bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Itraconazole and Rifampin on the Pharmacokinetics of Mobocertinib (TAK‐788), an Oral Epidermal Growth Factor Receptor Inhibitor, in Healthy Volunteers
Authors: Zhang Steven , Jin Shu , Griffin Celina , Feng Zhongling , Lin Jianchang , Venkatakrishnan Karthik , Gupta Neeraj 
Published: June 2021

AbstractMobocertinib (TAK‐788) is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open‐label, 2‐period, fixed‐sequence, 2‐part study (NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of mobocertinib, AP32960, and AP32914 by 527% (geometric least‐squares mean [LSM] ratio, 6.27; 90% confidence interval [CI], 5.20‐7.56). Coadministration of rifampin with mobocertinib decreased the combined molar AUC0‐∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04‐0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.
Cost to Medicare of Delayed Adalimumab Biosimilar Availability
Authors: Lee ChangWon C. , Najafzadeh Mehdi , Kesselheim Aaron S. , Sarpatwari Ameet 
Published: June 2021

Launched in 2002, originator adalimumab (Humira) is the top revenue‐generating drug in the United States. Between 2016 and 2019, the US Food and Drug Administration approved 5 adalimumab biosimilars, yet none have been marketed owing to patent dispute settlements. We sought to calculate the cost of this delayed entry to Medicare over this period by estimating the difference between reported spending on originator adalimumab and estimated spending on originator and biosimilar adalimumab products assuming timely biosimilar market entry. Estimates of potential biosimilar spending were calculated based on the following evidence‐based projections: (i) market capture of 15% for the first biosimilar and 5.5% for successive biosimilars in their first year on the market, and 5% annually thereafter; (ii) price reductions of 3.5% per year and 2.4% per additional biosimilar entry for originator adalimumab; and (iii) price discounts of 25% at launch, 3.4% per year, and 1.7% per additional biosimilar entry for biosimilar adalimumab. Based on these assumptions, had adalimumab biosimilars launched upon approval, estimated non‐rebate spending on them would have been $18.3 million in 2016, $225.7 million in 2017, $436.2 million in 2018, and $727.7 million in 2019, whereas estimated non‐rebate spending on originator adalimumab would have been $2.33 billion, $2.04 billion, $1.78 billion, and $1.42 billion. Cumulative spending on adalimumab would have thus been $8.98 billion instead of an observed $12.11 billion. Accounting for estimated rebates, total predicted savings would have been $2.19 billion. Reforms for timely biosimilar availability will be critical in ensuring optimal savings for Medicare after biosimilar approval.
Analysis on Dielectric, Thermal, and Mechanical Characteristics of Nickel Boro Phthalate NLO Crystal for Optoelectronic Applications
Authors: Divya M. , Malliga P. , Sagayaraj P. , Joseph Arul Pragasam A. 
Published: June 2021

AbstractDielectric, thermal, and mechanical behavior of an efficient nonlinear crystal, nickel boro phthalate (NBP), grown by a slow evaporation solution growth technique, is characterized for optoelectronic applications. Ultraviolet absorption study identifies the lower cutoff wavelength as 281 nm. This low value along with transparency in the visible and infrared regions establishes that NBP is a probable nonlinear material. The frequency and the temperature dependency of dielectric constant and dielectric loss are probed. AC conductivity and activation energy are computed, to examine the semiconducting ability of the crystal. Thermal gravimetric analysis and differential thermal analysis are carried out to determine the decomposition temperature. Mechanical characterization is performed by the Vickers microhardness test. The study reveals that NBP comes under the category of soft material. Mechanical properties such as the elastic stiffness constant, brittleness index, yield strength, and fracture toughness are explored.
Animal‐borne video systems provide insight into the reproductive behavior of the Asian black bear
Authors: Naganuma Tomoko , Tanaka Mii , Tezuka Shiori , M.J.G. Steyaert Sam , Tochigi Kahoko , Inagaki Akino , Myojo Hiroaki , Yamazaki Koji , Koike Shinsuke 
Published: June 2021

