bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in the diagnosis, evaluation, and management of leptomeningeal disease
Authors: Sener Ugur , Kumthekar Priya , Boire Adrienne 
Published: December 2021

Abstract
Leptomeningeal metastasis (LM) is a devastating complication of cancer with variable clinical presentation and limited benefit from existing treatment options. In this review, we discuss advances in LM diagnostics and therapeutics with the potential to reverse this grim course. Emerging cerebrospinal fluid circulating tumor cell and cell-free tumor DNA analysis technologies will improve diagnosis of LM, while providing crucial genetic information, capturing tumor heterogeneity, and quantifying disease burden. Circulating tumor cells and cell-free tumor DNA have utility as biomarkers to track disease progression and treatment response. Treatment options for LM include ventriculoperitoneal shunting for symptomatic relief, radiation therapy including whole-brain radiation and focal radiation for bulky leptomeningeal involvement, and systemic and intrathecal medical therapies, including targeted and immunotherapies based on tumor mutational profiling. While existing treatments for LM have limited efficacy, recent advances in liquid biopsy together with increasing availability of targeted treatments will lead to rational multimodal individualized treatments and improved patient outcomes.
Animal models of brain metastasis
Authors: Miarka Lauritz , Valiente Manuel 
Published: December 2021

Abstract
Modeling of metastatic disease in animal models is a critical resource to study the complexity of this multi-step process in a relevant system. Available models of metastatic disease to the brain are still far from ideal but they allow to address specific aspects of the biology or mimic clinically relevant scenarios. We not only review experimental models and their potential improvements but also discuss specific answers that could be obtained from them on unsolved aspects of clinical management.
The microenvironment of brain metastases from solid tumors
Authors: Srinivasan Ethan S , Deshpande Krutika , Neman Josh , Winkler Frank , Khasraw Mustafa 
Published: December 2021

Abstract
Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood–brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.
Modulation of the blood-tumor barrier to enhance drug delivery and efficacy for brain metastases
Authors: Blethen Kathryn E , Arsiwala Tasneem A , Fladeland Ross A , Sprowls Samuel A , Panchal Dhruvi M , Adkins Chris E , Kielkowski Brooke N , Earp Leland E , Glass Morgan J , Pritt Trenton A , Cabuyao Yssabela M , Aulakh Sonikpreet , Lockman Paul R 
Published: December 2021

Abstract
The blood-brain barrier is the selectively permeable vasculature of the brain vital for maintaining homeostasis and neurological function. Low permeability is beneficial in the presence of toxins and pathogens in the blood. However, in the presence of metastatic brain tumors, it is a challenge for drug delivery. Although the blood-tumor barrier is slightly leaky, it still is not permissive enough to allow the accumulation of therapeutic drug concentrations in brain metastases. Herein, we discuss the differences between primary brain tumors and metastatic brain tumors vasculature, effects of therapeutics on the blood-tumor barrier, and characteristics to be manipulated for more effective drug delivery.
Emergent immunotherapy approaches for brain metastases
Authors: Wang Jianbo , Tawbi Hussein A 
Published: December 2021

AbstractBrain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.
Itch perception is reflected by neuronal ignition in the primary somatosensory cortex
Authors: Chen Xiao-Jun , Liu Yan-He , Xu Ning-Long , Sun Yan-Gang 
Published: December 2021

Abstract
Multiple cortical areas including the primary somatosensory cortex (S1) are activated during itch signal processing, yet cortical representation of itch perception remains unknown. Using novel miniature two-photon microscopic imaging in free-moving mice, we investigated the coding of itch perception in S1. We found that pharmacological inactivation of S1 abolished itch-induced scratching behavior, and the itch-induced scratching behavior could be well predicted by the activity of a fraction of layer 2/3 pyramidal neurons, suggesting that a subpopulation of S1 pyramidal neurons encoded itch perception, as indicated by immediate subsequent scratching behaviors. With a newly established optogenetics-based paradigm that allows precisely controlled pruritic stimulation, we found that a small fraction of S1 neurons exhibited an ignition-like pattern at the detection threshold of itch perception. Our study revealed the neural mechanism underlying itch perceptual coding in S1, thus paving the way for the study of cortical representation of itch perception at the single-neuron level in freely moving animals.
A diagnostic conundrum in the context of a pandemic of Coronavirus Disease 2019 (COVID-19)
Authors: Abraham Deborah L , Omatseye Joyce , Gittens Jason 
Published: December 2021

ABSTRACT
A 52-year-old with lung cancer and brain metastases, on a 3-month weaning regime of dexamethasone, had a coincidental finding of bilateral, patchy ground-glass opacifications of both central and peripheral lung fields on computed tomography (CT). This was reported to be a sign of Coronavirus Disease 2019 (COVID-19). On Day 13, due to poor clinical progression and multiple negative reverse transcriptase-polymerase chain reaction tests for COVID-19, an alternative diagnosis was sought. Subsequently, this led to a diagnosis of Pneumocystis jirovecii pneumonia. This case demonstrates complicating factors in the diagnosis of COVID-19 and the presence of cognitive bias during a pandemic, which may lead clinicians to overlook a diagnosis, which may otherwise be addressed earlier.
Laser additive manufacturing of metallic glasses: issues in vitrification and mechanical properties
Authors: Madge Shantanu V , Greer A Lindsay 
Published: December 2021

AbstractBulk metallic glasses (BMGs), on account of their attractive properties, have now begun to witness a few commercial applications, e.g. in coatings and micro-gears. Additive manufacturing (AM) or 3D printing, although established for crystalline alloys, has only recently been used for synthesizing BMG components. The issues arising in 3D printing of BMGs are of current relevance, and this review focuses on the key scientific aspects, namely vitrification (or crystallization) during printing, mechanical properties of printed glassy alloys and the use of AM in identifying newer BMGs. Available data on crystallization during printing of a variety of BMGs are analysed in terms of schematic time–temperature–transformation diagrams and the complex interplay between thermal cycles, the presence of quenched-in nuclei in the glass and oxygen contamination in a way that is hoped to be broadly applicable to most alloy systems. Also reviewed are three key factors influencing mechanical properties of printed BMGs, i.e. porosity, crystallinity and oxygen contamination and thereby potential strategies for improvement are suggested. The review concludes with a discussion on the use of AM for combinatorial alloy development aimed at identifying better glass-forming compositions, which may in turn facilitate greater use of AM in manufacturing glassy components with desired properties.
Water, Fish and Property in Colonial India, 1860–1890
Authors: Shankar Devika 
Published: December 2021

Abstract
Almost exactly a hundred years after the Permanent Settlement of 1793 revolutionized property relations in Bengal, a far less studied legislation would subtly extend the rule of property to include the province’s waters. Bengal’s Private Fisheries Protection Act 1889, which is usually regarded as having been motivated by conservationist or economic concerns, was in fact an attempt to resolve intractable legal problems surrounding the status of flowing waters and fish that had confounded judges and colonial officials in India for decades. Could water be owned like land? And could fish swimming in open waters be claimed as property? These questions would give rise to a number of important disputes in colonial India in the late nineteenth century, during a time associated with unprecedented changes in the agrarian economy. Coinciding with other legal manoeuvres that increasingly helped to render water as property in other parts of the world, the Private Fisheries Protection Act and important judgments that preceded it helped to create exceptional private rights over flowing waters in colonial India. Turning to these developments, this article examines the ways in which judges attempted to resolve contradictions generated by water’s very materiality in an economy that rested so heavily on property.
A 2-oxoglutarate-dependent dioxygenase converts dihydrofuran to furan in Salvia diterpenoids
Authors: Song Jiao-Jiao , Fang Xin , Li Chen-Yi , Jiang Yan , Li Jian-Xu , Wu Sheng , Guo Juan , Liu Yan , Fan Hang , Huang Yan-Bo , Wei Yu-Kun , Kong Yu , Zhao Qing , Xu Jing-Jing , Hu Yong-Hong , Chen Xiao-Ya , Yang Lei 
Published: December 2021

Abstract
Tanshinone ⅡA (TⅡA), a diterpene quinone with a furan ring, is a bioactive compound found in the medicinal herb redroot sage (Salvia miltiorrhiza Bunge), in which both furan and dihydrofuran analogs are present in abundance. Progress has been made recently in elucidating the tanshinone biosynthetic pathway, including heterocyclization of the dihydrofuran D-ring by cytochrome P450s; however, dehydrogenation of dihydrofuran to furan, a key step of furan ring formation, remains uncharacterized. Here, by differential transcriptome mining, we identified six 2-oxoglutarate-dependent dioxygenase (2-ODD) genes whose expressions corresponded to tanshinone biosynthesis. We showed that Sm2-ODD14 acts as a dehydrogenase catalyzing the furan ring aromatization. In vitro Sm2-ODD14 converted cryptotanshinone to TⅡA and thus was designated TⅡA synthase (SmTⅡAS). Furthermore, SmTⅡAS showed a strict substrate specificity, and repression of SmTⅡAS expression in hairy root by RNAi led to increased accumulation of total dihydrofuran-tanshinones and decreased production of furan-tanshinones. We conclude that SmTⅡAS controls the metabolite flux from dihydrofuran- to furan-tanshinones, which influences medicinal properties of S. miltiorrhiza.
Suppression of chloroplast triose phosphate isomerase evokes inorganic phosphate-limited photosynthesis in rice
Authors: Suzuki Yuji , Ishiyama Keiki , Yoon Dong-Kyung , Takegahara-Tamakawa Yuki , Kondo Eri , Suganami Mao , Wada Shinya , Miyake Chikahiro , Makino Amane 
Published: December 2021

AbstractThe availability of inorganic phosphate (Pi) for ATP synthesis is thought to limit photosynthesis at elevated [CO2] when Pi regeneration via sucrose or starch synthesis is limited. We report here another mechanism for the occurrence of Pi-limited photosynthesis caused by insufficient capacity of chloroplast triose phosphate isomerase (cpTPI). In cpTPI-antisense transgenic rice (Oryza sativa) plants with 55%–86% reductions in cpTPI content, CO2 sensitivity of the rate of CO2 assimilation (A) decreased and even reversed at elevated [CO2]. The pool sizes of the Calvin–Benson cycle metabolites from pentose phosphates to 3-phosphoglycerate increased at elevated [CO2], whereas those of ATP decreased. These phenomena are similar to the typical symptoms of Pi-limited photosynthesis, suggesting sufficient capacity of cpTPI is necessary to prevent the occurrence of Pi-limited photosynthesis and that cpTPI content moderately affects photosynthetic capacity at elevated [CO2]. As there tended to be slight variations in the amounts of total leaf-N depending on the genotypes, relationships between A and the amounts of cpTPI were examined after these parameters were expressed per unit amount of total leaf-N (A/N and cpTPI/N, respectively). A/N at elevated [CO2] decreased linearly as cpTPI/N decreased before A/N sharply decreased, owing to further decreases in cpTPI/N. Within this linear range, decreases in cpTPI/N by 80% led to decreases up to 27% in A/N at elevated [CO2]. Thus, cpTPI function is crucial for photosynthesis at elevated [CO2].
Old Boys’ Clubs and Upward Mobility Among the Educational Elite
Authors: Michelman Valerie , Price Joseph , Zimmerman Seth D 
Published: December 2021

AbstractThis article studies how exclusive social groups shape upward mobility and whether interactions between low- and high-status peers can integrate the top rungs of the economic and social ladders. Our setting is Harvard University in the 1920s and 1930s, where new groups of students arriving on campus encountered a social system centered on exclusive old boys’ clubs. Combining archival and census records, we first show that students from prestigious private feeder schools are overrepresented in old boys’ clubs, while academic high achievers and ethnic minorities are almost completely absent. Club members earn $32\%$ more than other students and are more likely to work in finance and join country clubs, both characteristic of the era’s elite. We use random variation in room assignment to show that exposure to high-status peers expands gaps in college club membership, adult social club membership, and finance careers by high school type, with large positive effects for private school students and zero or negative effects for others. To conclude, we turn to more recent cohorts. We show that the link between exclusive college clubs and finance careers persists across the twentieth century even as Harvard diversifies, and that elite university students from the highest-income families continue to outearn their peers.
Off-farm income and direct payments—an indispensable diversification strategy of Swiss farmers
Authors: El Benni Nadja , Schmid Dierk 
Published: December 2021

Abstract
Following the theory of a farm household model, the relations between farm and farmer characteristics, including two different kinds of direct payments, and their effects on the off-farm labour allocation decisions of farm operators were analysed. Swiss farm accountancy data network (FADN) data of the years 2017, 2018, and 2019 for the whole sample and two different income groups were used to model both off-farm labour participation and supply decisions. The results show that diversification into off-farm employment is a highly relevant strategy of Swiss farmers and that direct payments are a complementary income source. Above a certain level, biodiversity payments show a substitution effect, meaning that off-farm participation is reduced. Off-farm labour supply is related not to direct payments but to production type and technology, with dairy and organic farmers having spent fewer days engaging in off-farm employment. Education positively correlates to off-farm labour participation. Even though off-farm income and direct payments are an indispensable income source for Swiss farmers, income-related policy goals cannot be considered achieved in terms of either farm or household income. Whether public money would be better spent on education than on unprofitable farm businesses should be analysed in future studies.
Clinical presentation and treatment response in patients with polymyalgia rheumatica and giant cell arteritis during a 40-week follow-up
Authors: Emamifar Amir , Hess Søren , Ellingsen Torkell , Gerke Oke , Ahangarani Farahani Ziba , Syrak Hansen Per , Jensen Hansen Inger Marie , Thye-Rønn Peter 
Published: December 2021

