bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of BAX and caspase‐3, as well as downregulation of Bcl‐2 during treatment with indeno[1,2‐b]quinoxalin derivatives, mediated apoptosis in human cancer cells
Authors: Fayed Eman A. , Gohar Nirvana A. , Farrag Amel M. , Ammar Yousry A. 
Published: February 2022

AbstractCancer is the world's foremost cause of death. There are over 100 different forms of cancer. Cancers are frequently named after the organs or tissues in which they develop. As a part of our aim to develop promising anticancer agents, a series of new indeno[1,2‐b]quinoxaline derivatives were synthesized. All of the synthesized compounds were tested for anticancer activity in vitro in three human cancer cell lines: the HCT‐116 colon cancer cell line, the HepG‐2 liver cancer cell line, and the MCF‐7 breast cancer cell line. Among the tested derivatives, 2, 3, 5, 12, 21, and 22 showed exceptional antiproliferative activities against the three tested cell lines compared to the reference standard imatinib. These compounds were, therefore, selected for further investigations. Evaluation of their cytotoxicity against a normal human cell line (WI‐38) was performed, to ensure their safety and selectivity (IC50 > 92 μM). Then, induction of apoptosis by the most active compounds was found to be accomplished by downregulation of Bcl‐2 and upregulation of BAX and caspase‐3. After that, the most promising apoptotic compound that increases the caspase‐3 and BAX expression and downregulates Bcl‐2 activity (3) was assessed for its impact on the cell cycle distribution in HepG‐2 cells: The most potent derivative (3) induced cell cycle arrest at the G2/M phase. Finally, in silico evaluation of the ADME properties indicated that compound 3 is orally bioavailable and can be readily synthesized on a large scale.
C5‐Iminosugar modification of casein kinase 1δ lead 3‐(4‐fluorophenyl)‐5‐isopropyl‐4‐(pyridin‐4‐yl)isoxazole promotes enhanced inhibitor affinity and selectivity
Authors: von Drathen Thorsten , Ure Elizabeth M. , Kirschner Stefan , Roth Aileen , Meier Laura , Woolhouse Anthony D. , Cameron Scott A. , Knippschild Uwe , Peifer Christian , Luxenburger Andreas 
Published: February 2022

AbstractThe quest for isoform‐selective and specific ATP‐competitive protein kinase inhibitors is of great interest, as inhibitors with these qualities will come with reduced toxicity and improved efficacy. However, creating such inhibitors is very challenging due to the high molecular similarity of kinases ATP active sites. To achieve selectivity for our casein kinase (CK) 1 inhibitor series, we elected to endow our previous CK1δ‐hit, 3‐(4‐fluorophenyl)‐5‐isopropyl‐4‐(pyridin‐4‐yl)isoxazole (1), with chiral iminosugar scaffolds. These scaffolds were attached to C5 of the isoxazole ring, a position deemed favorable to facilitate binding interactions with the ribose pocket/solvent‐open area of the ATP binding pocket of CK1δ. Here, we describe the synthesis of analogs of 1 ((−)‐/(+)‐34, (−)‐/(+)‐48), which were prepared in 13 steps from enantiomerically pure ethyl (3R,4S)‐ and ethyl (3S,4R)‐1‐benzyl‐4‐[(tert‐butyldimethylsilyl)oxy]‐5‐oxopyrrolidine‐3‐carboxylate ((–)‐11 and (+)‐11), respectively. The synthesis involved the coupling of Weinreb amide‐activated chiral pyrrolidine scaffolds with 4‐ and 2‐fluoro‐4‐picoline and reaction of the resulting 4‐picolyl ketone intermediates ((–)‐/(+)‐40 and (–)‐/(+)‐44) with 4‐fluoro‐N‐hydroxybenzenecarboximidoyl chloride to form the desired isoxazole ring. The activity of the compounds against human CK1δ, ‐ε, and ‐α was assessed in recently optimized in vitro assays. Compound (–)‐34 was the most active compound with IC50 values (CK1δ/ε) of 1/8 µM and displayed enhanced selectivity toward CK1δ.
Endothelial Cell–Activating Antibodies in COVID‐19
Authors: Shi Hui , Zuo Yu , Navaz Sherwin , Harbaugh Alyssa , Hoy Claire K. , Gandhi Alex A. , Sule Gautam , Yalavarthi Srilakshmi , Gockman Kelsey , Madison Jacqueline A. , Wang Jintao , Zuo Melanie , Shi Yue , Maile Michael D. , Knight Jason S. , Kanthi Yogendra 
Published: February 2022

