bluuebunny/crossref_metadata_2025 huggingface dataset:
Unbalanced translocation der(5;17) resulting in a TP53 loss as recurrent aberration in myelodysplastic syndrome and acute myeloid leukemia with complex karyotype
Authors: Warnstorf Daria , Bawadi Randa , Schienke Andrea , Strasser Renate , Schmidt Gunnar , Illig Thomas , Tauscher Marcel , Thol Felicitas , Heuser Michael , Steinemann Doris , Davenport Claudia , Schlegelberger Brigitte , Behrens Yvonne Lisa , Göhring Gudrun
Published: January 2021

A complex karyotype, detected in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), is associated with a reduced median survival. The most frequent chromosomal aberrations in complex karyotypes are deletions of 5q and 17p harboring the tumor suppressor gene TP53. The unbalanced translocation der(5;17) involving chromosome 5q and 17p is a recurrent aberration in MDS/AML, resulting in TP53 loss. We analyzed the karyotypes of 178 patients with an unbalanced translocation der(5;17) using fluorescence R−/G‐banding analysis. Whenever possible, fluorescence in situ hybridization (FISH) (n = 138/141), multicolor FISH (n = 8), telomere length measurement (n = 9), targeted DNA sequencing (n = 13), array‐CGH (n = 7) and targeted RNA sequencing (n = 2) were conducted. The der(5;17) aberration was accompanied with loss of genetic material in 7q (53%), −7 (27%), gain of 21q (29%), +8 (17%) and − 18 (16%) and all analyzed patients (n = 13) showed a (likely) pathogenic variant inTP53. The der(5;17) cohort showed significantly shortened telomeres in comparison to the healthy age‐matched controls (P < .05), but there was no significant telomere shortening in comparison to MDS/AML patients with a complex karyotype without der(5;17). No fusion genes resulted from the unbalanced translocation. This study demonstrates that the unbalanced translocation der(5;17) is associated with a biallelic inactivation of TP53 due to a deletion of TP53 in one allele and a pathogenic variant of the second TP53 allele. Since the breakpoints are located within (near‐) heterochromatic regions, alterations of DNA methylation or histone modifications may be involved in the generation of der(5;17).
Administrative Coding in Electronic Health Care Record‐Based Research of NAFLD: An Expert Panel Consensus Statement
Authors: Hagström Hannes , Adams Leon A. , Allen Alina M. , Byrne Christopher D. , Chang Yoosoo , Grønbæk Henning , Ismail Mona , Jepsen Peter , Kanwal Fasiha , Kramer Jennifer , Lazarus Jeffrey V. , Long Michelle T. , Loomba Rohit , Newsome Philip N. , Rowe Ian A. , Ryu Seungho , Schattenberg Jörn M. , Serper Marina , Sheron Nick , Simon Tracey G. , Tapper Elliot B. , Wild Sarah , Wong Vincent Wai‐Sun , Yilmaz Yusuf , Zelber‐Sagi Shira , Åberg Fredrik
Published: January 2021

Background and Aims

Electronic health record (EHR)‐based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach and Results

Researchers with an interest in EHR‐based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR‐based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions

This expert panel consensus statement can help harmonize and improve generalizability of EHR‐based NAFLD research.
Excessive focus on risk? Non‐performing loans and efficiency of microfinance institutions
Authors: Zamore Stephen , Beisland Leif Atle , Mersland Roy
Published: January 2021

Microfinance is a banking market in which operating costs are high, while non‐performing loans (NPLs) rates are low. While the existing literature tends to explain that the high operating costs arise from the provision of small loans, we argue that excessive efforts to control loan losses can also be a contributing factor. Therefore, this article investigates the relationship between NPLs and the cost efficiency of microfinance institutions (MFIs). Using a unique global sample of rated MFIs and applying stochastic frontier analysis together with Granger‐causality test and generalized method of moments (GMM), we find, in contrast to positive linear relationship evidence in commercial banking studies, a nonlinear (U‐shape) relationship between operating costs and NPLs. This implies that MFIs need to balance their cost efficiency with asset quality.
Forecasting stock prices using a data mining method: Evidence from emerging market
Authors: Farid Saqib , Tashfeen Rubeena , Mohsan Tahseen , Burhan Arsal
Published: January 2021

