bluuebunny/crossref_metadata_2025_split huggingface dataset:
Update of genetic variants in CEP120 and CC2D2A—With an emphasis on genotype‐phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies
Authors: Barroso‐Gil Miguel , Olinger Eric , Ramsbottom Simon A. , Molinari Elisa , Miles Colin G. , Sayer John A. 
Published: January 2021

AbstractBackgroundMutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue‐specific preservation of the amount of expressed functional protein.MethodsWe systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120‐ and CC2D2A‐associated disease and we combined in silico and ex vivo approaches to study tissue‐specific transcripts and identify molecular targets for exon skipping.ResultsWe confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases.ConclusionGenotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
Quasi‐steady state chemical exchange saturation transfer (QUASS CEST) analysis—correction of the finite relaxation delay and saturation time for robust CEST measurement
Authors: Sun Phillip Zhe 
Published: January 2021

PurposeCEST provides a MR contrast mechanism sensitizing to the exchange between dilute labile and bulk water protons. However, the CEST effect depends on the RF saturation duration and relaxation delay, which need to be long to reach its steady state. Our study aims to estimate the QUAsi‐Steady State (QUASS) CEST signal from experiments with shorter saturation and relaxation delay times.MethodsThe evolution of the CEST signal was modeled as a function of the bulk water longitudinal relaxation rate during the relaxation delay (Td) and spin‐lock relaxation rate during the RF saturation (Ts), from which the QUASS CEST effect is solved. Numeric simulations were programmed to compare the apparent CEST and QUASS CEST effects as a function of Ts and Td times. We also performed CEST MRI experiments from a creatine–gel pH phantom under serially varied Ts and Td times.ResultsThe numeric simulation showed that although the apparent CEST effect depends on Td and Ts, the QUASS CEST solution has little dependence. Phantom results showed that the routine CEST pH contrast could be described by a nonlinear regression model (ie, ). We had = (P < 5e−8) and (P < 5e−6). For the QUASS CEST analysis, we modeled the pH contrast as , using a linear regression model. We had (P < 5e−9) and (P < 0.01), the slope of which is minimal.ConclusionsThe QUASS CEST algorithm provides a post‐processing solution that facilitates robust CEST measurement.
Functionalized graphene oxide as a nanocarrier for multiple suppressive miRNAs to inhibit human intrahepatic cholangiocarcinoma
Authors: Yang Hui , Shi Gaona , Ge Chen , Huang Jie , Wan Lingfei , Wang Zhaohai , Liu Yunhui , Jia Runqing , Wang Minglian , Zhang Liming , Zhang Zhijun , Yan Xinlong 
Published: January 2021

AbstractThe restoration of suppressed miRNAs is a promising therapeutic approach for treating tumors; however, efficient delivery remains a challenge. Herein, we aimed to develop a polyethylenimine (PEI) functionalized graphene oxide nanosheets (GO‐PEI) as a suppressive miRNA delivery system to treat human intrahepatic cholangiocarcinoma (ICC). We found that the GO‐PEI complex possessed excellent transfection efficacy and acceptable toxicity. Furthermore, using our miRNA array analysis and The Cancer Genome Atlas (TCGA) dataset, we selected four miRNAs (miR‐194‐5p, miR‐125b‐5p, miR‐122‐5p, and let‐7c‐5p) that are remarkably downregulated in ICC samples compared to that in adjacent tissues. The GO‐PEI complexed with the four miRNAs (GO‐PEI‐4miR) achieved a higher miRNA transfection efficiency than Lipo2000, as verified by quantitative reverse transcription polymerase chain reaction (qRT‐PCR) assays, immunofluorescence, and flow cytometry analyses. In addition, in vitro experiments revealed that GO‐PEI‐4miR remarkably restored the repressed miRNAs, thereby significantly repressing tumor sphere formation, colony formation, drug resistance, and markedly inhibiting the target genes of these miRNAs and cancer stem cell‐related markers. Furthermore, both tumor weights and bioluminescent imaging analysis indicated that the GO‐PEI‐4miR significantly reduced tumor formation in vivo. Taken together, these results demonstrate that GO‐PEI could be a potential delivery system for multiple repressive miRNAs in ICC therapy.
Recent advances in metal nanoparticle‐based floating gate memory
Authors: Chen Hongye , Zhou Ye , Han Su‐Ting 
Published: January 2021