ObjectiveWhile endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID‐19, the upstream mediators of endotheliopathy remain, for the most part, unknown. This study was undertaken to identify circulating factors contributing to endothelial cell activation and dysfunction in COVID‐19.MethodsHuman endothelial cells were cultured in the presence of serum or plasma from 244 patients hospitalized with COVID‐19 and plasma from 100 patients with non–COVID‐19–related sepsis. Cell adhesion molecules (E‐selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 [ICAM‐1]) were quantified using in‐cell enzyme‐linked immunosorbent assay.ResultsSerum and plasma from COVID‐19 patients increased surface expression of cell adhesion molecules. Furthermore, levels of soluble ICAM‐1 and E‐selectin were elevated in patient serum and correlated with disease severity. The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID‐19 serum to activate endothelium. Depletion of total IgG from antiphospholipid antibody–positive serum markedly reduced the up‐regulation of cell adhesion molecules. Conversely, supplementation of control serum with patient IgG was sufficient to trigger endothelial activation.ConclusionThese data are the first to indicate that some COVID‐19 patients have potentially diverse antibodies that drive endotheliopathy, providing important context regarding thromboinflammatory effects of autoantibodies in severe COVID‐19.
Introducing immunohistochemistry to the molecular biology laboratory
Authors: Chen Audrey , Tarapore Eric , To Allisen G. , Catolico Davis M. , Nguyen Kelly C. , Coleman Melissa J. , Spence Rory D. 
Published: February 2022

AbstractWidely used in research laboratories, immunohistochemistry (IHC) is a transferable skill that prepares undergraduate students for a variety of careers in the biomedical field. We have developed an inquiry‐based learning IHC laboratory exercise, which introduces students to the theory, procedure, and data interpretation of antibody staining. Students are tasked with performing IHC using an “unknown” antibody and then asked to identify the cells or molecular structures within the nervous systems specific for that unknown antibody. In two lab sessions, students are exposed to handling of delicate brain slices, fluorescent microscopy, and data analysis using the Allen Brain Atlas (ABA), an online freely accessible database of mRNA transcript expression patterns in the brain. Here, we present guidelines for easy implementation in the classroom and assess learning gains achieved by the students upon completion of the IHC laboratory module. Students clearly displayed an increase in knowledge in data interpretation, procedural knowledge, and theory surrounding IHC. Thus, this module works as an inquiry‐based learning based method to introduce IHC principles to undergraduate students.
Clinical significance and outcomes of bilateral and unilateral recurrent laryngeal nerve lymph node dissection in esophageal squamous cell carcinoma: A large‐scale retrospective cohort study
Authors: Zhang Shuishen , Liu Qianwen , Li Bin , Jia Minghan , Cai Xiaoli , Yang Weixiong , Liao Shufen , Wu Zhongkai , Cheng Chao , Fu Jianhua 
Published: February 2022

AbstractBackgroundThe survival benefits of recurrent laryngeal nerve lymph node dissection (RLNLD) in esophageal squamous cell carcinoma (ESCC) are still under debate, and the prognostic value of unilateral RLNLD has been rarely studied. Therefore, the aim of the present study was to investigate the clinical significance and outcomes of RLNLD in ESCC in a large‐scale cohort study, to shed light on the outcomes of unilateral RLNLD, and to identify the factors that affect the prognostic outcome of RLNLD.MethodsWe retrospectively reviewed 1153 patients with thoracic ESCC who underwent right thoracotomy with lymphadenectomy. The impact of RLNLD on disease‐free survival (DFS) and overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline variables in pairwise comparisons. Subgroup analysis of survival and postoperative complications was conducted for selective RLNLD.ResultsRLN lymph node (LN) metastasis was independently associated with tumor location and most other LN station metastases. RLNLD was an independent prognostic factor for DFS and OS. Both patients who underwent unilateral and bilateral RLNLD had significantly better DFS and OS than the non‐RLNLD patients. Furthermore, pairwise comparisons with IPTW confirmed these results, and we found that patients who underwent bilateral RLNLD had better survival than those who underwent unilateral RLNLD. However, subgroup analysis showed that there was no survival benefit and higher morbidity after bilateral RLNLD for patients with cancer in the lower thoracic esophagus, and elderly and female patients.ConclusionRLN LN metastasis is very frequent in ESCC, and both unilateral and bilateral RLNLD have considerable survival benefits. Selective RLNLD with better survival and lower morbidity was recommend for some defined subgroups.
Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition
Authors: Kamihara Junne , Zhou Jing , LaDuca Holly , Wassner Ari J. , Dalton Emily , Garber Judy E. , Black Mary Helen 
Published: February 2022

AbstractPurposeMultigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined.MethodsClinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants (“pathogenic variants”) were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk.ResultsOf 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone.ConclusionsA high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under‐recognized component of cancer predisposition syndromes.
Hepatocellular carcinoma after a sustained virological response by direct‐acting antivirals harborsTP53inactivation
Authors: Imamura Taisuke , Okamura Yukiyasu , Ohshima Keiichi , Uesaka Katsuhiko , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ohgi Katsuhisa , Otsuka Shimpei , Ohnami Sumiko , Nagashima Takeshi , Hatakeyama Keiichi , Kakuda Yuko , Sugino Takashi , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken 
Published: February 2022

AbstractIntroductionThe genomic characteristics of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) and its differences according to whether an SVR was achieved by treatment with direct‐acting antivirals (DAA) or interferon (IFN) are still not fully understood.MethodsSixty‐nine surgically resected HCCs from patients with hepatitis C virus infection were analyzed by gene expression profiling and whole‐exome sequencing.ResultsAmong the 69 HCC patients, 34 HCCs in which an SVR was not achieved at the time of surgery were classified as HCV‐positive, and 35 HCCs in which an SVR was achieved at the time of surgery were classified as HCV‐SVR. According to the HCV treatment, 35 HCV‐SVR HCCs were classified into two groups: eight tumors with DAA (HCV‐SVR‐DAA) and 24 tumors with interferon (HCV‐SVR‐IFN). The frequency of samples withARID2mutations was significantly lower in HCV‐SVR than in HCV‐positive tumors (p = 0.048). In contrast, the frequency of samples withPREX2mutations was significantly higher in HCV‐SVR samples than in HCV‐positive samples (p = 0.048). Among the patients with HCV‐SVR, the frequency of samples withTP53mutations was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors (p = 0.030).TP53inactivation scores in HCV‐SVR‐DAA tumors were found to be significantly enhanced in comparison to HCV‐SVR‐IFN tumors (p = 0.022). In addition, chromosomal instability and PI3K/AKT/mTOR pathway signatures were enhanced in HCV‐SVR‐DAA tumors. HCV‐SVR‐DAA was significantly associated with portal vein invasion (p = 0.003) in comparison to HCV‐SVR‐IFN.ConclusionOur dataset potentially serves as a fundamental resource for the genomic characteristics of HCV‐SVR‐DAA tumors. Our comprehensive genetic profiling by WES revealed significant differences in the mutation rate of several driver genes between HCV‐positive tumors and HCV‐SVR tumors. Furthermore, it was revealed that the frequency of samples with mutations inTP53was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors.
Mixed hemangioma of the external auditory canal and the tympanic membrane in a young woman: A case report
Authors: Lygeros Spyridon , Athanasopoulos Michael , Daniilidi Alexandra , Danielides Gerasimos , Grigoriadis Kyriakos D. , Danielides Vasileios 
Published: February 2022

AbstractHemangiomas are benign vascular tumors frequently located in the head and neck area, but rarely encountered in the ear, often originally misdiagnosed due to their rarity and absence of specific clinical manifestations. We report the second case of a mixed hemangioma involving the external auditory canal in literature to date.
Awake tracheal intubation: Videolaryngoscopy in a pediatric institution: Use of guidelines and multidisciplinary team preparation to facilitate performance of an unfamiliar technique in a pediatric setting
Authors: Skelly James Richard , Wauchope Jessica , Collreavey Michael , Walsh Bill 
Published: February 2022

AbstractFormal guidelines for awake tracheal intubation have recently been published providing a streamlined process for the first time. We present a case of awake videolaryngoscopy in the pediatric setting, not previously reported. Application of guidelines and careful team preparation facilitated performance of a novel technique in our pediatric institution. A multidisciplinary approach with ENT colleagues provided a patient‐specific airway management plan for a rare airway pathology.
Maternal mirror syndrome with foetal hydrops due to isoimunization by anti‐KPa antibodies: A case report and narrative literature review
Authors: Pina Moreno Juan , Ortega Abad Virginia , Perez Corral Ana , Garcia‐Tizon Larroca Santiago 
Published: February 2022

AbstractWe present a rare case of mirror syndrome due to anti‐Kpa antibodies, which can be difficult to identify with routine screening tests.
Collaboration of perioperative management in an adult patient with 22 q 11.2 deletion syndrome: A case report
Authors: Ito Mikiko , Tokura Tatsuya , Miyauchi Tomoya , Sato (Boku) Aiji , Kimura Hiroyuki , Tsuchihashi Hayami , Katayama Yoshiko 
Published: February 2022

AbstractA 24‐year‐old woman diagnosed with 22 q 11.2 deletion syndrome was referred for multiple extractions. Due to the syndrome, the patient had schizophrenia, cardiac anomalies, and maxillofacial complications. This case report suggested that a multidisciplinary team approach is important for perioperative management of patients with 22 q 11.2 deletion syndrome.
Cinchona Alkaloid‐Derived Zwitterions Catalyzed Enantioselective Steglich Rearrangement and Aldol Reaction of O‐Acylated Oxindoles
Authors: Lam Ying‐Pong , Huang Jingxian , Jiang Xiaojian , Yeung Ying‐Yeung 
Published: February 2022

