bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS‐G12D mutation drives immune suppression and the primary resistance of anti‐PD‐1/PD‐L1 immunotherapy in non‐small cell lung cancer
Authors: Liu Chengming , Zheng Sufei , Wang Zhanyu , Wang Sihui , Wang Xinfeng , Yang Lu , Xu Haiyan , Cao Zheng , Feng Xiaoli , Xue Qi , Wang Yan , Sun Nan , He Jie 
Published: July 2022

AbstractBackgroundAlthough immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.MethodsThe association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS‐mutant NSCLC, such as CD8+ tumor‐infiltrating lymphocytes (TILs) and PD‐L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs.ResultsWe observed the inferior efficacy of ICIs in KRAS‐G12D‐mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS‐mutant NSCLC, KRAS‐G12D point mutation negatively correlated with PD‐L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS‐G12D mutation suppressed PD‐L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down‐regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD‐L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD‐L1 inhibitor monotherapy in a mouse model with KRAS‐G12D‐mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up‐regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo‐immunotherapy in patients with KRAS‐G12D‐mutant NSCLC compared with ICI monotherapy.ConclusionsOur study elucidated the molecular mechanism by which KRAS‐G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS‐G12D‐mutant NSCLC.
Peroxidase Activity of Myoglobin Variants Reconstituted with Artificial Cofactors
Authors: Guo Chao , Chadwick Robert J. , Foulis Adam , Bedendi Giada , Lubskyy Andriy , Rodriguez Kyle J. , Pellizzoni Michela M. , Milton Ross D. , Beveridge Rebecca , Bruns Nico 
Published: July 2022

AbstractMyoglobin (Mb) can react with hydrogen peroxide (H2O2) to form a highly active intermediate compound and catalyse oxidation reactions. To enhance this activity, known as pseudo‐peroxidase activity, previous studies have focused on the modification of key amino acid residues of Mb or the heme cofactor. In this work, the Mb scaffold (apo‐Mb) was systematically reconstituted with a set of cofactors based on six metal ions and two ligands. These Mb variants were fully characterised by UV‐Vis spectroscopy, circular dichroism (CD) spectroscopy, inductively coupled plasma mass spectrometry (ICP‐MS) and native mass spectrometry (nMS). The steady‐state kinetics of guaiacol oxidation and 2,4,6‐trichlorophenol (TCP) dehalogenation catalysed by Mb variants were determined. Mb variants with iron chlorin e6 (Fe−Ce6) and manganese chlorin e6 (Mn−Ce6) cofactors were found to have improved catalytic efficiency for both guaiacol and TCP substrates in comparison with wild‐type Mb, i. e. Fe‐protoporphyrin IX‐Mb. Furthermore, the selected cofactors were incorporated into the scaffold of a Mb mutant, swMb H64D. Enhanced peroxidase activity for both substrates were found via the reconstitution of Fe−Ce6 into the mutant scaffold.
Effects of long‐term exposure to MST‐312 on lung cancer cells tumorigenesis: Role of SHH/GLI‐1 axis
Authors: Villarinho Nicolas Jones , Vasconcelos Flavia da Cunha , Mazzoccoli Luciano , da Silva Robaina Marcela Cristina , Pessoa Luciana Santos , Siqueira Pablo Enrique Torres , Maia Raquel Ciuvalschi , de Oliveira Diego Madureira , Leite de Sampaio e Spohr Tania Cristina , Lopes Giselle Faria 
Published: July 2022