AbstractNonvolatile memory is distinguished for the application in many electronic products due to its excellent charge storage ability. Nevertheless, as the device dimensions are scaled down, floating gate memory encounters various challenges: the increasing leakage current leading to a serious reliability issue and the decreasing of charge density. Hence, metal nanoparticle‐based floating gate memory has been proposed and become a promising candidate for nonvolatile memories due to its outstanding operation speed, excellent scalability, and favorable reliability. This review briefly introduces the classification of memory devices. The operation mechanisms, fabrication and characterization of metal nanoparticle‐based floating gate memory are discussed based on research activities reported in recent years.
Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up
Authors: Finn Richard S. , Rugo Hope S. , Gelmon Karen A. , Cristofanilli Massimo , Colleoni Marco , Loi Sherene , Schnell Patrick , Lu Dongrui R. , Theall Kathy Puyana , Mori Ave , Gauthier Eric , Bananis Eustratios , Turner Nicholas C. , Diéras Véronique 
Published: January 2021

Abstract

Background
Previous studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure.

Patients and Methods
Data were pooled from three randomized studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA-1/-2) and pre- and postmenopausal women who had progressed on prior ET (PALOMA-3).

Results
Updated cutoff dates were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). Total person-years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any-grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p &lt; .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all-grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET.

Conclusion
This 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2− ABC.

Implications for Practice
Several treatments for patients with breast cancer are associated with long-term or latent adverse events. This long-term, 5-year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia
Authors: Delgado Julio , Josephson Filip , Camarero Jorge , Garcia-Ochoa Blanca , Lopez-Anglada Lucia , Prieto-Fernandez Carolina , Hennik Paula B. van , Papadouli Irene , Gisselbrecht Christian , Enzmann Harald , Pignatti Francesco 
Published: January 2021

Abstract

On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE-CL-007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06–0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13–0.3) arms compared with the ChlObi arm. The second trial (ACE-CL-309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20–0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit-risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU.

Implications for Practice
Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.
Activity of Sorafenib Plus Capecitabine in Previously Treated Metastatic Colorectal Cancer
Authors: George Thomas J. , Ivey Alison M. , Ali Azka , Lee Ji-Hyun , Wang Yu , Daily Karen C. , Ramnaraign Brian H. , Tan Sanda A. , Terracina Krista P. , Read Thomas E. , Dang Long H. , Iqbal Atif 
Published: January 2021

Abstract

Lessons Learned
Treatment for patients with metastatic colorectal cancer (mCRC) typically involves multiple lines of therapy with eventual development of treatment resistance. In this single-arm, phase II study involving heavily pretreated patients, the combination of sorafenib and capecitabine yielded a clinically meaningful progression-free survival of 6.2 months with an acceptable toxicity profile. This oral doublet therapy is worthy of continued investigation for clinical use in patients with mCRC.

Background
Capecitabine (Cape) is an oral prodrug of the antimetabolite 5-fluorouracil. Sorafenib (Sor) inhibits multiple signaling pathways involved in angiogenesis and tumor proliferation. SorCape has been previously studied in metastatic breast cancer.

Methods
This single-arm, phase II study was designed to evaluate the activity of SorCape in refractory metastatic colorectal cancer (mCRC). Patients received Sor (200 mg p.o. b.i.d. max daily) and Cape (1,000 mg/m2 p.o. b.i.d. on days 1–14) on a 21-day treatment cycle. Primary endpoint was progression-free survival (PFS) with preplanned comparison with historical controls.

Results
Forty-two patients were treated for a median number of 3.5 cycles (range 1–39). Median PFS was 6.2 (95% confidence interval [CI], 4.3–7.9) months, and overall survival (OS) was 8.8 (95% CI, 4.3–12.2) months. One patient (2.4%) had partial response (PR), and 22 patients (52.4%) had stable disease (SD) for a clinical benefit rate of 54.8% (95% CI, 38.7%–70.2%). Hand-foot syndrome was the most common adverse event seen in 36 patients (85.7%) and was grade ≥ 3 in 16 patients (38.1%). One patient (2.4%) had a grade 4 sepsis, and one patient (2.4%) died while on treatment.