Stock price forecasting is considered a challenging task because of the various characteristics of financial time series. In this study, we attempt to predict stock prices using data mining techniques in an emerging market. The study uses decision tree model, CRISP‐DM (Cross‐Industry Standard Process for data mining) for analysis by employing WEKA software. The study sample consists of ten firms of five different sectors listed on Pakistan Stock Exchange (PSX). The findings show accuracy ratios range between 50% and 60%. The findings imply that market participants can disclose higher returns by considering information embedded in previous stock prices. In addition, investors can take more prudent buy‐sell decisions in view of our findings.
Pilot monitoring and evaluation of the WHO postpartum family planning compendium mobile application: An in‐depth, qualitative study
Authors: Sonalkar Sarita , Maya Ernest , Adanu Richard , Samba Ali , Mumuni Kareem , McAllister Arden , Fishman Jessica , Schurr Danielle , Schreiber Courtney A. , Kolev Svetlin , Doe Roseline , Eluned Gaffield Mary
Published: January 2021

Objective

To assess the feasibility, functionality and acceptability of a mobile application (app), the World Health Organization (WHO) Postpartum Family Planning (PPFP) Compendium, in clinical care.

Method

This prospective qualitative study was conducted among family planning providers routinely delivering PPFP care in Accra, Ghana. We conducted in‐depth interviews at baseline and 3 months after app introduction. We elicited expected technological, psychological and environmental barriers to use, actual use in clinical settings, and feedback for app improvement. With inter‐coder reliability, we analyzed the content of interview transcripts.

Results

Twenty providers participated in baseline interviews, and 19 participated in follow‐up interviews. At baseline, providers did not have significant technological barriers to its use and felt the app was acceptable, but were concerned about the appropriateness of using an app during clinical care. At 3‐month follow‐up, 18 out of 19 participants reported using the app weekly, and found the app acceptable for use in clinical care. Providers recommended expanding clinical content and including similar guidance relevant to times outside the postpartum period.

Conclusion

Use of a PPFP counseling app to aid family planning providers in clinical care delivery is feasible and acceptable. Providers recommended inclusion of similar guidance relevant to times outside the postpartum period.
Summary of reference chemicals evaluated by the fish short‐term reproduction assay, OECD TG229, using Japanese Medaka,Oryzias latipes
Authors: Onishi Yuta , Tatarazako Norihisa , Koshio Masaaki , Okamura Tetsuro , Watanabe Haruna , Sawai Atsushi , Yamamoto Jun , Ishikawa Hidenori , Sato Tomomi , Kawashima Yukio , Yamazaki Kunihiko , Iguchi Taisen
Published: January 2021

Under the Organisation for Economic Co‐operation and Development (OECD), the Ministry of the Environment of Japan (MOE) added Japanese medaka (Oryzias latipes) to the test guideline fish short‐term reproduction assay (FSTRA) developed by the United States Environmental Protection Agency (US EPA) using fathead minnow (Pimephales promelas). The FSTRA was designed to detect endocrine disrupting effects of chemicals interacting with the hypothalamic–pituitary–gonadal axis (HPG axis) such as agonists or antagonists on the estrogen receptor (Esr) and/or the androgen receptor (AR) and steroidogenesis inhibitors. We conducted the FSTRA with Japanese medaka, in accordance with OECD test guideline number 229 (TG229), for 16 chemicals including four Esr agonists, two Esr antagonists, three AR agonists, two AR antagonists, two steroidogenesis inhibitors, two progesterone receptor agonists, and a negative substance, and evaluated the usability and the validity of the FSTRA (TG229) protocol. In addition, in vitro reporter gene assays (RGAs) using Esr1 and ARβof Japanese medaka were performed for the 16 chemicals, to support the interpretation of the in vivo effects observed in the FSTRA. In the present study, all the test chemicals, except an antiandrogenic chemical and a weak Esr agonist, significantly reduced the reproductive status of the test fish, that is, fecundity or fertility, at concentrations where no overt toxicity was observed. Moreover, vitellogenin (VTG) induction in males and formation of secondary sex characteristics (SSC), papillary processes on the anal fin, in females was sensitive endpoints to Esr and AR agonistic effects, respectively, and might be indicators of the effect concentrations in long‐term exposure. Overall, it is suggested that the in vivo FSTRA supported by in vitro RGA data can adequately detect effects on the test fish,O. latipes, and probably identify the mode of action (MOA) of the chemicals tested.
Obesity and Responsiveness to Food Marketing Before and After Bariatric Surgery
Authors: Cornil Yann , Plassmann Hilke , Aron‐Wisnewsky Judith , Poitou‐Bernert Christine , Clément Karine , Chabert Michèle , Chandon Pierre
Published: January 2021

