [6,6,6‐(CO)(dppe)‐arachno‐6,9‐NiSB8H10] (7). The CO molecule is very weakly bound and is lost readily even in the solid state. Similarly to 1, the isonido‐iridathiaundecaboranes [(L)2‐H‐isonido‐IrSB9H9] (L = PMe3 and PMe2Ph) also reversibly takes up NH3 to afford [8,8,8‐(PMe3)2(NH3)‐nido‐8,7‐IrSB9H10]·NH3 (8) and [8,8,8‐(PMe2Ph)2(NH3)‐nido‐8,7‐IrSB9H10] (9) quantitatively. The ferrathiaborane compound [1,1,3‐(dppe)2‐1,2‐closo‐FeSB9H9] (11) was isolated in trace yield when [FeCl2(dppe)] was used as the starting metal complex. When appropriate, the compounds were characterized by single‐crystal X‐ray diffraction studies, multielement NMR spectroscopy together with DFT gauge including atomic orbitals (GIAO) chemical‐shielding calculations, IR spectroscopy and elemental analysis.
Linear Selective C–H Bond Alkylation with Activated Olefins Catalyzed by Cp*CoIII
Authors: Barsu Nagaraju , Emayavaramban Balakumar , Sundararaju Basker
Published: July 2017

A simple and efficient method for Cp*CoIII‐catalyzed C–H bond alkylation using activated olefins was developed. Selective C–H monoalkylation was performed at ambient temperature. One‐pot symmetrical dialkylation and sequential unsymmetrical C–H dialkylation were performed to give the desired products in excellent yields. The reaction was found to proceed through an M–alkyl intermediate after migratory insertion, and this intermediate undergoes protodemetalation to give the expected alkylated product along with the regenerated catalyst.
Ultrasound‐Promoted Enantioselective Decarboxylative Protonation of α‐Aminomalonate Hemiesters by Chiral Squaramides: A Practical Approach to Both Enantiomers of α‐Amino Esters
Authors: Some Surajit , Kim Han Yong Bae, Mun Jong , Zhang Yong Jian , Song Choong Eui
Published: July 2017

Herein, we report an ultrasound‐promoted enantioselective decarboxylative protonation reaction of α‐aminomalonate hemiesters 1 in the presence of chiral cinchona‐derived squaramide Brønsted bases under mild conditions, which afforded both the (S)‐ and (R)‐enantiomers of α‐amino acid derivatives 2 in excellent yields (> 90 %) and excellent enantioselectivities (up to 98 % ee).
Hybrid‐Type Squaramide‐Fused Amino Alcohol Organocatalysts for Enantioselective Diels–Alder Reactions of 3‐Hydroxy‐2‐Pyridones with Maleimides
Authors: Chennapuram Madhu , Subba Reddy U. V. , Seki Chigusa , Okuyama Yuko , Kwon Eunsang , Uwai Koji , Tokiwa Michio , Takeshita Mitsuhiro , Nakano Hiroto
Published: July 2017

The hybrid‐type squaramide‐fused amino alcohol (SFAA) containing both a Brønsted basic site and a hydrogen‐bonding site in the molecule showed high catalytic activity as an organocatalyst in the enantioselective Diels–Alder (DA) reactions of 3‐hydroxy‐2‐pyridones with maleimides to afford chiral endo‐4‐hydroxy‐2‐azabicyclo[2.2.2]octanes (4‐hydroxyisoquinuclidines) with excellent chemical yields and enantioselectivities (up to 95 % yield and 98 % ee). In particular, the use of 4‐brominated 2‐pyridones afforded the corresponding chiral 4‐hydroxyisoquinuclidines with both excellent chemical yields and enantioselectivities (95 %, 98 % ee) with an opposite absolute stereochemistry in comparison with the chiral endo‐DA adducts obtained from the reactions performed with common 3‐hydroxy‐2‐pyridones. The DA adducts obtained could be used as synthetic precursors for several natural products that have a broad spectrum of fascinating biologically activities.
Regioselective Chlorination and Suzuki–Miyaura Cross‐Coupling of 4‐Alkoxycoumarins, 4‐Alkoxy‐2‐pyrones, and Related Heterocycles
Authors: Prendergast Aisling M. , McGlacken Gerard P.
Published: July 2017