AbstractObjectivesThe aim was to study the clinical features of PMR/GCA and clinical predictors of treatment response during a 40-week follow-up period.MethodsClinical data on 77 patients with newly diagnosed PMR/GCA who were treated with oral glucocorticoids were gathered at baseline and during a 40-week follow-up period. A unilateral temporal artery biopsy (TAB) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT were undertaken at diagnosis. In total, each patient was seen on five occasions (i.e. baseline and weeks 4, 16, 28 and 40). Treatment response was assessed by considering clinical evaluations and results of inflammatory markers.ResultsOf 77 patients [49 (63.6%) female; mean age 71.8 (8.0) years], 64 (83.1%) patients had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. The patients reported that clinical symptoms, apart from scalp pain and duration of morning stiffness, improved significantly at week 4 and remained lower at week 40 compared with the relative frequencies at baseline. Besides, all components of physical examination showed significant improvement and remained lower at week 40 compared with the baseline. A complete response was seen in 68.7, 62.9, 44.1 and 33.3% of patients at weeks 4, 16, 28 and 40, respectively. Several clinical features, including female biological sex, younger age, fewer relapses and a lower level of baseline ESR, were significantly associated with a better treatment response. Treatment response during the follow-up period was independent of TAB results and fluorodeoxyglucose uptakes on 18F-FDG PET/CT at diagnosis.ConclusionObtaining valid disease-specific outcome measures for evaluating treatment efficacy in PMR and GCA that can be applied universally is clearly an unmet clinical need.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov, NCT02985424.
ImmunoStart: preparing patients for immunosuppression
Authors: Martin Charlotte , Muls Vinciane , Brasseur Céline , Meric de Bellefon Laurent , Lam Hoai Xuan-Lan , Vanderhilst Jeroen , Delforge Marc , Di Romana Silvana 
Published: December 2021

Abstract

Objectives
Patients with immune-mediated inflammatory disease (IMID) present an increased risk of infection. Here, we present the concept of a preventive consultation called ImmunoStart and the first results of its implementation in the care pathway of patients with IMID.

Methods
Relevant information about vaccination history, tuberculosis exposure and other infectious risks were collected through blood sampling, complete anamnesis, chest X-ray and Mantoux test. During the ImmunoStart consultation, vaccination schedules, specific treatments and risk considerations were discussed.

Results
Between October 2016 and February 2020, 437 patients were seen at an ImmunoStart consultation, mainly referred by rheumatologists (56%), dermatologists (25%) and gastroenterologists (18%). A total of 421 (96%) patients needed at least one vaccine (a mean of 3.3 vaccines per patient). Live attenuated vaccine was indicated for 45 patients (10%), requiring them to reduce or interrupt their immunosuppressive drug(s). Ninety-two patients (21%) were treated for latent tuberculosis infection.

Conclusion
This preventive consultation provides a centralized and systematic setting for the direct management of patients with IMID in need of vaccination, treatment of latent disease and specific advice regarding their immunomodulating treatments.
Amorphous calcium magnesium phosphate nanocomposites with superior osteogenic activity for bone regeneration
Authors: Jiang Yingying , Tan Shuo , Hu Jianping , Chen Xin , Chen Feng , Yao Qianting , Zhou Zhi , Wang Xiansong , Zhou Zifei , Fan Yunshan , Liu Junjian , Lin Yize , Liu Lijia , He Shisheng 
Published: December 2021

Abstract
The seek of bioactive materials for promoting bone regeneration is a challenging and long-term task. Functionalization with inorganic metal ions or drug molecules is considered effective strategies to improve the bioactivity of various existing biomaterials. Herein, amorphous calcium magnesium phosphate (ACMP) nanoparticles and simvastatin (SIM)-loaded ACMP (ACMP/SIM) nanocomposites were developed via a simple co-precipitation strategy. The physiochemical property of ACMP/SIM was explored using transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and high-performance liquid chromatograph (HPLC), and the role of Mg2+ in the formation of ACMP/SIM was revealed using X-ray absorption near-edge structure (XANES). After that, the transformation process of ACMP/SIM in simulated body fluid (SBF) was also tracked to simulate and explore the in vivo mineralization performance of materials. We find that ACMP/SIM releases ions of Ca2+, Mg2+ and PO43−, when it is immersed in SBF at 37°C, and a phase transformation occurred during which the initially amorphous ACMP turns into self-assembled hydroxyapatite (HAP). Furthermore, ACMP/SIM displays high cytocompatibility and promotes the proliferation and osteogenic differentiation of MC3T3-E1 cells. For the in vivo studies, lamellar ACMP/SIM/Collagen scaffolds with aligned pore structures were prepared and used to repair a rat defect model in calvaria. ACMP/SIM/Collagen scaffolds show a positive effect in promoting the regeneration of calvaria defect after 12 weeks. The bioactive ACMP/SIM nanocomposites are promising as bone repair materials. Considering the facile preparation process and superior in vitro/vivo bioactivity, the as-prepared ACMP/SIM would be a potential candidate for bone related biomedical applications.