AbstractPrevious studies on the mating system of the Asian black bear (Ursus thibetanus) have been limited to observations of captive populations and estimations of multiple paternities. Hence, the mating system of wild bears remains poorly understood. Animal‐borne camera systems (i.e., cameras mounted on animals) provide novel tools to study the behavior of elusive animals. Here, we used an animal‐borne video system to record the activities of wild bears during the mating season. Video camera collars were attached to four adult Asian black bears (male “A” and “B,” and female “A” and “B”) captured in Tokyo, central Japan, in May and June 2018. The collars were retrieved in July 2018, after which the video data were downloaded and analyzed in terms of bear activity and mating behavior. All the bears were found to interact with other uniquely identifiable bears for some of the time (range 9–22 days) during the deployment period (range 36–45 days), and multiple mating in males was documented. Both males and females exhibited different behaviors on social days (i.e., days when the bear interacted with conspecifics) compared with solitary days (i.e., days with no observed interactions with conspecifics). Compared with solitary days, the bears spent a lower proportion of time on foraging activities and higher proportion of time on resting activities on social days. Our results suggest that Asian black bears have a polygamous mating system, as both sexes consort and potentially mate with multiple partners during a given mating season. Furthermore, bears appeared to reduce their foraging activities on social days and engaged more in social interactions.
Trajectory of left ventricular geometry and diastolic dysfunction in hereditary transthyretin cardiac amyloidosis
Authors: Akatsuka Tatsuya , Fujimoto Naoki , Ishiyama Masaki , Nakamori Shiro , Imanaka‐Yoshida Kyoko , Dohi Kaoru 
Published: June 2021

AbstractAmyloid transthyretin (ATTR) depositions cause left ventricular (LV) hypertrophy, diastolic dysfunction, and heart failure. The time course of changes in LV geometry and diastolic dysfunction has not been fully reported in patients with ATTR cardiomyopathy. A 79‐year‐old woman with previous myocardial infraction presented with shortness of breath on exertion, and progressive bilateral lower extremity weakness and polyneuropathy. She was diagnosed with Val30Met hereditary ATTR cardiomyopathy by cardiac biopsy and genetic testing. During the past 5 year period, significant LV concentric remodelling with small LV cavity occurred, resulting in an increased LV stiffness and prolonged LV relaxation. This case report highlights the time course of changes in LV geometry and diastolic function and the importance of early diagnosis of ATTR cardiomyopathy.
Synthesis, Structure, and Bonding Properties of Hypercoordinate Triorganotin Compounds Featuring Three O→Sn Interactions
Authors: Kameo Hajime , Izumi Daisuke , Matsuzaka Hiroyuki 
Published: June 2021

AbstractHere, heptacoordinate and hexacoordinate triorganotin compounds [o‐{(Ph2)(O)P}C6H4]3SnX (X=F (2 a), Cl (2 b), Me (2 f)) featuring three O→Sn interactions were synthesized. Chloro (2 b) and methyl (2 f) compounds were obtained from the oxygenation of the heptacoordinate triorganotin compounds {o‐(Ph2P)C6H4}3SnX (X=Cl (1 b), Me (1 f)) bearing three P donors. The fluorination of 2 b using tetrabutylammonium fluoride (TBAF) yielded the fluoro analogue 2 a. Structural studies were performed on a series of hypercoordinate triorganotin compounds, 2. The chloro analogue (2 b) exhibited a hexacoordinate geometry attributed to the Sn−Cl bond cleavage, where the highly electrophilic stannyl cation was stabilized by three O donors. In contrast, both the fluoro (2 a) and methyl (2 f) analogues exhibited heptacoordinate structures. Although 2 f adopted a tricapped tetrahedral geometry, 2 b is classified to adopt a distinctly rare bicapped trigonal pyramidal geometry featuring one strong LP(O)→σ*(Sn−F) interaction and two weak LP(O)→σ*(Sn−C) interactions (LP: lone pair electrons). The origin of the structural alternations depending on the substituent is discussed using density functional theory (DFT) calculations.
The variations of free radical and index gas CO in spontaneous combustion of coal gangue under different oxygen concentrations
Authors: Jiang Xiaoyuan , Yang Shengqiang , Zhou Buzhuang , Song Wanxin , Cai Jiawen , Xu Qin , Zhou Quanchao , Yang Kai 
Published: June 2021