Conclusion
SorCape in this heavily pretreated population yielded a reasonable PFS with manageable but notable toxicity. The combination should be investigated further.
β‐arrestin2 recruitment at the β2 adrenergic receptor: A luciferase complementation assay adapted for undergraduate training in pharmacology
Authors: Ferraiolo Mattia , Beckers Pauline , Marquet Nicolas , Roumain Martin , Ruiz Lucie , Dupuis Nadine , Hanson Julien , Hermans Emmanuel 
Published: January 2021

AbstractIn the context of pharmacology teaching, hands‐on activities constitute an essential complement to theoretical lectures. Frequently, these activities consist in exposing fresh animal tissues or even living animals to selected drugs and qualitatively or quantitatively evaluating functional responses. However, technological advancements in pharmacological research and the growing concerns for animal experimentation support the need for innovative and flexible in vitro assays adapted for teaching purposes. We herein report the implementation of a luciferase complementation assay (LCA) enabling to dynamically monitor β‐arrestin2 recruitment at the β2 adrenergic receptor in the framework of pharmacological training at the faculty of Pharmacy and Biomedical Sciences. The assay allowed students to quantitatively characterize the competitive antagonism of propranolol, and to calculate pEC50, pKB, and pA2 values after a guided data analysis session. Moreover, the newly implemented workshop delivered highly reproducible results and were generally appreciated by students. As such, we report that the luciferase complementation‐based assay proved to be a straightforward, robust, and cost‐effective alternative to experiments performed on animal tissues, constituting a useful and flexible tool to enhance and update current hands‐on training in the context of pharmacological teaching.
Functional characterization of the defective CYP2C9 variant CYP2C9*18
Authors: Liu Jian , Chen Hao , Wang Shuang‐Hu , Zhou Quan , Geng Pei‐Wu , Zhou Yun‐Fang , Wu Hua‐Lan , Shi Hai‐Feng , Wang Fang , Yang Jie‐Fu , Cai Jian‐Ping , Dai Da‐Peng 
Published: January 2021

AbstractCytochrome P450 2C9 (CYP2C9) is one of the most important drugs metabolizing enzymes and accounts for the metabolism of about 13%–17% of clinical drugs. Like other members in CYP2 family, CYP2C9 gene exhibits great genetic polymorphism among different races and individuals. CYP2C9*18 is one CYP2C9 allelic variant identified in a Southeast Asian population and is estimated to cause the amino acid substitutions of I359L and D397A in CYP2C9 enzyme simultaneously. Limited by the low expression level in bacteria and COS‐7 cells, no valuable enzyme kinetics have been reported on this CYP2C9 variant. In this study, the baculovirus‐based system was used for the high expression of recombinant CYP2C9 s in insect cells. As a result, together with I359L substitution, D397A could significantly decrease the protein expression of CYP2C9.18 in insect cells, although substitution of D397A alone had no effect on the expression of CYP2C9 in vitro. As compared with that of wild‐type enzyme, both CYP2C9.18 variant and D397A variant could decrease more than 80% of the catalytic activity of CYP2C9 enzyme toward three probe substrates, suggesting that caution should be exercised when patients carrying CYP2C9*18 taking medicines metabolized by CYP2C9 enzyme with a narrow therapeutic window.
Intraspecies variation of Metarhizium brunneum against the green peach aphid, Myzus persicae, provides insight into the complexity of disease progression
Authors: Reingold Victoria , Kottakota Chandrasekhar , Birnbaum Nitsan , Goldenberg Malka , Lebedev Galina , Ghanim Murad , Ment Dana 
Published: January 2021

AbstractBACKGROUNDIntensive application of chemical insecticides is required for aphid pest control. Among the biorational alternatives, entomopathogenic fungi are the most sustainable biocontrol agents; those of the order Hypocreales attack and cause fungal disease in arthropod hosts, with variations in host susceptibility attributed to both fungal and host characteristics. We evaluated inter‐ and intraspecies variations in Metarhizium spp. virulence and differences in fungal disease progression on adult and nymph stages of the green peach aphid, Myzus persicae (Sulzer), a parthenogenetically reproducing insect species.RESULTSMinor interspecies diversity was detected between the generalist Metarhizium species examined. Interestingly, significant intraspecies diversity was observed between Metarhizium brunneum isolates Mb7 and MbK. Infected adult aphids demonstrated similar disease progression for both isolates, mortality rates of more than 80% and fivefold reduction in fecundity. However, nymph mortality was detected only following MbK infection, with 50% mortality and significant reduction in molting rates. Confocal laser scanning microscopy demonstrated the variation in the disease stages of conidial adhesion and hemocoel colonization on each examined day post inoculation for each isolate. Significantly faster disease progression was observed in MbK‐infected versus Mb7‐infected nymphs, the latter demonstrating a higher percentage of uninfected nymphs accompanied with aphid molting.CONCLUSIONSThe observed intraspecies variation suggests that altered conidial adhesion to the nymph cuticle is a major factor affecting virulence. We prove the role of nymph ecdysis as a defense mechanism disrupting fungal infection. Because significant differences were observed between closely related isolates, this study emphasizes the importance of appropriate isolate selection for biological control. © 2021 Society of Chemical Industry
Versatile Nanoscale Metal–Organic Frameworks (nMOFs): An Emerging 3D Nanoplatform for Drug Delivery and Therapeutic Applications
Authors: Wen Ting , Quan Guilan , Niu Boyi , Zhou Yixian , Zhao Yiting , Lu Chao , Pan Xin , Wu Chuanbin 
Published: January 2021