Chlorination of the coumarin framework was achieved by using trichloroisocyanuric acid, which has several advantages over N‐chlorosuccinimide, particularly with respect to cost‐effectiveness and toxicity. The Suzuki–Miyaura cross‐coupling of the chlorinated 4‐alkoxycoumarins with a range of aryl‐ and heteroarylboronic acids was then carried out in the presence of Pd(OAc)2 and 2‐(dicyclohexylphosphino)‐2′,6′‐dimethoxybiphenyl (SPhos) in an environmentally benign solvent. This transformation afforded the coupled products in yields up to 99 %. Sensitive functional groups such as aldehydes and nitriles were tolerated under the reaction conditions, and the protocol could be performed on a gram scale. The cross‐coupling method was also successfully extended to related 2‐pyrone, 2‐pyridone, and 2‐quinolone derivatives to give yields up to 96 %. This is the first time cross‐coupling conditions have been shown to be general across this range of heterocyclic substrates. The demethylation of the Suzuki–Miyaura products allowed for access to 3‐aryl‐4‐hydroxycoumarins.
Sceptrin – Enantioselective Synthesis of a Tetrasubstituted all‐trans Cyclobutane Key Intermediate
Authors: Barra Lena , Dickschat Jeroen S.
Published: July 2017

The asymmetric synthesis of both enantiomers of tetrasubstituted all‐trans dimethyl 3,4‐diacetylcyclobutane‐1,2‐dicarboxylate with high enantiomeric purity (>98 % ee) using a valine‐derived chiral auxiliary in a diastereoselective photodimerization is reported. The absolute configuration was assigned by single‐crystal X‐ray diffraction analysis. Because this cyclobutane is a key intermediate in the total synthesis of (–)‐sceptrin and ageliferin, our findings strengthen the recently revised absolute configurations of these pyrrole‐imidazole alkaloids.
Homochiral metal‐organic frameworks based on amino acid ligands for HPLC separation of enantiomers
Authors: Zhang Jun‐Hui , Nong Rui‐Yu , Xie Sheng‐Ming , Wang Bang‐Jin , Ai Ping , Yuan Li‐Ming
Published: July 2017

Natural amino acids are well known to form coordination polymers with transition metal ions. In this study, six homochiral metal‐organic frameworks constructed from Zn2+ or Co2+ ions and various enantiopure amino acid (L‐tyrosine, L‐histidine, L‐tryptophan and L‐glutamic acid), namely [Zn(L‐tyr)]n(L‐tyrZn), [Zn4(btc)2(Hbtc)(L‐His)2(H2O)4]·1.5H2O, {[Zn2(L‐trp)2(bpe)2(H2O)2]·2H2O·2NO3}n, [Co2(L‐Trp)(INT)2(H2O)2(ClO4)], [Co2(sdba)((L‐Trp)2] and [Co(L‐Glu)(H2O)·H2O]∞, were synthesized according to the methods previously reported in the literature. The six homochiral MOFs were explored as the chiral stationary phases for high‐performance liquid chromatographic separation of enantiomers using hexane/isopropanol or hexane/dichloromethane as mobile phase. Various types of enantiomers such as alcohols, amines, ketones, ethers, organic acids, etc. can be resolved on these homochiral MOF columns. The results revealed that the enantioseletivities of homochiral MOFs based on amino acids as chiral bridging ligands used as stationary phases are practical in HPLC.
VEGF and TWIST1 in a 16‐biomarker immunoprofile useful for prognosis of breast cancer patients
Authors: Schirosi Laura , De Summa Simona , Tommasi Stefania , Paradiso Angelo , Gasparini Giampietro , Popescu Ondina , Simone Giovanni , Mangia Anita
Published: July 2017

This study concerns the expression of biomarkers involved in diverse pathways, such as progression, DNA repair mechanisms and angiogenesis to establish an immunoprofile capable of characterizing sporadic versus familial breast cancers (BCs). The aim was to identify a patient subgroup with a different clinical outcome, which could then be directed towards new targeted therapies. Hierarchical cluster analysis (HCA) was carried out using the immunohistochemical score from tissue microarray sections of an initial cohort of 183 (88 sporadic and 95 familial) patients with invasive BC. For the survival analysis, only those patients with complete follow‐up were considered. The HCA revealed a 16‐protein immunoprofile, nine of which represent the core, as was also found when familial and sporadic BCs were analysed individually. The 16‐biomarker immunoprofile was able to identify a group of patients (Group 1) with a more aggressive tumour phenotype. Survival analyses showed that VEGF+/TWIST1‐ patients with familial BC of Group 1 tended to demonstrate a lower DFS than the VEGF‐/TWIST1+ sporadic BC patients of Group 2 (p = 0.052). Moreover, the entire cohort of VEGF+/TWIST1‐ patients showed a statistically worse DFS than the patients with VEGF‐/TWIST1+ expression (p = 0.034). In conclusion, we found that tumour stratification based on an immunoprofile is useful to predict the patient clinical behaviour. In particular, our study indicates that the clustering of tumors on the basis of this immunoprofile suggests the possibility to differentiate familial from sporadic BCs and to clinically select those patients who are more likely to benefit from inhibition of the VEGF pathway.
The clinical impact of tumour‐infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: A cohort study
Authors: Berntsson Jonna , Svensson Maria C , Leandersson Karin , Nodin Björn , Micke Patrick , Larsson Anna H , Eberhard Jakob , Jirström Karin
Published: July 2017

Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular reference to the anatomical subsite of the primary tumour. The density of CD3+, CD8+ and FoxP3+ tumour‐infiltrating T cells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population‐based cohort. Kaplan–Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5‐year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8+ cell density was a favourable prognostic factor for patients with right‐sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29–0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8+ cells and right‐sidedness (p = 0.031). High FoxP3+ cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR = 0.54, 95% CI 0.30‐0.99), and CD3+ cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3+ or FoxP3+ cells and sidedness. These results demonstrate that the prognostic impact of tumour‐infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.
DS‐8201a, a new HER2‐targeting antibody–drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2‐positive gastric cancer T‐DM1 resistance
Authors: Takegawa Naoki , Nonagase Yoshikane , Yonesaka Kimio , Sakai Kazuko , Maenishi Osamu , Ogitani Yusuke , Tamura Takao , Nishio Kazuto , Nakagawa Kazuhiko , Tsurutani Junji
Published: July 2017

Anti‐HER2 therapies are beneficial for patients with HER2‐positive breast or gastric cancer. T‐DM1 is a HER2‐targeting antibody–drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T‐DM1 resistance. DS‐8201a is a new ADC incorporating an anti‐HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan‐derivative topoisomerase I inhibitor (DXd). DS‐8201a has a drug‐to‐antibody‐ratio (DAR) of 8, which is higher than that of T‐DM1 (3.5). Owing to these unique characteristics and unlike T‐DM1, DS‐8201a is effective against cancers with low‐HER2 expression. In the present work, T‐DM1‐resistant cells (N87‐TDMR), established using the HER2‐positive gastric cancer line NCI‐N87 and continuous T‐DM1 exposure, were shown to be susceptible to DS‐8201a. The ATP‐binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87‐TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T‐DM1 sensitivity. Therefore, resistance to T‐DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS‐8201a inhibited the growth of N87‐TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS‐8201a relative to T‐DM1 compensates for increased efflux. Notably, N87‐TDMR xenograft tumor growth was prevented by DS‐8201a. In conclusion, the efficacy of DS‐8201a as a treatment for patients with T‐DM1‐resistant breast or gastric cancer merits investigation.
Connexin 43 upregulation by dioscin inhibits melanoma progression via suppressing malignancy and inducing M1 polarization
Authors: Kou Yu , Ji Liyan , Wang Haojia , Wang Wensheng , Zheng Hongming , Zou Juan , Liu Linxin , Qi Xiaoxiao , Liu Zhongqiu , Du Biaoyan , Lu Linlin
Published: July 2017

Connexin 43 (Cx43), a vital gap junction protein in tumor microenvironment (TME), is a novel molecular target for melanoma chemotherapeutics due to its tumor suppressive function. Dioscin, an herbal steroidal saponin, exerts anti‐tumor effects while the underlying mechanism is unclear. Using WB, FACS, and immunofluorescence methodologies, we found dioscin significantly activated the transcription and translation of Cx43 via the retinoid acid signaling pathway and simultaneously enhanced the transporting function of Cx43. Through stimulating Cx43, dioscin remarkably suppressed the migratory and invasive capacities of B16 cells, and notably decreased pluripotency markers of cancer stem cells and epithelial‐to‐mesenchymal transition in B16 cells and animal tumor tissues. Conversely, dioscin improved the secretion of pro‐inflammatory cytokines (IL‐6, TNFα, and IL‐1β), and the phagocytic capacity of tumor‐associated macrophages by increasing M2‐to‐M1 phenotype transition. More strikingly, even in Cx43 functional deficient B16 and RAW264.7 cells, dioscin still dramatically reversed the aggravated tumor malignancy and reduced macrophage phagocytic activity. Two classical metastasis animal models were utilized in vivo and results showed that dioscin showed significant anti‐metastatic effects, which is closely related to the expression of Cx43 either in in situ tumor or metastatic lung nodes. In conclusion, dioscin targets Cx43 to suppress the tumor cell malignancy and activate macrophage sensitivity, thereby targeting melanoma microenvironment.
Assessment of sexually related personal distress accompanying premenopausal sexual dysfunction with an Arabic version of the Female Sexual Distress Scale
Authors: Ahmed Magdy R. , Shaaban Mohamed M. , Meky Heba K.
Published: July 2017

Objective

To assess sexually related personal distress among premenopausal women with female sexual dysfunction (FSD) via a validated Arabic version of the Female Sexual Distress Scale (FSDS).

