bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States
Authors: Pollack Seth M. , Somaiah Neeta , Araujo Dejka M. , Druta Mihaela , Van Tine Brian A. , Burgess Melissa A. , Chawla Sant P. , Seetharam Mahesh , Okuno Scott H. , Bohac Chet , Chen Michael , Yurasov Sergey , Attia Steven
Published: May 2020

Background

Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials.

Methods

In this multi‐center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first‐line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression‐free survival (PFS) were evaluated using the Kaplan‐Meier method and Cox regression.

Results

At start of first‐line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first‐line therapy for SS was 24.7 months (95% CI, 20.9‐29.4) and 7.5 months, respectively (95% CI, 6.4‐8.4). Median OS and median PFS from start of first‐line therapy for MRCL was 29.9 months (95% CI, 27‐44.6) and 8.9 months (95% CI 4.5‐12.0).

Conclusions

To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real‐world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.
Clinical outcomes of abiraterone acetate and predictors of its treatment duration in metastatic castration‐resistant prostate cancer: Real‐world experience in the Southeast Asian cohort
Authors: Lim Jasmine , Amantakul Akara , Shariff Nisha , Lojanapiwat Bannakij , Alip Adlinda , Ong Teng Aik , Thevarajah Shankaran , Ahmayuddin Firdaus , Mathew Adeline , Sriplakich Supon , Vuthiwong Jaraspong , Chong Flora Li Tze , Saad Marniza
Published: May 2020

It is of much interest to understand the efficacy of abiraterone acetate (AA) in routine clinical practice. We assessed the clinical outcome of AA in patients with metastatic castration‐resistant prostate cancer (mCRPC) and determined clinical factors associated with AA treatment duration in real‐world setting. This real‐world cohort consisted of 93 patients with mCRPC treated with AA in Thailand (58.1%) and Malaysia (41.9%). Primary endpoints were overall survival (OS) and biochemical progression‐free survival (bPFS). Secondary endpoints were predictors associated with AA treatment duration evaluated with Cox proportional hazards regression. Around 74% were chemotherapy‐naïve. The median AA treatment duration was 10 months (IQR 5.6‐17.1). Malaysians had a relatively lower median OS and bPFS (OS 17.8 months; 95% CI 6.4‐29.1, bPFS 10.4 months; 95% CI 8.8‐12.0) compared to Thais (OS 27.0 months; 95% CI 11.3‐42.7, bPFS 14.0 months; 95% CI 5.8‐22.2), although it did not achieve statistical significance (P > .05). Patients with longer AA treatment duration (>10 months) had lower risk of death and longer bPFS, compared to those with shorter AA treatment duration (≤10 months) (hazard ratio [HR] 0.10, 95% CI 0.05‐0.22 and HR 0.13, 95% CI 0.06‐0.25, respectively). Multivariable analysis showed that PSA at AA initiation, presence of PSA response and chemotherapy‐naive were independently associated with AA duration (P < .05). Abiraterone acetate is well‐tolerated in the Southeast Asian cohort with comparable survival benefits to other Asian populations in real‐world setting. Lower PSA levels at AA initiation, presence of PSA response, and chemotherapy‐naive were significant in determining AA treatment duration.
Redox‐Active Phenolic Compounds Mediate the Cytotoxic and Antioxidant Effects of Carpodesmia tamariscifolia (=Cystoseira tamariscifolia)
Authors: Moussa Hanaa , Quezada Elías , Viña Dolores , Riadi Hassane , Gil‐Longo José
Published: May 2020

Carpodesmia tamariscifolia is a brown alga rich in (poly)phenols with important cytotoxic and antioxidant effects. However, the relationship between its chemical composition and its effects is unknown. The aim of this study is to identify the potential compounds and mechanisms responsible for its main effects. The alga was extracted consecutively with hexane, dichloromethane and methanol and further fractionated using Sephadex LH‐20 and silica gel columns when appropriate. The fractions were subjected to thin‐layer chromatography and liquid chromatography‐mass spectrometry analysis and evaluated for their total phenolic content (Folin‐Ciocalteu assay), radical scavenging activity (DPPH assay), cytotoxic activity (MTT assay on the SH‐SY5Y cell line), and ability to generate H2O2 (Amplex Red assay). Chromatographic and phenolic analyses of the fractions indicate that abundant redox‐active phenols are present in all the fractions and that a high amount of prenylated hydroquinone derivatives is present in the apolar ones. In the hexane and dichloromethane fractions, the cytotoxic and antioxidant activities are closely related to their phenolic content, whereas in the methanol fractions, the cytotoxicity is negatively related to the phenolic content and the antioxidant activity is positively related to it. In the same tests, hydroquinone behaves as both strong cytotoxic and antioxidant agent. H2O2 assay shows that C. tamariscifolia fractions and hydroquinone can autoxidize and generate H2O2. Our results suggest that redox‐active phenols produce the pharmacological effects described for C. tamariscifolia and that the hydroquinone moiety of prenylated hydroquinone derivatives is responsible for both cytotoxic (through a pro‐oxidant mechanism secondary to its autoxidation) and antioxidant effects of the apolar fractions.
Infrared Spectroscopy Reveals the Preferred Motif Size and Local Disorder in Parallel Stranded DNA G‐Quadruplexes
Authors: Price David A. , Kartje Zachary J. , Hughes Joanna A. , Hill Tayler D. , Loth Taylor M. , Watts Jonathan K. , Gagnon Keith T. , Moran Sean D.
Published: May 2020