AbstractA class of cinchona alkaloid‐derived zwitterions has been successfully applied to achieve highly enantioselective Steglich rearrangement. A series of O‐acylated oxindoles afforded C‐acylated oxindoles possessing a quaternary stereocenter. These products were obtained in high yields and with excellent enantioselectivity. The same catalytic protocol was also found to be applicable in the asymmetric aldol reaction of oxindoles. Studies were conducted to elucidate a clearer mechanism. These findings will advance the development of new reaction protocols that exploit cinchona alkaloid‐derived zwitterions as asymmetric nucleophilic catalysts.
Electrolyte Modification for Long‐Life Zn Ion Batteries: Achieved by Methanol Additive
Authors: Lin Xian‐Sen , Wang Zi‐Rui , Ge Lin‐Heng , Xu Jun‐Wei , Ma Wen‐Qing , Ren Man‐Man , Liu Wei‐Liang , Yao Jin‐Shui , Zhang Chang‐Bin 
Published: February 2022

AbstractAlthough zinc‐ion batteries are regarded as important alternatives for Li‐ion batteries, the dendrite issues and side reactions are major obstacles for their development. Here, inspired by the idea of electrolyte modification, a simple and low‐cost approach, that methanol is used as additive into Zn2+‐containing electrolyte for long‐life Zn ion batteries, was developed. Methanol can mix with water in any ratio through the formation of hydrogen bonds, which participates in the solvation shell of Zn2+ion in a manner of forming the [Zn(OH2)x(CH3OH)y]2+cations. The interaction between Zn2+, methanol and water can effectively suppress the side reactions. As a result, Zn/Zn symmetric cell shows a long‐term stability for over 480 h at 1 mA cm−2with 1 mAh cm−2. In addition, full battery based on the MnO2cathode exhibits an improved capacity retention after 100 cycles at 0.1 A g−1and an excellent electrochemical performance at low temperature.
Characterization of Asx Turn Types and Their Connate Relationship with β‐Turns
Authors: D'mello Viola C. , Goldsztejn Gildas , Rao Mundlapati Venkateswara , Brenner Valérie , Gloaguen Eric , Charnay‐Pouget Florence , Aitken David J. , Mons Michel 
Published: February 2022

AbstractModels of asparagine‐containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn‐Ala and Asn‐Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H‐bond that was very similar to a type II’ β‐turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence‐dependent behavior. In Asn‐Ala sequences, the Asx turn was found in conjunction with a type I β‐turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II’ (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone β‐turn. In contrast, the Asx turns observed in Asn‐Gly sequences extensively adopted a type II Asx‐turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn‐Gly sequence is also often found in combination with a hydrated β‐bulge supports the premise that a Asn‐Gly sequence might efficiently promote the formation of the β‐bulge secondary structure.
Skeletal Transformation Triggered by C−F Bond Activation after Photochemical Rearrangement of Fluorinated [7]Helicenes
Authors: Matsuda Chikako , Igarashi Ryo , Katagiri Hiroshi , Murase Takashi 
Published: February 2022

AbstractTri‐ and tetra‐fluorinated [7]helicenes are photolabile and undergo a double fluorine atom transfer. Herein, we show that the transferred product further undergoes a skeletal transformation on silica gel. The transformation begins with activation of the allylic C−F bond on the silanol surface. Then, the resulting carbocation readily undergoes a regioselective nucleophilic aromatic substitution with water, depending on the position of the fluorine substituents. Hexafluoro‐2‐propanol also activated the allylic C−F bond and acted as a nucleophile. These findings support the generation of a highly reactive cationic electrophilic intermediate in the successive transformations involving fluorine atoms.
Intra‐ and extra‐cranial BCOR‐ITD tumours are separate entities within the BCOR‐rearranged family
Authors: Bouchoucha Yassine , Tauziède‐Espariat Arnault , Gauthier Arnaud , Guillemot Delphine , Bochaton Dorian , Vibert Julien , Carton Matthieu , Watson Sarah , Grossetête Sandrine , Quignot Chloé , Orbach Daniel , Corradini Nadège , Schleiermacher Gudrun , Bourdeaut Franck , Simbozel Marie , Dufour Christelle , Minard‐Colin Véronique , Brahmi Mehdi , Tirode Franck , Pissaloux Daniel , Karanian Marie , Machet Marie‐Christine , Masliah‐Planchon Julien , Delattre Olivier , Cardoen Liesbeth , Pierron Gaëlle , Doz François 
Published: February 2022

AbstractBCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin.