Miracle-dz/UniFAR-FTUs huggingface dataset:
Brainstem gliomas in pregnancy: a systematic review†

Abstract Introduction: Although brainstem gliomas are a rare group of neoplasias, when they affect pregnant women, there can be challenges with diagnosis and management. This study describes a case of brainstem glioma diagnosed in pregnancy and systematically reviews the literature on brainstem gliomas in pregnancy to provide guidance for management. Material and methods: We searched five databases from inception until October 2016 using subject headings and keywords related to pregnancy and brainstem glioma, and included original research articles that described pregnancy outcomes in women with brainstem glioma. Data extraction and quality assessment using the Joanna Briggs Institute Critical Appraisal Checklist for case reports were performed in duplicate. Outcomes were reported as proportions. The study protocol was registered with the Prospero International Prospective Register of Systematic Reviews (CRD42017060196). Results: We screened 2737 titles and abstracts, and 89 full-texts. Twelve articles describing 17 pregnancies in 16 women were included in the analysis. The median gestational age at presentation was 23 weeks. All but one case presented with neurologic deficit. Magnetic resonance (MRI) imaging conclusively diagnosed all cases. Surgical tumor resection (n = 4) and radiation therapy (n = 3) were successfully undertaken during pregnancy. There were no reported sequelae of maternal oncological management on neonatal wellbeing. Maternal mortality was high (8/16, 50%) both during (n = 5) and within 4 weeks (n = 3) of pregnancy. Pregnancy losses included one pregnancy termination and four miscarriages (associated with maternal mortality). Of the 12 live-born babies, five were premature. Two of these were the result of spontaneous preterm labor and three were delivered prematurely to facilitate glioma management. There was one case of fetal growth restriction. Conclusions: Although the symptoms of brainstem gliomas often mimic those commonly encountered in pregnancy, neurologic deficits warrant urgent investigation. MRI is the diagnostic modality of choice in pregnancy. Brainstem gliomas are associated with high maternal mortality and appropriate management, including surgical tumor resection and radiation therapy, should not be delayed on account of pregnancy. Pregnancy outcomes are favorable although there is a risk of preterm birth. Key message Brainstem gliomas are associated with high maternal mortality and timely diagnosis using magnetic resonance imaging and treatment including surgical resection and radiation therapy should not be delayed during pregnancy. Pregnancy outcomes are generally favorable except for risk of preterm birth.
Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer

Data from patients and a mouse model show that surgery for bladder cancer causes immune dysfunction and decreases efficacy of immunotherapy. Low-dose rapamycin mitigated these problems through effects on the tumor and through modulating T-cell function. The mechanistic target of rapamycin (mTOR) integrates environmental inputs to regulate cellular growth and metabolism in tumors. However, mTOR also regulates T-cell differentiation and activation, rendering applications of mTOR inhibitors toward treating cancer complex. Preclinical data support distinct biphasic effects of rapamycin, with higher doses directly suppressing tumor cell growth and lower doses enhancing T-cell immunity. To address the translational relevance of these findings, the effects of the mTOR complex 1 (mTORC1) inhibitor, rapamycin, on tumor and T cells were monitored in patients undergoing cystectomy for bladder cancer. MB49 syngeneic murine bladder cancer models were tested to gain mechanistic insights. Surgery-induced T-cell exhaustion in humans and mice and was associated with increased pulmonary metastasis and decreased PD-L1 antibody efficacy in mouse bladder cancer. At 3 mg orally daily, rapamycin concentrations were 2-fold higher in bladder tissues than in blood. Rapamycin significantly inhibited tumor mTORC1, shown by decreased rpS6 phosphorylation in treated versus control patients (P = 0.008). Rapamycin reduced surgery-induced T-cell exhaustion in patients, evidenced by a significant decrease in the prevalence of dysfunctional programmed death-1 (PD-1)–expressing T cells. Grade 3 to 4 adverse event rates were similar between groups, but rapamycin-treated patients had a higher rate of wound complications versus controls. In conclusion, surgery promoted bladder cancer metastasis and decreased the efficacy of postoperative bladder cancer immunotherapy. Low-dose (3 mg daily) oral rapamycin has favorable pharmacodynamic and immune modulating activity in surgical patients and has the potential to decrease surgery-induced immune dysfunction.
Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

Neuroinflammation is one of the key secondary injury mechanisms triggered by traumatic brain injury (TBI). Microglial activation, a hallmark of brain neuroinflammation, plays a critical role in regulating immune responses after TBI and contributes to progressive neurodegeneration and neurologic deficits following brain trauma. Here we evaluated the role of neutral sphingomyelinase (nSMase) in microglial activation by examining the effects of the nSMase inhibitors altenusin and GW4869 in vitro (using BV2 microglia cells and primary microglia), as well as in a controlled cortical injury (CCI) model in adult male C57BL/6 mice. Pretreatment of altenusin or GW4869 prior to lipopolysaccharide (LPS) stimulation for 4 or 24 hours, significantly downregulated gene expression of the pro-inflammatory mediators TNF-α, IL-1β, IL-6, iNOS, and CCL2 in microglia and reduced the release of nitric oxide and TNF-α. These nSMase inhibitors also attenuated the release of microparticles and phosphorylation of p38 MAPK and ERK1/2. In addition, altenusin pretreatment also reduced the gene expression of multiple inflammatory markers associated with microglial activation after experimental TBI, including TNF-α, IL-1β, IL-6, iNOS, CCL2, CD68, NOX2, and p22phox. Overall, our data demonstrate that nSMase inhibitors attenuate multiple inflammatory pathways associated with microglial activation in vitro and after experimental TBI. Thus, nSMase inhibitors may represent promising therapeutics agents targeting neuroinflammation.
A novel age‐related venous amyloidosis derived from EGF‐containing fibulin‐like extracellular matrix protein 1