SummaryIn order to study the effect of oxygen concentrations on the change of active groups in the oxidation process of coal gangue, the airflows of different oxygen concentrations were prepared to simulate the oxidation and heating process of coal gangue under oxygen concentrations of 0%, 5%, 10%, 15%, and 21%. During the oxidation and heating process, the free radical parameters were measured at different temperatures in real time. The results show that in the early stage of coal gangue oxidation, the g factor remains at a lower level and do not start to increase until certain temperatures are reached. Besides, the higher the oxygen concentration is, the lower the temperature at which the g factor begins to increase. When the oxygen concentrations are 0%, 5%, 10%, 15%, and 21%, the corresponding temperatures are 225, 200, 150, 150, and 125°C, respectively. Furthermore, with the increase of oxidation temperature, the free radical concentrations experience four stages, namely, the slow increase stage, the rapid increase stage, the stagnant increase stage, and the final increase stage. And the higher the oxygen concentration is, the shorter the free radical stagnant increase stage is. During the oxidation of coal gangue, the line widths decrease slowly before 150°C, and then start to plunge and finally stabilize near the minimum at 350°C. Moreover, the higher the oxygen concentration is, the smaller the minimum values of line widths are. In the oxidation process of coal gangue, the gas product CO amounts are first at a lower level, and then begin to increase rapidly after 150°C. At the same temperature, the increased rates of CO production in coal gangue under the oxygen concentrations of 10%, 15%, and 21% are significantly higher than those under the oxygen concentrations of 0% and 5%. Based on the variation law of free radical parameters in coal gangue under different oxygen concentrations, the actual spontaneous combustion of gangue hills was analyzed and the free radical reaction mechanism of spontaneous combustion of gangue hills was discussed. The research results are of guiding significance for the treatment of spontaneous combustion of coal gangue.
Oral nano‐curcumin formulation efficacy in the management of mild to moderate outpatient COVID‐19: A randomized triple‐blind placebo‐controlled clinical trial
Authors: Ahmadi Reza , Salari Soofia , Sharifi Mohammad Davood , Reihani Hamidreza , Rostamiani Mohammad Bagher , Behmadi Morteza , Taherzadeh Zhila , Eslami Saeed , Rezayat Seyed Mahdi , Jaafari Mahmoud Reza , Elyasi Sepideh 
Published: June 2021

AbstractBackgroundCurcumin, a natural polyphenolic compound, is proposed as a potential treatment option for patients with coronavirus disease by inhibiting the entry of virus to the cell, encapsulation of the virus and viral protease, as well as modulating various cellular signaling pathways. In this study, the efficacy and safety of nanocurcumin oral formulation has been evaluated in patients with mild‐moderate Coronavirus disease 2019 (COVID‐19) in outpatient setting.MethodsIn this triple‐blind randomized placebo‐controlled clinical trial, sixty mild to moderate COVID‐19 patients in outpatient setting who fulfilled the inclusion criteria were randomly allocated to treatment (n = 30) group to receive oral nanocurcumin formulation (Sinacurcumin soft gel which contains 40 mg curcuminoids as nanomicelles), two soft gels twice a day after food for 2 weeks or placebo (n = 30) group. Patients’ symptoms and laboratory data were assessed at baseline and during follow‐up period and compared between two groups.ResultsAll symptoms except sore throat resolved faster in the treatment group and the difference was significant for chills, cough and smell and taste disturbances. The CRP serum level was lower in the treatment group at the end of two weeks and the lymphocyte count was significantly higher in treatment group. No significant adverse reaction reported in the treatment group.ConclusionOral nanoformulation of curcumin can significantly improve recovery time in patients with mild to moderate COVID‐19 in outpatient setting. Further studies with larger sample size are recommended.
Microbial characterization of the Japanese traditional pickle senmaizuke produced by two different manufacturing processes
Authors: Iguchi Hiroyuki 
Published: June 2021

AbstractSenmaizuke, a traditional turnip pickle, prepared in Kyoto, Japan, is produced via two types of manufacturing processes: with and without vinegar for fermentation. The aim of this study was to reveal the microbial community and growth behavior in the products and manufacturing processes of two types of senmaizuke. Microbial growth analysis of commercial senmaizuke products showed that both types harbored 102–108 colony forming units (CFU)/g of lactic acid bacteria (LAB) and 102–104 of yeast. The fermented‐type products showed successive growth of LAB during the pickling and ripening processes, whereas LAB in vinegar‐type products showed growth only at the preliminary pickling step before vinegar addition; however, the bacteria were viable at the ripening step. LAB in the vinegar‐type products showed growth when the pH of the pickle was neutralized, indicating that acidification via vinegar retards LAB growth. Metagenomic sequencing showed that the fermented‐type products harbored Lactobacillus, Leuconostoc, and other halophilic and psychrophilic bacteria, with a higher bacterial diversity than in the vinegar‐type products. In the vinegar‐type products, Lactobacillus, Leuconostoc, or both were predominant. Culture tests using LAB isolates and turnip medium suggested that a change in the dominance of Leuconostoc to Lactobacillus members observed in the fermented‐type products during pickling and ripening processes was attributed to the low pH sensitivity of Leuconostoc as well as a relatively long lag phase of growth for adapting to the pickling environment. The findings of this study will be useful for the appropriate quality control and assurance procedure of senmaizuke.
Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain
Authors: Nutma Erik , Gebro Emeline , Marzin Manuel C. , van der Valk Paul , Matthews Paul M. , Owen David R. , Amor Sandra 
Published: June 2021