Infrared spectroscopy detects the formation of G‐quadruplexes in guanine‐rich nucleic acid sequences through shifts in the guanine C=O stretch mode. Here, we use ultrafast 2D infrared (IR) spectroscopy and isotope substitution to show that these shifts arise from vibrational delocalization among stacked G‐quartets. This provides a direct measure of the sizes of locally ordered motifs in heterogeneous samples with substantial disordered regions. We find that parallel‐stranded, potassium‐bound DNA G‐quadruplexes are limited to five consecutive G‐quartets and 3–4 consecutive layers are preferred for longer polyguanine tracts. The resulting potassium‐dependent G‐quadruplex assembly landscape reflects the polyguanine tract lengths found in genomes, the ionic conditions prevalent in healthy mammalian cells, and the onset of structural disorder in disease states. Our study describes spectral markers that can be used to probe other G‐quadruplex structures and provides insight into the fundamental limits of their formation in biological and artificial systems.
The long noncoding RNA NR_045363 involves cardiomyocyte apoptosis and cardiac repair via p53 signal pathway
Authors: Chen Xianda , Wang Jue , Nie Yu , Chu Maoping
Published: May 2020

Long noncoding RNAs (lncRNAs) can participate in various biological behaviors, including regulating cell differentiation, proliferation, and apoptosis. The investigators have previously confirmed that highly conserved lncRNA NR_045363 controls cardiomyocyte (CM) proliferation and cardiac repair. The present study investigates the effects of NR_045363 on CM apoptosis. Seven‐day‐old mice were subjected to permanent left anterior descending coronary artery ligation (LAD), and the NR_045363 expression was analyzed by quantitative real‐time polymerase chain reaction (qRT‐PCR). The expression of NR_045363 in the MI group significantly exceeded the Sham group during the first week after the operation. The NR_045363 expression was knocked down in primary cultured CMs using an NR_045363‐targeting lncRNA Smart silencer, and the apoptosis of CMs was analyzed by terminal‐deoxynucleoitidyl transferase mediated nick end labeling and Annexin‐V/PI double staining. These present results indicate that the NR_045363 knockdown significantly promoted the apoptosis of CMs. In order to investigate the underlying mechanism, RNA‐sequencing (RNA‐seq) was performed, and ingenuity pathway analysis (IPA) was used to analyze the RNA‐seq results. The RNA‐seq data revealed that a total of 2,291 genes were upregulated or downregulated in NR_045363 knockdown CMs, and the IPA analysis indicated that tumor protein 53 (p53) was the upstream regulator. In vivo, the NR_045363 overexpression through the AAV9 system improved the heart function after MI in 7‐day‐old mice and inhibited the CM apoptosis. These data suggest that NR_045363 is involved in CM apoptosis and that NR_045363 overexpression exerts positive effects on cardiac repair by alleviating CM apoptosis through the inhibition of the p53 pathway.
Regulation of an Ambient‐Light‐Induced Photocyclization Pathway (Norrish–Yang Versus 6π) by Substituent Choice
Authors: Liu Hui , Gao Hu , Wang Sisi , Yao Shengxin , Wu Fan , Zhao Yue , Chan Kin Shing , Shen Zhen
Published: May 2020

Photocyclization, irrespective of whether multiple steps (e.g., Norrish–Yang cyclization) or a single concerted step (e.g., 6π photocyclization) are involved, is an intramolecular photochemical process resulting in the formation of one new single bond to afford a ring system. In particular, visible‐light‐induced photocyclization offers a green and sustainable route to organic cyclic compounds that are difficult to access by thermal reactions. Herein, we describe the ambient light‐induced intramolecular photocyclization of a series of donor/acceptor chromophores 1 d–3 d containing two types of photoresponsive motifs, namely an electron‐deficient BF2‐chelated ketone fused with an electron‐rich thiophene, and probe the solution‐phase and solid‐state photochromic performance of these compounds. The results reveal that simple variation of R substituents on the diaryl moiety allows one to control the intramolecular photocyclization mechanism with high photochemical selectivity, e.g., under ambient light, methyl‐substituted 1 d and 2 d undergo reversible 6π photocyclization, whereas ethyl‐substituted 3 d exclusively undergoes irreversible Norrish–Yang photocyclization. Single‐crystal X‐ray analysis of Norrish–Yang cyclization products reveals the formation of four pairs of conformational enantiomers differing in the dihedral angle between benzothiophene and the BF2 core, namely (±)N‐3 d@68°, (±)N‐3 d@‐77°, (±)N‐3 d@‐78°, and (±)N‐3 d@‐102°. The UV/Vis absorption spectra of 1 d–3 d cover a broad visible‐light region (380–572 nm), while DFT and TD‐DFT calculations reveal that absorption in this region is dominated by the charge‐transfer (CT) transition from the thiophene‐centered HOMO to the LUMO of the electron‐deficient π‐conjugated BF2‐chelated unit and the n→π* and π→π* transitions within the latter unit. The spatial separation of the HOMO and LUMO of these dyes promotes triplet‐state generation and self‐photosensitizes intramolecular photocyclization in the visible‐light region. Three‐dimensional time‐resolved and steady‐state emission spectra of 3 d show that the Norrish–Yang photocyclization takes place within milliseconds with excellent conversion efficiency (96 %).
Rhodium(I)‐NHC Complexes Bearing Bidentate Bis‐Heteroatomic Acidato Ligands as gem‐Selective Catalysts for Alkyne Dimerization
Authors: Galiana‐Cameo María , Borraz Marina , Zelenkova Yaroslava , Passarelli Vincenzo , Lahoz Fernando J. , Pérez‐Torrente Jesús J. , Oro Luis A. , Di Giuseppe Andrea , Castarlenas Ricardo
Published: May 2020