Although food marketing is often accused of increasing population obesity, the relationship between individual responsiveness to marketing and obesity has yet to be established: Are people with obesity more responsive to food marketing and, if so, is it a stable trait or can it be reversed by bariatric surgery? We studied the responses to three common marketing tactics that frame foods and portions as healthier than they really are in three groups of women: (a) a group of patients with obesity before, 3 months, and 12 months after bariatric surgery, (b) a control group of lean women, and (c) another control group of women with obesity but not seeking any treatment for their obesity. People with obesity were initially more responsive to food marketing, but bariatric surgery reduced their responsiveness down to the level of lean people. In addition to documenting another potential psychological consequence of bariatric surgery, our study suggests that the higher responsiveness of people with obesity is not a stable individual predisposition and supports the notion of a reciprocal relationship between obesity and sensitivity to environmental influences.
Bioaugmentation with Ruminiclostridium thermocellumM3 to enhance thermophilic hydrogen production from agricultural solid waste
Authors: Sheng Tao , Meng Qingbin , Wen Xuechen , Sun Caiyu , Yang Lisha , Li Lixin
Published: January 2021

BACKGROUND

High‐efficiency saccharification technology is one of the bottlenecks of cellulosic bio‐hydrogen production. Cellulosic feedstocks saccharification currently performed by commercial cellulase, which is composed of different fungal cellulase. Compared with fungi, thermocellulosic bacteria represented by Ruminiclostridium thermocellum have a complete cellulase system, and a higher cellulase catalytic efficiency than fungi; however, R. thermocellum is susceptible to feedback inhibition by cellobiose, which limits the application of R. thermocellum on cellulosic bio‐hydrogen production. In this study, a strain named R. thermocellum M3, which is not subject to feedback inhibition by cellobiose, was used in the bio‐hydrogen production of cellulosic agricultural waste feedstocks to explore the feasibility of bacterial saccharification of cellulosic substrates for biological hydrogen production.

RESULTS

Results of batch tests indicate that the combination of domestic sewage sludge and strain M3 promoted the hydrogen production for different lignin content feedstocks (rice straw: from 0.66 to 6.42 mmol H2/g substrate; corn cob: from 0.61 to 5.55 mmol H2/g substrate; pine wood waste: from 0.58 to 5.32 mmol H2/g substrate), which were competitive with the combination of domestic sewage sludge and Trichoderma viride cellulase. Specific activity analysis indicates that compared with the addition of T. viride cellulase, the addition of strain M3 completed the cellulase system in sludge.

CONCLUSION

Thermo‐anaerobic bacteria R. thermocellum M3 enhanced the hydrogen production of the consolidated bioprocessing (CBP) of raw lignocellulosic agricultural wastes and, more importantly, provided a promising solution for the CBP strategy in the industrial application of lignocellulose bioconversion. © 2021 Society of Chemical Industry
In water organic synthesis: Introducing itaconic acid as a recyclable acidic promoter for efficient and scalable synthesis of quinoxaline derivatives at room temperature
Authors: Tamuli Kashyap J. , Nath Shyamalendu , Bordoloi Manobjyoti
Published: January 2021

Substituted quinoxaline derivatives are traditionally synthesized by co‐condensation of various starting materials. Herein, we describe a novel environmentally benign in water synthetic route for the synthesis of structurally and electronically diverse ninety quinoxalines with readily available substituted o‐phenylenediamine and 1,2‐diketones using cheap and biodegradable itaconic acid as a mild acid promotor in 1 hours. The reaction is performed at room temperature, which proceeds through cyclo‐condensation reaction followed by obtaining the aforesaid nitrogen‐containing heterocyclic adducts without performing the column chromatography up to 96% total yields. The simplicity, high efficiency, and reusable of the catalyst merits this reaction condition as “green synthesis” which enables it to be useful in synthetic transformations upto gram scale level.
Structure of the gonoduct of the viviparous teleost Cnesterodon decemmaculatus (Jenyns, 1842) (Poeciliidae)
Authors: Santamaría‐Martín Carlos J. , Plaul Silvia E. , Campuzano Caballero Juan C. , Uribe Mari C. , Barbeito Claudio G.
Published: January 2021