AbstractReplicative immortality is a key feature of cancer cells and it is maintained by the expression of telomerase, a promising target of novel therapies. Long‐term telomerase inhibition can induce resistance, but the mechanisms underlying this process remain unclear. The Sonic hedgehog pathway (SHH) is an embryogenic pathway involved in tumorigenesis and modulates the transcription of telomerase. We evaluated the effects of long‐term treatment of the telomerase inhibitor MST‐312 in morphology, proliferation, resistance, and in the SHH pathway molecules expression levels in lung cancer cells. Cells treated for 12 weeks with MST‐312 showed changes in morphology, such as spindle‐shaped cells, and a shift in the distribution of F‐ACTIN from cortical to diffuse. Treatment also significantly reduced cells' efficiency to form spheroids and their clonogenic potential, independently of the cell cycle and telomeric DNA content. Moreover, GLI‐1 expression levels were significantly reduced after 12 weeks of MST‐312 treatment, indicating a possible inhibition of this signaling axis in the SHH pathway, without hindering NANOG and OCT4 expression. Here, we described a novel implication of long‐term treatment with MST‐312 functionally and molecularly, shedding new light on the molecular mechanisms of this drug in vitro.
A comprehensive review of chemokine CXC17 (VCC1) in cancer, infection, and inflammation
Authors: Gowhari Shabgah Arezoo , Jadidi‐Niaragh Farhad , Ebrahimzadeh Farnoosh , Mohammadi Hamed , Askari Elham , Pahlavani Naseh , Malekahmadi Mahsa , Ebrahimi Nik Maryam , Gholizadeh Navashenaq Jamshid 
Published: July 2022

AbstractA crucial component of the immune system are chemokiness. Chemokine's dysregulation has been linked to a number of pathological diseases. Recently, CXCL17, a chemokine belonging to the CXC subfamily, was identified. With regard to a number of physiological conditions and disorders, CXCL17 either has homeostatic or pathogenic effects. Some research suggests that CXCL17 is an orphan ligand, despite the fact that G protein‐coupled receptor (GPR) 35 has been suggested as a possible receptor for CXCL17. Since CXCL17 is primarily secreted by mucosal epithelia, such as those in the digestive and respiratory tracts, under physiological circumstances, this chemokine is referred to as a mucosal chemokine. Macrophages and monocytes are the cells that express GPR35 and hence react to CXCL17. In homeostatic conditions, this chemokine has anti‐inflammatory, antibacterial, and chemotactic properties. CXCL17 promotes angiogenesis, metastasis, and cell proliferation in pathologic circumstances like malignancies. However, other studies suggest that CXCL17 may have anti‐tumor properties. Additionally, studies have shown that CXCL17 may have a role in conditions such as idiopathic pulmonary fibrosis, multiple sclerosis, asthma, and systemic sclerosis. Additionally, deregulation of CXCL17 in some diseases may serve as a biomarker for diagnosis and prognosis. Clarifying the underlying mechanism of CXCL17's activity in homeostatic and pathological situations may thus increase our understanding of its role and hold promise for the development of novel treatment strategies.
Case of multiple furuncular myiasis in Northeast Ethiopia
Authors: Dires Abebe , Kebede Assen , Gedamu Sisay , Dires Tadila 
Published: July 2022

AbstractHuman myiasis is a neglected disease caused by parasitic infestation of the skin, cavities, and other body parts by larvae (maggots) of a wide variety of dipteran flies. Here, we present a case of multiple furuncular myiasis caused by Cordylobia anthropophaga in a 61‐year‐old woman from Northeast Ethiopia.
Co‐infection of Klebsiella pneumonia, Cytomegalovirus, Aspergillus and Zygomycete in a patient with SARS‐CoV‐2
Authors: Pourabdollah Toutkaboni Mihan , Hakamifard Atousa , Abtahian Zahra , Mirahmadian Arefeh , Rahdar Mohammad , Mokhber Dezfuli Mojtaba , Tabarsi Payam 
Published: July 2022

AbstractCo‐infection between severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and other pathogens has become a serious threat. There are the reports of fungal, bacterial, and viral co‐infections with SARS‐CoV‐2. We report the unusual case of concomitant aspergillosis, mucormycosis, cytomegalovirus pneumonia, and also klebsiella pneumoniae empyema as the complication of SARS‐CoV‐2.
Hydrocarbon Soluble Alkali‐Metal‐Aluminium Hydride Surrog[ATES]
Authors: Banerjee Sumanta , Macdonald Peter A. , Orr Samantha A. , Kennedy Alan R. , van Teijlingen Alexander , Robertson Stuart D. , Tuttle Tell , Mulvey Robert E. 
Published: July 2022