AbstractFor decades, nanoscale metal–organic frameworks (nMOFs) have attracted extensive interest in biomedicine due to their distinct characteristics, including facile synthesis, porous interior, and tunable biocompatibility. With high porosity, versatile nMOFs allow for the facile encapsulation of various therapeutic agents with exceptionally high payloads. Constructed from metal ions and organic linkers through coordination bonds, nMOFs with plentiful functional groups enable the surface modification for active targeting and enhanced biocompatibility. This review outlines the up‐to‐date progresses on the exploration of nMOFs in the field of biomedicine. First, the classification and synthesis of nMOFs are discussed, followed by the concrete introduction of drug loading strategies of nMOFs and mechanisms of stimulation‐responsive drug release. Second, the smart designs of the nMOFs‐based platforms for anticancer and antibacterial treatment are summarized. Finally, the basic challenges faced by nMOFs research and the great potential of biomimetic nMOFs are presented. This review article affords an inspiring insight into the interdisciplinary research of nMOFs and their biomedical applications, which holds great expectation for their further clinical translation.
Effects of sand, asphalt and 3‐degree hind toe or heel elevation on horse kinematics
Authors: Caure Sébastien , Bonomelli Natacha , Carro Marielle , Leveillard Denis , Blanville Faustine , Mortagne Perrine , Cousty Matthieu , Weller Renate 
Published: January 2021

AbstractBackground:Although the effects of both the surfaces and plantar angles on equine locomotion have been widely discussed, limited scientific data are available.Methods:Our objectives were to determine the effects of two surfaces (asphalt and sand) and of 3‐degree hind toe or heel elevation on horse kinematics in an experimental study. Six saddle horses were shod with a reference shoeing (REF), characterized by a fore aluminium (REF F) and hind steel racehorse (REF H) shoeing. Two dimensional kinematic videos compared horse's kinematic parameters when walking and trotting on asphalt and sand. On asphalt, REF was also compared with REF F and a modified REF H with additional 3‐degree hind‐toe or ‐heel wedges.Results:On asphalt versus sand, horses had, at the trot, a shorter stride duration and forelimb maximal retraction, and at walk and trot, a greater fetlock, carpus, elbow and tarsus extension, a greater fore and hind limbs maximal protraction and a shorter hind limbs maximal retraction. Increasing the plantar angle decreased the tarsus and hind fetlock extension, in contrast to fore‐limb, on asphalt during the stance phase.Conclusions:These findings could be useful to adapt rehabilitation programs related to fore and hind limb pathologies, at slow gaits.
Alternative anaesthetic management in a reintervention for correction of a left‐to‐right shunting patent ductus arteriosus (PDA) in a dog
Authors: Medina‐Serra Roger , Palacios Carolina , McMillan Matthew 
Published: January 2021

AbstractA three‐year‐old, male neutered, 2.7 kg Chihuahua was referred for correction of a type IIA, left‐to‐right shunting PDA. The correction of the PDA required two separate interventions. During the first intervention, a minimally invasive transvascular correction of the PDA that was converted to a thoracotomy was suspended after the evidence of iatrogenic haemopericardium. The second intervention, scheduled after the resolution of the haemopericardium, consisted of surgical ligation of the PDA via thoracotomy. Long periods of hypotension (mean arterial pressure below 60 mm Hg) were observed during the first intervention, during which anaesthesia was maintained with a combination of sevoflurane and infusions of fentanyl and lidocaine. The use of total intravenous anaesthesia with alfaxalone in conjunction with locoregional techniques in the second intervention provided smooth anaesthesia with improved cardiovascular stability.