A series of Rh(κ2‐BHetA)(η2‐coe)(IPr) complexes bearing 1,3‐bis‐hetereoatomic acidato ligands (BHetA) including carboxylato (O,O), thioacetato (O,S), amidato (O,N), thioamidato (N,S), and amidinato (N,N), have been prepared by reaction of the dinuclear precursor [Rh(μ‐Cl)(IPr)(η2‐coe)]2 with the corresponding anionic BHetA species. The RhI‐NHC‐BHetA compounds catalyze the dimerization of aryl alkynes, showing excellent selectivity for the head‐to‐tail enynes. Among them, the acetanilidato‐based catalyst has shown an outstanding catalytic performance reaching unprecedented TOF levels of 2500 h−1 with complete selectivity for the gem‐isomer. Investigation of the reaction mechanism supports a non‐oxidative pathway in which the BHetA ligand behaves as proton shuttle through intermediate κ1‐HBHetA species. However, in the presence of pyridine as additive, the identification of the common RhIIIH(C≡CPh)2(IPr)(py)2 intermediate gives support for an alternative oxidative route.
Stabilizing DNAzymes through Encapsulation in a Metal–Organic Framework
Authors: Zhong Huiye , Lo Wei‐Shang , Man Tiantian , Williams Benjamin P. , Li Dan , Chen Sheng‐Yu , Pei Hao , Li Li , Tsung Chia‐Kuang
Published: May 2020

DNAzymes are a promising class of bioinspired catalyst; however, their structural instability limits their potential. Herein, a method to stabilize DNAzymes by encapsulating them in a metal–organic framework (MOF) host is reported. This biomimetic mineralization process makes DNAzymes active under a wider range of conditions. The concept is demonstrated by encapsulating hemin‐G‐quadruplex (Hemin‐G4) into zeolitic imidazolate framework‐90 (ZIF‐90), which indeed increases the DNAzyme's structural stability. The stabilized DNAzymes show activities in the presence of Exonuclease I, organic solvents, or high temperature. Owing to its elevated stability and heterogeneous nature, it is possible to perform catalysis under continuous‐flow conditions, and the DNAzyme can be reactivated in situ by introducing K+. Moreover, it is found that the encapsulated DNAzyme maintains its high enantiomer selectivity, demonstrated by the sulfoxidation of thioanisole to (S)‐methyl phenyl sulfoxide. This concept of stabilizing DNAzymes expands their potential application in chemical industry.
Synthesis of Tamoxifen‐Artemisinin and Estrogen‐Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer
Authors: Fröhlich Tony , Mai Christina , Bogautdinov Roman P. , Morozkina Svetlana N. , Shavva Alexander G. , Friedrich Oliver , Gilbert Daniel F. , Tsogoeva Svetlana B.
Published: May 2020

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC‐3) and breast cancer (MCF‐7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines – for example, EC50 (PC‐3) down to 1.07 μM, and EC50 (MCF‐7) down to 2.08 μM – thus showing higher activities than their parent compounds 4‐hydroxytamoxifen (afimoxifene, 7; EC50=75.1 (PC‐3) and 19.3 μM (MCF‐7)), dihydroartemisinin (2; EC50=263.6 (PC‐3) and 49.3 μM (MCF‐7)), and artesunic acid (3; EC50=195.1 (PC‐3) and 32.0 μM (MCF‐7)). The most potent compounds were the estrogen‐artemisinin hybrids 27 and 28 (EC50=1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC50=2.08 μM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.
Functional organization and connectivity of the dorsal column nuclei complex reveals a sensorimotor integration and distribution hub
Authors: Loutit Alastair J. , Vickery Richard M. , Potas Jason R.
Published: May 2020

The dorsal column nuclei complex (DCN‐complex) includes the dorsal column nuclei (DCN, referring to the gracile and cuneate nuclei collectively), external cuneate, X, and Z nuclei, and the median accessory nucleus. The DCN are organized by both somatotopy and modality, and have a diverse range of afferent inputs and projection targets. The functional organization and connectivity of the DCN implicate them in a variety of sensorimotor functions, beyond their commonly accepted role in processing and transmitting somatosensory information to the thalamus, yet this is largely underappreciated in the literature. To consolidate insights into their sensorimotor functions, this review examines the morphology, organization, and connectivity of the DCN and their associated nuclei. First, we briefly discuss the receptors, afferent fibers, and pathways involved in conveying tactile and proprioceptive information to the DCN. Next, we review the modality and somatotopic arrangements of the remaining constituents of the DCN‐complex. Finally, we examine and discuss the functional implications of the myriad of DCN‐complex projection targets throughout the diencephalon, midbrain, and hindbrain, in addition to their modulatory inputs from the cortex. The organization and connectivity of the DCN‐complex suggest that these nuclei should be considered a complex integration and distribution hub for sensorimotor information.
The effect of a single‐sided pole shoe and slot on reducing torque ripple in a switched reluctance motor
Authors: Ma Hongzhong , Huang Chaozhi , Liu Xiping , Shi Wangfeng , Liu Wei
Published: May 2020