AbstractTo monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro‐inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro‐inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans.
Microglia contribute to social behavioral adaptation to chronic stress
Authors: Piirainen Sami , Chithanathan Keerthana , Bisht Kanchan , Piirsalu Maria , Savage Julie Conner , Tremblay Marie‐Eve , Tian Li 
Published: June 2021

AbstractMicroglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive response of the brain and behavior toward stress using a mild and adaptive stress model – chronic restraint stress (CRS) – with wild type (WT) and CX3CR1‐GFP (CX3CR1[G]) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive‐like behaviors, but instead strengthened social dominance and short‐term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region‐specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206+microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1‐deficient microglia showed decreased CD206+ while increased MHCII+ subpopulations and hypo‐ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206+ microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1‐GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS‐treated mouse brains and showed a smaller interactome with other brain genes in the dorsal‐lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress.
Differences in survival and mortality in minority ethnic groups with dementia: A systematic review and meta‐analysis
Authors: Co Melissa , Couch Elyse , Gao Qian , Martinez Andrea , Das‐Munshi Jayati , Prina Matthew 
Published: June 2021

AbstractObjectivesAlthough there are disparities in both risk of developing dementia and accessibility of dementia services for certain minority ethnic groups in the United States and United Kingdom, disparities in survival after a dementia diagnosis are less well‐studied. Our objective was to systematically review the literature to investigate racial/ethnic differences in survival and mortality in dementia.MethodsWe searched Embase, Ovid MEDLINE, Global Health and PsycINFO from inception to November 2018 for studies comparing survival or mortality over time in at least two race/ethnicity groups. Studies from any country were included but analysed separately. We used narrative synthesis and random‐effects meta‐analysis to synthesise findings. The Newcastle–Ottawa Scale was used to assess quality and risk of bias in individual studies.ResultsWe identified 22 articles, most from the United States (n = 17), as well as the United Kingdom (n = 3) and the Netherlands (n = 1). In a meta‐analysis of US studies, hazard of mortality was lower in Black/African American groups (Pooled Hazard Ratio = 0.86, 95% CI = 0.82–0.91, I2 = 17%, from four studies) and Hispanic/Latino groups (Pooled HR = 0.65, 95% CI = 0.50–0.84, I2 = 86%, from four studies) versus comparison groups. However, study quality was mixed, and in particular, quality of reporting of race/ethnicity was inconsistent.ConclusionLiterature indicates that Black/African American and Hispanic/Latino groups may experience lower mortality in dementia versus comparison groups in the United States, but further research, using clearer and more and consistent reporting of race/ethnicity, is necessary to understand what drives these patterns and their implications for policy and practice.
Reply to Letter to the Editor regarding “Elective neck dissection and its extent in Salivary gland cancers: A Dilemma”
Authors: Westergaard‐Nielsen Marie , Godballe Christian , Eriksen Jesper Grau , Larsen Stine Rosenkilde , Kiss Katalin , Agander Tina , Ulhøi Benedicte Parm , Wittenborg Charabi Birgitte , Klug Tejs Ehlers , Jacobsen Henrik , Johansen Jørgen , Kristensen Claus Andrup , Andersen Elo , Andersen Maria , Bjørndal Kristine 
Published: June 2021

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Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer
Authors: Chaudhary Nazia , Choudhary Bhagya Shree , Shah Sanket Girish , Khapare Nileema , Dwivedi Nehanjali , Gaikwad Anagha , Joshi Neha , Raichanna Jinsy , Basu Srikanta , Gurjar Murari , P.K. Smitha , Saklani Avanish , Gera Poonam , Ramadwar Mukta , Patil Prachi , Thorat Rahul , Gota Vikram , Dhar Sujan K. , Gupta Sanjay , Das Manjula , Dalal Sorab N. 
Published: June 2021

AbstractLipocalin 2 is a siderophore‐binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over‐expressed, it leads to resistance to 5‐fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over‐expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo‐resistance and transformation in vitro, and a decrease in tumor progression and chemo‐resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in our study can serve as the basis for a potential therapeutic in patients who do not respond to chemotherapy.