During embryogenesis, teleost females do not develop Müllerian ducts, which form the oviducts in all other vertebrates. Thus, when they reach sexual maturity they do not have oviducts. In viviparous teleosts, the lack of oviducts means that the development of the embryos occurs as an intraovarian gestation, unique among vertebrates. The ovary is an unpaired hollow organ whose cavity is continuous with the caudal portion, the gonoduct, characterized by the absence of germinal cells, which opens to the exterior at the gonopore. The gonoduct attains essential function as a barrier between the germinal region of the ovary and the exterior during all reproductive stages. This study describes the functional morphology of the gonoduct in the viviparous teleost Cnesterodon decemmaculatus during non‐gestation (previtellogenesis and vitellogenesis) and gestation. The ovaries were processed using histological techniques and stained with hematoxylin–eosin, and periodic acid Schiff. The gonoduct has two regions: cephalic and caudal, and is formed by three histological layers, which are, from inside to the periphery: (a) tunica mucosa; (b) tunica muscularis; and (c) tunica serosa. In the cephalic region there are mucosal folds extending into the lumen and forming a structure similar to a cervix. The histology of the gonoduct indicates essential functions, that is, (a) the control of the luminal diameter in the limit to the germinal region of the ovary by the presence of a cervix; (b) during insemination the gonoduct receives the spermatozoa, may store and transport them to the germinal region; (c) the presence of melano‐macrophage centers indicates support of immunological processes, especially during gestation when these centers increase in size; (d) production of exocrine secretions; and (e) it is the birth canal, internally lined by an ciliated epithelium and surrounded by smooth musclesboth tissues supposedly supporting the birth process.
Sinonasal complications associated with endoscopic orbital decompression
Authors: Suresh Rishi , Soparkar Charles N. , Alford Eugene L.
Published: January 2021

Objective

Characterize sinonasal complications associated with endoscopic orbital decompression for thyroid eye disease (TED).

Methods

Retrospective analysis of patients who underwent endoscopic orbital decompression at Houston Methodist Hospital by two otolaryngologists and one ophthalmologist between May 2016 and February 2020 for TED. Patient ethnicity, age, laterality, operative approach (middle turbinectomy vs middle turbinate sparing), and history of prior sinusitis were collected.

Results

One hundred and forty‐five orbital decompressions met the inclusion criteria. Postoperative obstructive sinusitis where herniated orbital fat caused obstruction of the sinus ostium occurred in 5.5% of operations. Patients who had a prior history of sinusitis were more likely to develop postoperative obstructive sinusitis (P = .02). The middle turbinectomy approach was more likely to show a reduced incidence of postoperative sinusitis (P = .014).

Conclusion

Given the increased difficulty of managing sinonasal complications in the context of a decompressed orbit, efforts should be made to identify factors that might reduce the incidence of postoperative endonasal complications. The current study suggests that resection of the middle turbinate may allow for increased space for orbital fat herniation and lead to a decreased incidence of postoperative obstructive sinusitis.

Level of Evidence

IV.
Determinants of common benefits and private benefits in innovation alliances
Authors: Samant Shantala , Kim Jongwook
Published: January 2021

We identify the ex ante conditions that incentivize the development of common benefits and private benefits from alliances. Building on transaction costs economics and the knowledge‐based view, we argue that a commitment to exchange know‐how encourages cooperation and is positively related to common benefits, that is, benefits shared by all partners. We also argue that a firm's absorptive capacity and knowledge base relative to its partner reduce reliance on the partner and are positively related to private benefits, that is, benefits enjoyed separately from partners. We test our hypotheses by examining patents, filed separately and jointly by partners in the biopharmaceutical industry in the United States.
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

Background

Mutations 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.

Methods

We 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.

Results

We 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.

Conclusion

Genotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
Reshaped crisis services establish new connections for Illinois center
Authors: Enos Gary
Published: January 2021

Forced to adjust its crisis operations during the COVID‐19 pandemic, Skokie, Illinois–based Turning Point Behavioral Health Care Center has cemented deeper bonds with clients while also managing to expand its service capacity. The lessons its leaders have learned over the past year have offered a roadmap for becoming a one‐stop shop for its community's behavioral health and related needs, according to the organization's CEO.
McCance‐Katz reflects on SAMHSA priorities, future challenges
Authors: Canady Valerie A.
Published: January 2021

In an interview last week with Mental Health Weekly, former Substance Abuse and Mental Health Services Administration (SAMHSA) Assistant Secretary for Mental Health and Substance Use Elinore McCance‐Katz, M.D., Ph.D., who announced her resignation last month, reflected on SAMHSA's achievements and national priorities, especially amid COVID‐19, and the need for increased funding to address the mental health and substance use disorder needs of Americans.
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

Purpose

CEST 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.