The switched reluctance motor (SRM) has the high level of vibration and noise, whose application is greatly limited in many fields. In this article, a novel stator for a SRM is designed to reduce torque ripple and is suitable for one‐directional or low‐speed reverse rotation. On the one hand, a shoe is added to the stator pole side in the rotating forward direction from the completely unaligned to the aligned position. On the other hand, a slot is set on the top of stator tooth. First, causes of vibration and torque ripple are analyzed. Second, it is indicated by the equivalent magnetic circuit (EMC) method that the air gap permeability of the model with the single‐sided pole shoe is larger than that of the conventional model in the nonoverlapping region between the stator and rotor. The influences of the angle and height of shoe on the air gap magnetic density, radial force, and torque ripple are analyzed. Third, the results from EMC method show that the radial force can be reduced by opening a slot at the top of stator pole arc. The width and depth of slot which has effect on the radial force and torque ripple are analyzed. Finally, finite element analysis results show that the decreases of 34.52% for the radial force wave peak and 43.39% for the torque ripple are achieved at the cost of a decrease of 8.54% for the average torque of the single‐sided pole and the slot model of the stator pole compared with the conventional model. Some experiments for the two prototypes verify that the torque ripple and radial force can be reduced by adopting the new model.
Charge Transfer and Metastable Ion Dissociation of Multiply Charged Molecular Cations Observed by Using Reflectron Time‐of‐Flight Mass Spectrometry
Authors: Kitashoji Akihiro , Kitagawa Kosei , Fujihara Akimasa , Yatsuhashi Tomoyuki
Published: May 2020

The front cover artwork is provided by the group of Prof. Tomoyuki Yatsuhashi (Osaka City University) as well as Dr. Akimasa Fujihara (Osaka Prefecture University). The image shows that the potential energy of a product ion formed by metastable ion dissociation can be larger than that of a multiply charged precursor ion. Read the full text of the Article at 10.1002/cphc.202000021.
Detection of IgM and IgG antibodies in patients with coronavirus disease 2019
Authors: Hou Hongyan , Wang Ting , Zhang Bo , Luo Ying , Mao Lie , Wang Feng , Wu Shiji , Sun Ziyong
Published: May 2020

Objectives

This study aimed to determine the IgM and IgG responses against severe acute respiratory syndrome coronavirus (SARS‐CoV)‐2 in coronavirus disease 2019 (COVID‐19) patients with varying illness severities.

Methods

IgM and IgG antibody levels were assessed via chemiluminescence immunoassay in 338 COVID‐19 patients.

Results

IgM levels increased during the first week after SARS‐CoV‐2 infection, peaked 2 weeks and then reduced to near‐background levels in most patients. IgG was detectable after 1 week and was maintained at a high level for a long period. The positive rates of IgM and/or IgG antibody detections were not significantly different among the mild, severe and critical disease groups. Severe and critical cases had higher IgM levels than mild cases, whereas the IgG level in critical cases was lower than those in both mild and severe cases. This might be because of the high disease activity and/or a compromised immune response in critical cases. The IgM antibody levels were slightly higher in deceased patients than recovered patients, but IgG levels in these groups did not significantly differ. A longitudinal detection of antibodies revealed that IgM levels decreased rapidly in recovered patients, whereas in deceased cases, either IgM levels remained high or both IgM and IgG were undetectable during the disease course.

Conclusion

Quantitative detection of IgM and IgG antibodies against SARS‐CoV‐2 quantitatively has potential significance for evaluating the severity and prognosis of COVID‐19.
Utility of single‐item questions to assess physical inactivity in patients with chronic heart failure
Authors: Blomqvist Andreas , Bäck Maria , Klompstra Leonie , Strömberg Anna , Jaarsma Tiny
Published: May 2020

Aim

The purpose of this study was to explore the utility of two single‐item self‐report (SR) questions to assess physical inactivity in patients with heart failure (HF).

Methods and results

This is a cross‐sectional study using data from 106 patients with HF equipped with accelerometers for 1 week each. Two SR items relating to physical activity were also collected. Correlations between accelerometer activity counts and the SR items were analysed. Patients were classified as physically active or inactive on the basis of accelerometer counts, and the SR items were used to try to predict that classification. Finally, patients were classified as having high self‐reported physical activity or low self‐reported physical activity, on the basis of the SR items, and the resulting groups were analysed for differences in actual physical activity. There were significant but weak correlations between the SR items and accelerometer counts: ρ = 0.24, P = 0.016 for SR1 and ρ = 0.21, P = 0.033 for SR2. Using SR items to predict whether a patient was physically active or inactive produced an area under the curve of 0.62 for SR1, with a specificity of 92% and a sensitivity of 30%. When dividing patients into groups on the basis of SR1, there was a significant difference of 1583 steps per day, or 49% more steps in the high self‐reported physical activity group (P < 0.001).