AbstractA series of group 1 hydrocarbon‐soluble donor free aluminates [AM(tBuDHP)(TMP)Al(iBu)2] (AM=Li, Na, K, Rb) have been synthesised by combining an alkali metal dihydropyridyl unit [(2‐tBuC5H5N)AM)] containing a surrogate hydride (sp3C−H) with [(iBu)2Al(TMP)]. These aluminates have been characterised by X‐ray crystallography and NMR spectroscopy. While the lithium aluminate forms a monomer, the heavier alkali metal aluminates exist as polymeric chains propagated by non‐covalent interactions between the alkali metal cations and the alkyldihydropyridyl units. Solvates [(THF)Li(tBuDHP)(TMP)Al(iBu)2] and [(TMEDA)Na(tBuDHP)(TMP)Al(iBu)2] have also been crystallographically characterised. Theoretical calculations show how the dispersion forces tend to increase on moving from Li to Rb, as opposed to the electrostatic forces of stabilization, which are orders of magnitude more significant. Having unique structural features, these bimetallic compounds can be considered as starting points for exploring unique reactivity trends as alkali‐metal‐aluminium hydride surrog[ATES].
Meso‐Carbon Atom Nucleophilic Attack Susceptibility in the Sterically Strained Antiaromatic Bis‐BODIPY Macrocycle and Extended Electron‐Deficient BODIPY Precursor**
Authors: Zatsikha Yuriy V. , Schrage Briana R. , Blesener Tanner S. , Harrison Laurel A. , Ziegler Christopher J. , Nemykin Victor N. 
Published: July 2022

AbstractA sterically strained 32π‐electron antiaromatic bis‐BODIPY macrocycle in which two BODIPY fragments are linked by p‐divinylbenzene groups was prepared and characterized. Unlike regular BODIPYs, the fluorescence in this macrocycle is quenched. The broad signals in the NMR spectra of the macrocycle were explained by the vibronic freedom of the p‐divinylbenzene fragments. The possible diradicaloid nature of the macrocycle was excluded on the basis of variable‐temperature EPR spectra in solution and in solid state, which is indicative of its closed‐shell quinoidal structure. The meso‐C−H bond in the macrocycle and its precursor BODIPY dialdehyde 3 forms a weak hydrogen bond with THF and is susceptible for the nucleophilic attack by organic amines and cyanide anion. The reaction products of such a nucleophilic attack have meso‐sp3 carbon atoms and were characterized by NMR, mass spectrometry and, in one case, X‐ray crystallography. Unlike the initial bis‐BODIPY macrocycle, the adducts have strong fluorescence in the 400 nm region. The electronic structure and spectroscopic properties of new chromophores were probed by density functional theory (DFT) and time‐dependent DFT (TDDFT) calculations and correlate well with the experimental data.
Development of an Enantioselective Allylic Alkylation of Acyclic α‐Fluoro‐β‐ketoesters for Asymmetric Synthesis of 3‐Fluoropiperidines
Authors: Han Jiaxin , Hoteite Larry , Harrity Joseph P. A. 
Published: July 2022

AbstractThe first useful enantioselective Pd‐catalyzed asymmetric allylic alkylation of α‐fluoro‐β‐ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α‐fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3‐fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.
Cost‐Effective 2D Ultrathin Metal‐Organic Layers with Bis‐Metallic Catalytic Sites for Visible Light‐Driven Photocatalytic CO2 Reduction
Authors: Wang Wei‐Jia , Zhang Yong‐Kang , Wu An‐Guo , He Liang‐Nian 
Published: July 2022