Methods

A cross‐sectional study was conducted among women attending Suez Canal University Hospital, Egypt, between May 2015 and July 2016. In a pilot study to evaluate test–retest reliability and internal consistency, 42 sexually active premenopausal women (aged ≥20 years) completed the Arabic FSDS at recruitment and 2 weeks later. Subsequently, premenopausal sexually active women (aged 20–45 years) were asked to complete the female sexual function index (FSFI) questionnaire; those with FSD (FSFI score ≤26.55) were invited to return to complete the validated version of the Arabic FSDS.

Results

The Arabic FSDS showed good test–retest reliability (Pearson correlation coefficient 0.93–0.98) and internal consistency (Cronbach α 0.83–0.92). Overall, 140 (58.1%) of 241 women who completed the FSFI had sexual dysfunction, of whom 51 (36.4%) had sexually related personal distress. Marriage duration was significantly increased among women with FSD (P<0.001). All FSFI sexual domains except lubrication were negatively correlated with FSDS.

Conclusion

FSD and sexually related personal distress were highly interrelated and prevalent. An Arabic version of the FSDS was found to be valid and reliable for evaluation of sexually related personal distress.
Assessing Criteria Affecting Performance of the Sefidroud Irrigation and Drainage Network Using TOPSIS–Entropy Theory
Authors: Aghajani Mahbobeh , Mostafazadeh‐Fard Behrouz , Navabian Maryam
Published: July 2017

Assessing criteria affecting the performance of irrigation networks helps us understand the current situation of irrigation projects, allocate water fairly and modify cropping patterns. Criteria affecting the performance of the Sefidroud Irrigation and Drainage Network were studied using TOPSIS‐entropy theory to select appropriate sites for cultivating rice. The Sefidroud Irrigation and Drainage Network includes three sub‐networks of Foumanat, Central and Eastern with 17 irrigation sub‐sub‐networks located in the northern part of Iran. Six criteria, technical, managerial, environmental, economic, social and soil–climatic, with 34 sub‐criteria, were selected to assess the performance of the Sefidroud Irrigation and Drainage Network for three scenarios: A (including all criteria), B (all criteria except technical and managerial) and C (only soil–climate criteria). The criteria and sub‐criteria were weighted using the entropy model and coded in the TOPSIS model. Results showed the technical, economic and managerial criteria had the greatest importance and the environmental and soil‐climatic criteria had the least for ranking irrigation sub‐sub‐networks for selecting suitable sites for cultivating rice. Farm demand, income ratio and rainfall were the most important sub‐criteria for scenarios A, B and C, respectively. Fomanat sub‐network was the best site for cultivating rice. The use of the TOPSIS and entropy models to manage irrigation networks is recommended. Copyright © 2017 John Wiley & Sons, Ltd.
Maternal alcohol consumption and altered miRNAs in the developing fetus: Context and future perspectives
Authors: Mandal Chanchal , Halder Debasish , Jung Kyoung Hwa , Chai Young Gyu
Published: July 2017

Alcohol is a teratogenic agent that can cause a wide range of developmental disorders, and sometimes, the effects persist throughout an individual's lifetime. Researchers have shown the involvement of epigenetic mechanisms in alcohol‐mediated disorders. Non‐coding RNAs are one of the major sources of epigenetic modifications, especially microRNAs. The association of microRNAs with alcohol consumption leads to a new focus on finding the molecular mechanisms of alcohol toxicity. It has been suggested that alcohol alters the relative expression of microRNAs and regulates target mRNA expression in both in vitro and in vivo models. Currently, we lack information regarding the relationship between altered microRNA expression and disease phenotypes in alcohol‐mediated disorders. In this review, we tried to gather all of the available information about the alcohol‐mediated dysregulation of microRNA expression in utero. We hope that our efforts will help future researchers identify major microRNAs in the field of prenatal alcohol toxicity and related therapeutics.
Prediction of Fractures and Major Cardiovascular Events in Men Using Serum Osteoprotegerin Levels: The Prospective STRAMBO Study
Authors: Szulc Pawel , Chapurlat Roland , Hofbauer Lorenz C
Published: July 2017