Conclusions

There might be utility in the single SR question for high‐specificity screening of large populations to identify physically inactive patients in order to assign therapeutic interventions efficiently where resources are limited.
Synthesis, Structure, and Reactivity of Monoguanidinate Rare‐Earth Metal Aminobenzyl Enolate Complexes
Authors: Jiang Wen , Zhang Li‐Jun , Zhang Li‐Xin
Published: May 2020

Two monoguanidinate rare‐earth metal aminobenzyl enolate complexes LRE(CH2C6H4NMe2‐o)(OCH=CH2)(THF) (L = (PhCH2)2NC(NC6H3iPr2‐2,6)2; RE = Y (1a), Lu (1b)) were synthesized via two pathways of the ring‐opening of THF, and their reactivities with some molecules were also explored. Reaction of complex 1a with iPrNCNiPr gave the insertion product LY[(NiPr2)2CCH2C6H4NMe2‐o](OCH=CH2)(THF) (2). Whereas, in the case of PhNCS, LY[SC(CH2C6H4NMe2‐o)NPh](OCH=CH2)(THF) (3) and the ligands redistribution binuclear yttrium enolate complex [LY(µ‐OCH=CH2)(OCH=CH2)]2 (4) were obtained. The protonolysis products LY(NHPh)(OCH=CH2)(THF)2 (5), LY(NHPh)2(THF)2 (6) and LY(NPh2)(OCH=CH2)(THF)2 (7) were achieved by reaction of 1a with arylamine. Moreover, the THF ring‐opening insertion products with unique structures {LY[O(CH2)4PPh2][µ‐O(CH2)4PPh2]}2 (8) and {LY(SCH2C6H4NMe2‐o)[µ‐O(CH2)4SCH2C6H4NMe2‐o]}2 (9) were afforded through reactions of complex 1a with diphenylphosphine and elemental sulfur. It was the first example of THF activation promoted by rare‐earth metal thiolate complex. And some interesting chemical transformations were observed in our work. Complexes 1 could also serve as efficient initiators in the ring‐opening polymerization of rac‐lactide.
Synthesis and Characterization of the Hexafluoridomolybdates(V) A[MoF6] (A = Li – Cs)
Authors: Stene Riane E. , Scheibe Benjamin , Petry Winfried , Kraus Florian
Published: May 2020

Invited for the cover of this issue is the group of Florian Kraus from Philipps‐Universität Marburg, Germany. The cover image shows a typical fluorine chemist synthesizing lithium hexafluoridomolybdate(V), Li[MoF6].
Imidazolium Based Fluorous N‐Heterocyclic Carbenes as Effective and Recyclable Organocatalysts for Redox Esterification
Authors: Červenková Šťastná Lucie , Bílková Veronika , Cézová Tereza , Cuřínová Petra , Karban Jindřich , Čermák Jan , Krupková Alena , Strašák Tomáš
Published: May 2020

A series of new highly fluorophilic ionic liquids (f > 110) was synthetized from 3‐iodopropyltris(3,3,4,4,5,5,6,6,7,7,8,8,8‐tridecafluorooctyl)silane and N‐alkyl imidazoles, followed by anion exchange. N‐heterocyclic carbenes generated in situ from obtained imidazolium salts were employed to catalyze redox esterification (umpolung) of cinnamaldehyde with alcohols. The most effective N‐methyl derivative with iodide as a counter anion was studied in detail with respect to the optimization of reaction conditions, substrate scope and recyclability. Recovery of the precatalyst was achieved using either fluorous extraction or performing the reaction in suitable fluorous biphase system with direct recycling of the fluorinated precatalyst phase. For both tested options, the catalytic activity did not significantly decrease within 5 subsequent cycles. The redox esterification was shown to proceed also in supercritical carbon dioxide (scCO2) as an alternative solvent where the activity of the fluorinated catalyst was also superior to the nonfluorinated model, while retaining the benefit of easy recycling.
A Novel Class of 7‐Membered Heterocyclic Compounds
Authors: Bauer Adriano , Borsos Eszter , Maulide Nuno
Published: May 2020

The work presented herein describes the synthesis of a formerly inaccessible class of heterocyclic compounds. The reaction relies on α‐phthalimido‐amides, which are readily prepared from amino acids in 2 simple reactions steps. Under amide activation conditions in which classical keteniminium ions are not formed, the nitrile solvent is incorporated into the new fused 7‐membered ring system. Due to the absence of a keteniminium intermediate, the stereogenic information in the α‐position is fully retained.
Optimization of an IgG1 CIEF separation by using narrow‐range ampholytes and DMSO as protein solubilizer
Authors: Cruzado‐Park Ingrid D.
Published: May 2020

CIEF is a powerful separation tool utilized in the characterization and relative quantitation of therapeutic mAb charged isoforms. However, one CIEF method is not capable of separating all mAbs with high resolution and reproducibility. Optimization of sample composition and separation parameters is expected when developing a CIEF method for a specific mAb. This paper summarizes a root cause investigation into why a validated CIEF separation method for MAK33 (a type of IgG1) was no longer reproducible. In addition, this paper introduces the concept of sample focusing volume, which is defined as the actual capillary volume occupied by the sample after focusing and explains why there is less protein precipitation and aggregation when using narrow‐range ampholytes than broad‐range ampholytes. The use of DMSO as protein solubilizer and possible replacement of urea is also explored in this work. Finally, this paper demonstrates that a new optimized CIEF method can achieve over 100 reproducible high‐resolution separations of MAK33 per neutral‐coated capillary.
A review on the 40th anniversary of the first regulation of drinking water disinfection by‐products
Authors: DeMarini David M.
Published: May 2020