Methods

The 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.

Results

The 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.

Conclusions

The 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

The 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

Nonvolatile 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

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 < .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

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

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

In 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

Cytochrome 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

BACKGROUND

Intensive 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.

RESULTS

Minor 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.

CONCLUSIONS

The 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

For 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

Background: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

A 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.
Freeform Volumetric Fabrication Using Actuated Robotic Hot Wire Cutter
Authors: Loh Paul , Hou Yuhan , Tse Chun Tung , Mo Jiaqi , Leggett David
Published: January 2021

This paper discusses the design, fabrication and operational workflow of a novel hot-wire cutter used as an end effector for a robotic arm. Typically, hot wire cutters used a linear cutting element which results in ruled surfaces geometry. While several researchers have examined the use of hot wire cutter with cooperative robotic arms to create non-ruled surface geometry, this research explores the use of an actuated hot wire cutter manoeuver by a single robotic arm to produce similar form. The paper outlines the machine making process and its workflow resulting in a 1:1 scale prototype. The paper concludes by examining how the novel tool can be applied to an urban stage design. The research set up a fabrication procedure that has the potential to be deployed as an on-site fabrication methodology.
G
4 flux, algebraic cycles and complex structure moduli stabilization
Authors: Braun A. P. , Valandro R.
Published: January 2021

Abstract

We construct G4 fluxes that stabilize all of the 426 complex structure moduli of the sextic Calabi-Yau fourfold at the Fermat point. Studying flux stabilization usually requires solving Picard-Fuchs equations, which becomes unfeasible for models with many moduli. Here, we instead start by considering a specific point in the complex structure moduli space, and look for a flux that fixes us there. We show how to construct such fluxes by using algebraic cycles and analyze flat directions. This is discussed in detail for the sextic Calabi-Yau fourfold at the Fermat point, and we observe that there appears to be tension between M2-tadpole cancellation and the requirement of stabilizing all moduli. Finally, we apply our results to show that even though symmetric fluxes allow to automatically solve several F-term equations, they typically lead to flat directions.
Severe skin toxicity during whole-brain radiotherapy, targeted therapy, and additional drug intake including St. John’s wort skin oil
Authors: Eichkorn Tanja , Schunn Fabian , Regnery Sebastian , Shafie Rami El , Hörner-Rieber Juliane , Adeberg Sebastian , Herfarth Klaus , Debus Jürgen , König Laila
Published: January 2021

Background

Metastatic non-small cell lung cancer (NSCLC) often requires a multimodal treatment including chemotherapy, targeted therapy and radiotherapy. In addition to this, many patients take supportive drugs. Since only scarce data on possible interactions between radiotherapy and pharmaceutical or herbal drugs exist, description of clinical cases is of special interest.

Case report

A patient with stage IV NSCLC was treated with docetaxel/ramucirumab followed by radiotherapy for brain and bone metastases while taking several other over-the-counter drugs (OTCs) including topical St. John’s wort skin oil.

Results

A 63-year-old female patient with stage IV NSCLC presented with 11 asymptomatic brain metastases and a painful osteolytic bone metastasis in the 12th thoracic vertebral body (T12). Four weeks before the start of palliative whole-brain radiotherapy and bone irradiation of T12, she was administered a combination of docetaxel and ramucirumab. At an administered dose of 24 Gy, the patient presented with severe folliculitis capitis, while skin examination over the thoracolumbar spine was unremarkable although skin dose was similar. After thorough questioning, the patient reported using a herbal skin oil that contained St. John’s wort for scalp care only, but not for skin care of her back during radiotherapy. After stopping the topical application of the skin oil, folliculitis improved with a course of systemic and topical antibiotics within 10 days, though the healing process was prolonged and included desquamation and hyperpigmentation.

Conclusion

St. John’s wort seems to be a significant radiosensitizer for photon radiotherapy and can cause severe skin toxicity even though the literature lacks data on this interaction. As an OTC, it is easily accessible and often used by oncological patients due to antidepressant and local antimicrobial and pain-relieving effects.