Fragility fractures and cardiovascular diseases often coincide. However, data on shared risk factors and markers are scarce. Our aim was to assess the independent associations of serum osteoprotegerin (OPG) levels with the risk of fracture and cardiovascular outcomes (acute coronary syndrome, cardiac death) in older men. A cohort of 819 home-dwelling men aged 60 to 87 years was followed prospectively for 8 years. Serum OPG was measured at baseline by ELISA. Bone mineral density (BMD) at femoral neck and Trabecular Bone Score (TBS) were assessed by DXA. Clinical risk factors and Fracture Risk Assessment Tool (FRAX) were assessed. The incident events (self-reported peripheral fractures and acute coronary syndrome, cardiac death reported by a proxy) confirmed by a health professional were retained for the statistical analysis. Incident vertebral fractures were assessed on lateral DXA scans after 4 and 8 years. Hazard risk (HR) was assessed using the Cox model. After adjustment for FRAX corrected for femoral neck BMD and TBS, diabetes mellitus, ischemic heart disease, and prior falls, the risk of fracture was twofold higher in the highest versus the lowest OPG quartile (HR 2.35; 95% CI, 1.35 to 4.10). The risk of vertebral and nonvertebral fracture was higher in the highest versus the lowest OPG quartile (OR 2.76 [95% CI, 1.08 to 7.05] and HR 2.46 [95% CI, 1.23 to 4.92]). The risk of major osteoporotic fracture was higher in the fourth versus the first OPG quartile (HR 2.43; 95% CI, 1.16 to 5.10). The risk of cardiovascular outcome (adjusted for confounders) was higher in the highest versus the lowest OPG quartile (HR 3.93; 95% CI, 1.54 to 10.04). The risk of fracture and cardiovascular outcome was higher in the highest OPG quartile versus the lower quartiles combined (HR 2.06 [95% CI, 1.35 to 3.14] and HR 2.98 [95% CI, 1.60 to 5.54], respectively). In conclusion, in older men, higher serum OPG levels represent an independent risk factor for cardiovascular and fracture risk. © 2017 American Society for Bone and Mineral Research.
The Effect of Intentional Weight Loss on Fracture Risk in Persons With Diabetes: Results From the Look AHEAD Randomized Clinical Trial
Authors: Johnson Karen C , Bray George A , Cheskin Lawrence J , Clark Jeanne M , Egan Caitlin M , Foreyt John P , Garcia Katelyn R , Glasser Stephen , Greenway Frank L , Gregg Edward W , Hazuda Helen P , Hergenroeder Andrea , Hill James O , Horton Edward S , Jakicic John M , Jeffery Robert W , Kahn Steven E , Knowler William C , Lewis Cora E , Miller Marsha , Montez Maria G , Nathan David M , Patricio Jennifer L , Peters Anne L , Pi-Sunyer Xavier , Pownall Henry J , Reboussin David , Redmon J Bruce , Steinberg Helmut , Wadden Thomas A , Wagenknecht Lynne E , Wing Rena R , Womack Catherine R , Yanovski Susan Z , Zhang Ping , Schwartz Ann V ,   for the Look AHEAD Study Group
Published: July 2017

Intentional weight loss is an important treatment option for overweight persons with type 2 diabetes mellitus (DM), but the effects on long-term fracture risk are not known. The purpose of this Look AHEAD analysis was to evaluate whether long-term intentional weight loss would increase fracture risk in overweight or obese persons with DM. Look AHEAD is a multicenter, randomized clinical trial. Recruitment began in August 2001 and follow-up continued for a median of 11.3 years at 16 academic centers. A total of 5145 persons aged 45 to 76 years with DM were randomized to either an intensive lifestyle intervention (ILI) with reduced calorie consumption and increased physical activity designed to achieve and maintain ≥7% weight loss or to diabetes support and education intervention (DSE). Incident fractures were ascertained every 6 months by self-report and confirmed with central adjudication of medical records. The baseline mean age of participants was 59 years, 60% were women, 63% were white, and the mean BMI was 36 kg/m2. Weight loss over the intervention period (median 9.6 years) was 6.0% in ILI and 3.5% in DSE. A total of 731 participants had a confirmed incident fracture (358 in DSE versus 373 in ILI). There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR 1.39; 95% CI, 1.02 to 1.89). An intensive lifestyle intervention resulting in long-term weight loss in overweight/obese adults with DM was not associated with an overall increased risk of incident fracture but may be associated with an increased risk of frailty fracture. When intentional weight loss is planned, consideration of bone preservation and fracture prevention is warranted. © 2017 American Society for Bone and Mineral Research.