AbstractAs novel generated 2D materials, metal‐organic layers (MOLs) have recently emerged as a potential platform for photocatalytic CO2 reduction reaction (PCO2RR). Such 2D structures negate the blemish of low‐density catalytic sites and low electron transmission efficiency on the surface of metal organic frameworks (MOFs), while retaining the advantage of low expenditure when using earth‐abundant metal nodes and meritorious applicability in the PCO2RR. Herein, it is reported that the 2D ultrathin layer material with bis‐metallic catalytic sites (Ni−O metal node and the Ni−N metal site) from bidentate ligand 2,2’‐bipyridine‐5,5’‐dicarboxylate (H2bpydc) and nickel(II) remarkably boosts the visible light‐driven PCO2RR performance with a CO yield of 2400 mmol g−1 for 18 h and a selectivity up to 99 %. Consequently, the effects of morphology, catalytic sites and intrinsic properties on PCO2RR efficiency have been investigated in detail. In this context, the ultrathin layer structure has been elucidated as the key point to facilitate electron transfer efficiency. Notably, the bis‐metallic catalytic sites with reasonable distance between two adjacent metals presumably induce synergistic effect and offer a guiding ideology for further designing high performance photocatalysts.
Boosting the Enantioselectivity of Conjugate Borylation of α,β‐Disubstituted Cyclobutenones with Monooxides of ChiralC2‐Symmetric Bis(phosphine) Ligands
Authors: Cui Ming , Zhao Zhi‐Yuan , Oestreich Martin 
Published: July 2022

AbstractChiral bis(phosphine) monooxides (BPMOs) derived fromC2‐symmetric bis(phosphines) have been found to induce superior levels of enantioselection in copper‐catalyzed conjugate borylation of α,β‐disubstituted cyclobutenones. More precisely, enantiomeric excesses as well as chemical yields are exceedingly high with (R,R)‐Bozphos as the chiral ligand while these values are low with parent (R,R)‐Me‐Duphos. A similar yet less pronounced effect was seen in the corresponding 1,6‐addition topara‐quinone methides.
Experimental methods in chemical engineering: Reactive extrusion
Authors: Zhuang Yanfa , Saadatkhah Nooshin , Morgani Mahdi Salehi , Xu Tianhuai , Martin Charlie , Patience Gregory S. , Ajji Abdellah 
Published: July 2022

AbstractReactive extrusion (REX) is a manufacturing technique that combines traditional melt extrusion with chemical reactions, including polymerization, polymer functionalization, and depolymerization (chemical recycling). Single screw, counter‐rotating, and co‐rotating twin‐screw extruders (TSE) are possible configurations, but the TSE is most effective for viscous media with better mixing capability, temperature and residence time distribution control, and self‐wiping (cleaning) performance. Compared to traditional polymer processing where monomers react in tanks, followed by compounding and pelletizing, REX can operate solvent‐free in a single step. This simplifies the downstream separation and saves equipment and operational costs. However, the short residence times (on the order of seconds to minutes) of extruders limit their applications to fast reactions. For longer reactions, a sequential design and string extruders with a batch reactor extend residence times. Furthermore, the surface‐to‐volume ratio decreases with increasing scale, which introduces design complexity to remove the heat of reaction. Here, we review REX working principles, apparatuses and their elements, applications and reactions, simulation/modelling and scale‐up considerations, as well as limitations and recommendations. Web of Science indexed 579 articles that mention REX between 2017 and 2021. A bibliometric analysis of these articles identified five research clusters: composite, nano‐composite, and thermal properties; degradation, crosslinking, rheology, and acid; crystallization, polypropylene, maleic anhydride, and rheological properties; morphology, compatibilization, and copolymer; and oxidative stress and mechanisms.
Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies
Authors: Ollila Thomas A. , Masel Rebecca H. , Reagan John L. , Lu Shaolei , Rogers Ralph D. , Paiva Kimberly J. , Taher Rashida , Burguera‐Couce Ella , Zayac Adam S. , Yakirevich Inna , Niroula Rabin , Barth Peter , Olszewski Adam J. 
Published: July 2022

BackgroundPatients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease‐19 (COVID‐19) infection and reduced response to vaccination.MethodsThe authors retrospectively analyzed serologic responses to initial and booster COVID‐19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID‐19–related outcomes.ResultsSeroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B‐cell–depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty‐three patients (8.8%) developed a COVID‐19 infection, and there were three COVID‐19–related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID‐19 infection, no patient with seroconversion died from COVID‐19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID‐19 infection.ConclusionsBooster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID‐19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID‐19 death in the otherwise high‐risk population.Lay summary

Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID‐19) vaccination.