Water disinfection, primarily by chlorination, is one of the greatest achievements of public health. However, more than half a century after its introduction, studies in the 1970s reported that (a) chlorine interacted with organic matter in the water to form disinfection by‐products (DBPs); (b) two DBPs, chloroform and bromoform, both trihalomethanes (THMs), were rodent carcinogens; (c) three brominated THMs were mutagenic; in six studies chlorinated drinking waters in the United States and Canada were mutagenic; and (d) in one epidemiological study there was an association between bladder cancer mortality and THM exposure. This led the U.S. Environmental Protection Agency to issue its first DBP regulation in 1979. Forty years later, >600 DBPs have been characterized, 20/22 have been shown to be rodent carcinogens, >100 have been shown to be genotoxic, and 1000s of water samples have been found to be mutagenic. Data support a hypothesis that long‐term dermal/inhalation exposure to certain levels of the three brominated THMs, as well as oral exposure to the haloacetic acids, combined with a specific genotype may increase the risk for bladder cancer for a small but significant population group. Improved water‐treatment methods and stricter regulations have likely reduced such risks over the years, and further reductions in potential risk are anticipated with the application of advanced water‐treatment methods and wider application of drinking water regulations. This 40‐year research effort is a remarkable example of sustained cooperation between academic and government scientists, along with public/private water companies, to find answers to a pressing public health question.
Serum‐free suspension cultured human cells can produce a high‐level of recombinant human erythropoietin
Authors: Costa e Silva Luciano , dos Santos Matheus Henrique , Heluy Tarik Reis , Biaggio Rafael Tagé , Ferreira Alexander Rodrigo , Milhomens Jonathan , Kashima Simone , El Nemer Wassim , El Hoss Sara , Picanço‐Castro Virgínia , Covas Dimas Tadeu , Swiech Kamilla
Published: May 2020

Currently, the majority of commercial recombinant therapeutic proteins are produced in nonhuman expression systems. Human cells are capable of producing recombinant proteins with post‐translational modifications that are more similar to native proteins which reduce immunogenicity. This article describes the potential of the human cell lines Sk‐Hep‐1, HKB‐11, and Huh‐7, cultured in serum‐free suspension conditions, to produce a complex recombinant glycoprotein, human erythropoietin (EPO). Recombinant cell lines were generated by lentiviral transduction and sorted by flow cytometry. All the recombinant cells presented high‐specific cell growth rates and a high level of rhEPO production. Maximum rhEPO concentrations achieved by Sk‐Hep‐1, HKB‐11, and Huh‐7 cells were 112.5 μg/mL, 112.7 μg/mL, and 571 μg/mL, respectively. The levels of rhEPO production by Huh‐7 cells were higher than the levels commonly reported in the literature for serum‐free suspension cultures. The rhEPO produced demonstrated biological activity measured through in vitro differentiation of CD34+ cells. In view of this, we demonstrate that Sk‐Hep‐1, HKB‐11, and Huh‐7 cell lines have good characteristics to be used as host cells for the production of complex recombinant glycoproteins, with special emphasis on Huh‐7 due to enhanced EPO production.
Efficacy and safety of perampanel monotherapy in patients with focal‐onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open‐label Study 342 (FREEDOM Study)
Authors: Yamamoto Takamichi , Lim Sung Chul , Ninomiya Hirotomo , Kubota Yuichi , Shin Won Chul , Kim Dong Wook , Shin Dong Jin , Hoshida Tohru , Iida Koji , Ochiai Taku , Matsunaga Risa , Higashiyama Hiroyuki , Hiramatsu Hidetaka , Kim Ji Hyun
Published: May 2020

Objective

Our study assessed perampanel monotherapy in patients (aged ≥12 years) with focal‐onset seizures (FOS) with or without focal to bilateral tonic‐clonic seizures (FBTCS) in Japan and South Korea.

Methods

Study 342 (NCT03201900; FREEDOM) is a single‐arm, open‐label, Phase III study. Patients initially received perampanel in a 32‐week 4‐mg/d Treatment Phase (6‐week Titration; 26‐week Maintenance Periods). If they experienced a seizure during the 4‐mg/d Maintenance Period, they could be up‐titrated to 8 mg/d across an additional 30‐week Treatment Phase (4‐week Titration; 26‐week Maintenance Periods). Primary endpoint was the seizure‐freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment‐emergent adverse events (TEAEs) were monitored.

Results

At data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4‐mg/d Titration Period, meaning 73 patients entered the 4‐mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure‐freedom rate in the 26‐week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9‐74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4‐83.5) at 4 or 8 mg/d. Cumulative probability of seizure‐onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5‐43.0) and 23.7% (95% CI: 15.4‐35.3) at 4 mg/d, and 18.2% (95% CI: 11.0‐29.3) and 23.3% (95% CI: 15.2‐34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness.

Significance

Perampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.
A study on genotype–environment interaction based on GGE biplot graphical method in sunflower genotypes (Helianthus annuus L.)
Authors: Ansarifard Isa , Mostafavi Khodadad , Khosroshahli Mahmood , Reza Bihamta Mohammad , Ramshini Hosein
Published: May 2020

GGE biplot technique is one of the appropriate methods for investigating the genotype–environment interaction. An experiment was conducted to examine and evaluate the stability and adaptability of grain yield of 12 sunflower genotypes using the randomized complete block design (RCBD) with three replications in five regions including Karaj, Birjand, Firooz‐Abad, Kashmar, and Arak within two agricultural years. Analysis of variance indicated that the effect of location, year, location × year, genotype, and genotype × location was significant at 1% probability level. Results of biplot analysis showed that the first and second principle components accounted 50.6% and 22.8%, respectively, and in total 73.4% of grain yield variance. In this study, genotype, location, year, year × location, genotype × location, genotype × year, and genotype × year × location explained 2.75%, 17.36%, 5.47%, 17%, 10.8%, 1.04%, and 7.48% of total variance, respectively. Investigating the polygon view led to the identification of three top genotypes and also three mega‐environment. The first mega‐environment included Karaj, Birjand, and Kashmar. The second was Arak, and the third was Firooz‐Abad. To study the kernel yield and stability of genotypes simultaneously, average coordinate view of environments was used and it was determined that genotype Zaria with the highest grain yield has high yield stability also. Ranking the cultivars based on the ideal genotype introduced the genotype Zaria as the best genotype. The highest grain yield belonged to Zaria cultivar at 3.34 t/ha followed by Favorite with 3.23 t/ha. Results obtained from ranking the environments based on the ideal environment introduced Kashmar and Birjand regions as the best environments. Examining the biplot figure for testing environments correlation confirms the positive correlation among Karaj, Birjand, and Kashmar. Correlation between Karaj with Arak, Karaj with Firooz‐Abad, and Arak with Firooz‐Abad was negative. Arak and Firooz‐Abad were highly discriminating and representative and would be used to identification of superior genotypes.
Analysis of TP53 aflatoxin signature mutation in hepatocellular carcinomas from Guatemala: A cross‐sectional study (2016‐2017)
Authors: Alvarez Christian S. , Ortiz Jeremy , Bendfeldt‐Avila Giovanna , Xie Yi , Wang Mingyi , Wu Dongjing , Higson Herbert , Lee Elisa , Teshome Kedest , Barnoya Joaquin , Kleiner David E. , Groopman John D. , Orozco Roberto , McGlynn Katherine A. , Gharzouzi Eduardo , Dean Michael
Published: May 2020

Background and aims

Guatemala has the highest incidence of hepatocellular carcinoma (HCC) in the Western hemisphere. The major risk factors in Guatemala are not well characterized, but the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) appears to be low, while the prevalence of aflatoxin (AFB1) exposure appears to be high. To examine whether AFB1 may contribute to the elevated incidence of HCC in Guatemala, this study examined the frequency of the AFB1‐signature mutation in the TP53 gene (R249S) as well as other somatic mutations. In addition, we assessed whether the frequency of the TP53 mutation differed by sex.

Methods

Formalin‐fixed, paraffin‐embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City between 2016 and 2017. In addition, tumor tissues preserved in RNAlater were also obtained. Sociodemographic and clinical information including HBV and HCV status were collected. Targeted sequencing of TP53 was performed in the FFPE samples, and a panel of 253 cancer‐related genes was sequenced in the RNAlater samples.

Results

Ninety‐one FFPE tissues were examined, from 52 men and 39 women. Median (IQR) age at diagnosis was 62 (51‐70). Among those with known HBV and HCV status, two were HBV+ and three were HCV+. Overall, 47% of the HCCs had a TP53 mutation. The AFB1‐signature R249S mutation was present in 24%. No overlap between the R249S mutation and HBV+ was observed in this cohort. Among 18 RNAlater samples examined, 44% had any TP53 mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes.

Conclusions

The presence of the TP53 R249S mutation in the samples studied suggests that AFB1 may contribute to the high incidence of HCC in Guatemala. The proportion of HBV+ tumors was low, suggesting that AFB1 may be associated with HCC in the absence of concomitant HBV infection. Further investigation of AFB1 and other risk factors for HCC in Guatemala is warranted.
miR‐506‐3p alleviates uncontrolled osteoclastogenesis via repression of RANKL/NFATc1 signaling pathway
Authors: Dinesh Palani , Kalaiselvan Sowmiya , Sujitha Sali , Rasool Mahaboobkhan
Published: May 2020

Bone erosion is the major cause of deformities in autoimmune disease conditions such as osteoporosis and rheumatoid arthritis. Aberrant receptor activator of nuclear factor kappa B ligand (RANKL) secretion in bone disorders have been implicated to promote uncontrolled osteoclast differentiation through the regulation of nuclear factor of activated T cells 1 (NFATc1) transcription factor. This phenomenon is governed by several molecular factors including microRNAs, which are under‐expressed during disease progression. This report focuses on elucidating the molecular mechanism of miR‐506‐3p towards the RANKL/NFATc1 pathway. miR‐506‐3p showed high binding affinity towards NFATc1 (ΔG = −22.4 kcal/mol). Bone marrow‐derived macrophages (BMMs) isolated from rats stimulated with RANKL (100 ng/ml) showed active expression of NFATc1 which differentiated into mature osteoclasts. Moreover, NFATc1 activation resulted in downstream secretion of various bone resorptive enzymes (cathepsin K, carbonic anhydrase II, tartarate acid phosphatase, and matrix metalloproteinase 9) which lead to active bone resorption. However, transfection of miR‐506‐3p resulted in selective repression of NFATc1 inside the cells. This further resulted in the diminished release of bone resorptive enzymes that were essential for the degradation of the bone. Overall, we predict that miR‐506‐3p can be used as a molecular intervention for RANKL/NFATc1 mediated osteoclastogenesis.
Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis
Authors: Ghafouri‐Fard Soudeh , Esmaeili Mohammadhosein , Taheri Mohammad , Samsami Majid
Published: May 2020