In this single‐institution review, less than one half of the patients studied made detectable antibodies.

For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination.

By the end of February 2022, 33 of the original 378 patients had a documented COVID‐19 infection.

The only deaths from COVID‐19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID‐19 infection.
On the JAP Method for the Indirect Determination of Delocalized Currents from Experimental Chemical Shifts**
Authors: Landi Alessandro , Summa Francesco F. , Zanasi Riccardo , Monaco Guglielmo 
Published: July 2022

AbstractThe JAP model (after Jirásek, Anderson, and Peeks) to retrieve global current strengths from experimental 1H chemical shifts has been tested with DFT computations. Both global and local tropicities are correctly predicted in most cases and the quantitative agreement is overall fair. An extension of the model is found to give improvement in an exemplary critical case, where the global delocalized current is negligible and the current density map is dominated by local currents.
Isolating Nuclei From Frozen Human Heart Tissue for Single‐Nucleus RNA Sequencing
Authors: Safabakhsh Sina , Sar Funda , Martelotto Luciano , Haegert Anne , Singhera Gurpreet , Hanson Paul , Parker Jeremy , Collins Colin , Rohani Leili , Laksman Zachary 
Published: July 2022

AbstractHeart disease is the leading cause of global morbidity and mortality. This is in part because, despite an abundance of animal and in vitro models, it has been a challenge to date to study human heart tissue with sufficient depth and resolution to develop disease‐modifying therapies for common cardiac conditions. Single‐nucleus RNA sequencing (snRNA‐seq) has emerged as a powerful tool capable of analyzing cellular function and signaling in health and disease, and has already contributed to significant advances in areas such as oncology and hematology. Employing snRNA‐seq technology on flash‐frozen human tissue has the potential to unlock novel disease mechanisms and pathways in any organ. Studying the human heart using snRNA‐seq is a key priority for the field of cardiovascular sciences; however, progress to date has been slowed by numerous barriers. One key challenge is the fact that the human heart is very resistant to shearing and stress, making tissue dissociation and nuclear isolation difficult. Here, we describe a tissue dissociation method allowing the efficient and cost‐effective isolation of high‐quality nuclei from flash‐frozen human heart tissue collected in surgical operating rooms. Our protocol addresses the challenge of nuclear isolation from human hearts, enables snRNA‐seq of the human heart, and paves the way for an improved understanding of the human heart in health and disease. Ultimately, this will be key to uncovering signaling pathways and networks amenable to therapeutic intervention and the development of novel biomarkers and disease‐modifying therapies. © 2022 Wiley Periodicals LLC.Basic Protocol: Human heart tissue dissociation and nuclear isolation for snRNA‐seq
Participative pricing and donation programs in a socially concerned supply chain
Authors: Sabbaghnia Ali , Heydari Jafar , Razmi Jafar 
Published: July 2022

AbstractThis study analyzes a participative pricing scheme, name‐your‐own‐price, as a practical marketing mechanism for a socially sustainable supply chain. There is an ongoing argument on the profitability of participative pricing. This study introduces a different approach in capturing optimal decisions of a corporate social responsibility practice. In the proposed approach, the manufacturer is willing to donate as long as, (I) business image is improving; thus, the potential market size is expanding and, (II) consumers are also donating through the proposed donation scheme. Results indicate that not only the total earnings are increasing, the market participation is also boosted. Further, operational decisions are coordinated successfully with a revenue‐sharing contract. Findings imply that there is a minimum threshold for manufacturer's participation ratio to ensure the profitability of the proposed scheme, not to mention consumer's donation size. Sensitivity analysis is conducted to prove the applicability of the proposed mechanism in real‐world applications.