Highly upregulated in liver cancer (HULC) was initially recognized during the screening of a hepatocellular carcinoma (HCC)‐specific gene library. Further studies demonstrated its aberrant upregulation in several other tumor types. The oncogenic roles of this long noncoding RNA (lncRNA) have been verified through expression studies as well as functional studies. Moreover, the results of knockdown experiments have indicated diminished carcinogenic effects of cancer cell line in nude mice following HULC silencing. More recent studies have shown that expression levels of this lncRNA might be used as diagnostic biomarkers in cancer patients. Moreover, mechanistical studies have revealed associations between HULC and two HCC‐related viruses namely hepatitis B and C viruses. Taken together, HULC can be regarded as a therapeutic target not only for HCC but also for a variety of human malignancies. In the current review, we summarized the recent literature about the role of HULC in the carcinogenesis and its potential application in cancer diagnosis and prognosis.
Impaired actin filaments decrease cisplatin sensitivity via dysfunction of volume‐sensitive Cl− channels in human epidermoid carcinoma cells
Authors: Shimizu Takahiro , Fujii Takuto , Ohtake Hironao , Tomii Toshie , Takahashi Ryuta , Kawashima Kentaro , Sakai Hideki
Published: May 2020

Cisplatin is a widely used platinum‐based anticancer drug in the chemotherapy of numerous human cancers. However, cancer cells acquire resistance to cisplatin. So far, functional loss of volume‐sensitive outwardly rectifying (VSOR) Cl− channels has been reported to contribute to cisplatin resistance of cancer cells. Here, we analyzed protein expression patterns of human epidermoid carcinoma KB cells and its cisplatin‐resistant KCP‐4 cells. Intriguingly, KB cells exhibited higher β‐actin expression and clearer actin filaments than KCP‐4 cells. The β‐actin knockdown in KB cells decreased VSOR Cl− currents and inhibited the regulatory volume decrease (RVD) process after cell swelling. Consistently, KB cells treated with cytochalasin D, which depolymerizes actin filaments, showed smaller VSOR Cl− currents and slower RVD. Cytochalasin D also inhibited cisplatin‐triggered apoptosis in KB cells. These results suggest that the disruption of actin filaments cause the dysfunction of VSOR Cl− channels, which elicits resistance to cisplatin in human epidermoid carcinoma cells.
Finding any given 2‐factor in sparse pseudorandom graphs efficiently
Authors: Han Jie , Kohayakawa Yoshiharu , Morris Patrick , Person Yury
Published: May 2020

Given an ‐vertex pseudorandom graph and an ‐vertex graph with maximum degree at most two, we wish to find a copy of in , that is, an embedding so that for all . Particular instances of this problem include finding a triangle‐factor and finding a Hamilton cycle in . Here, we provide a deterministic polynomial time algorithm that finds a given in any suitably pseudorandom graph . The pseudorandom graphs we consider are ‐bijumbled graphs of minimum degree which is a constant proportion of the average degree, that is, . A ‐bijumbled graph is characterised through the discrepancy property: for any two sets of vertices and . Our condition on bijumbledness is within a log factor from being tight and provides a positive answer to a recent question of Nenadov. We combine novel variants of the absorption‐reservoir method, a powerful tool from extremal graph theory and random graphs. Our approach builds on our previous work, incorporating the work of Nenadov, together with additional ideas and simplifications.
Effect of the CXCR4 antagonist plerixafor on endogenous neutrophil dynamics in the bone marrow, lung and spleen
Authors: Pillay Janesh , Tregay Nicola , Juzenaite Goda , Carlin Leo M. , Pirillo Chiara , Gaboriau David C. A. , Farahi Neda , Summers Charlotte , Lo Celso Cristina , Chilvers Edwin R. , Rankin Sara , De Filippo Katia
Published: May 2020

Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study, we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen, and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM-CSF-primed neutrophil entrapment or release in the lungs. Taken together, these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.
Binding of the placental growth factor to VEGF receptor type 1 modulates human T cell functions
Authors: Leplina Olga , Smetanenko Ekaterina , Tikhonova Marina , Batorov Egor , Tyrinova Tamara , Pasman Natalya , Ostanin Alexander , Chernykh Elena
Published: May 2020

The immunosuppressive properties of vascular endothelial growth factors (VEGFs) suggest a new role of angiogenic factors in T cell modulation in cancer and pregnancy. Most of VEGF effects on T cells are mediated through the VEGF receptor type 2 (VEGFR-2). This study aims to investigate the role of placental growth factor (PlGF) as a selective VEGFR-1 ligand in the modulation of human T cells functions. For this, PBMCs from healthy donors were stimulated with anti-CD3 mAbs (a-CD3) or Concanavalin A (ConA) in the absence or presence of PlGF and assessed for T cell proliferation, IL-10 production, programmed cell death, and the expression of inhibitory receptors (PD-1, CTLA-4, TIM-3) using radiometric (3H-thymidine incorporation) and FACS analysis. We showed that most T cells in freshly isolated PBMCs lacked VEGFR-1. However, activation with a-CD3 or ConA strongly increased the percentages of VEGFR-1 expressing CD4+ and CD8+ T cells. PlGF in a wide dose range suppressed PBMC cell proliferation, inhibiting both CD4+ and CD8+ T cells. Blockade of VEGFR-1, but not VEGFR-2 with neutralizing Abs completely abolished the suppressive effect of PlGF. Furthermore, we found that treatment with PlGF up-regulated IL-10 production in CD4+ and CD8+ T cells, promoted CD8+ T cells apoptosis and enhanced the expression of inhibitory receptors (PD-1 and TIM-3) on activated T cells. Our in vitro findings suggest the involvement of PlGF/VEGFR-1 signaling in the modulation of T cell responses in a-CD3-stimulated PBMCs.