Most intractable tissue‐degenerative disorders share a common pathogenic condition, so‐called proteinopathy. Amyloid‐related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid‐related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor‐containing fibulin‐like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C‐terminal regions of EFEMP1. In vitro studies showed that C‐terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age‐related venous amyloid‐related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid‐related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Streptomyces Cytochrome P450 Enzymes and Their Roles in the Biosynthesis of Macrolide Therapeutic Agents

The study of the genus Streptomyces is of particular interest because it produces a wide array of clinically important bioactive molecules. The genomic sequencing of many Streptomyces species has revealed unusually large numbers of cytochrome P450 genes, which are involved in the biosynthesis of secondary metabolites. Many macrolide biosynthetic pathways are catalyzed by a series of enzymes in gene clusters including polyketide and non-ribosomal peptide synthesis. In general, Streptomyces P450 enzymes accelerate the final, post-polyketide synthesis steps to enhance the structural architecture of macrolide chemistry. In this review, we discuss the major Streptomyces P450 enzymes research focused on the biosynthetic processing of macrolide therapeutic agents, with an emphasis on their biochemical mechanisms and structural insights.
Artificial intelligence in glaucoma

Purpose of review The use of computers has become increasingly relevant to medical decision-making, and artificial intelligence methods have recently demonstrated significant advances in medicine. We therefore provide an overview of current artificial intelligence methods and their applications, to help the practicing ophthalmologist understand their potential impact on glaucoma care. Recent findings Techniques used in artificial intelligence can successfully analyze and categorize data from visual fields, optic nerve structure [e.g., optical coherence tomography (OCT) and fundus photography], ocular biomechanical properties, and a combination thereof to identify disease severity, determine disease progression, and/or recommend referral for specialized care. Algorithms have become increasingly complex in recent years, utilizing both supervised and unsupervised methods of artificial intelligence. Impressive performance of these algorithms on previously unseen data has been reported, often outperforming standard global indices and expert observers. However, there remains no clearly defined gold standard for determining the presence and severity of glaucoma, which undermines the training of these algorithms. To improve upon existing methodologies, future work must employ more robust definitions of disease, optimize data inputs for artificial intelligence analysis, and improve methods of extracting knowledge from learned results. Summary Artificial intelligence has the potential to revolutionize the screening, diagnosis, and classification of glaucoma, both through the automated processing of large data sets, and by earlier detection of new disease patterns. In addition, artificial intelligence holds promise for fundamentally changing research aimed at understanding the development, progression, and treatment of glaucoma, by identifying novel risk factors and by evaluating the importance of existing ones.
Cholinesterases and Engineered Mutants for the Detection of Organophosphorus Pesticide Residues

Nowadays, pesticide residues constitute an increasing public health concern. Cholinesterases, acetylcholinesterase, and butyrylcholinesterase, are reported to be involved in detoxification processes owing to their capability of scavenging organophosphates and carbamates. Thus, these enzymes are targeted for the discovery of sensors aiming at detecting pesticide residues. In recent years, cholinesterase-based biosensors have attracted more and more attention in the detection of pesticides. Herein, this review describes the recent progress on the engineering of cholinesterases and the development of the corresponding sensors that could be used for the detection of organophosphorus pesticide residues.
Enhanced Thermoelectric Properties of Ca3−xAgxCo4O9 by the Sol–Gel Method with Spontaneous Combustion and Cold Isostatic Pressing

In this study, Ca3−xAgxCo4O9 ceramics were synthesized by the sol–gel method combined with spontaneous combustion and cold isostatic pressing. The Ca3−xAgxCo4O9 ceramics were characterized via X-ray diffraction and scanning electron microscopy. Thermoelectric properties of the ceramics were measured from 323 to 673 K. The results indicated that Ag doping significantly affected the microstructure and thermoelectric properties. With the increase in Ag content and gradual increase in electrical conductivity, the Seebeck coefficient first increased and then decreased, whereas the thermal conductivity exhibited the opposite case. The figure of merit, ZT, was 0.17 at 673 K for the Ca2.8Ag0. 2Co4O9 sample. These results indicated that the thermoelectric properties could be optimized remarkably with the substitution of Ag.
The Effect of Providing Free Eyeglasses on Children’s Mental Health Outcomes in China: A Cluster-Randomized Controlled Trial

If children with common vision problems receive and use eyeglasses, their educational performance rises. Without proper treatment, visually impaired children may not achieve educational gains and could suffer from poor mental health. We use a randomized controlled trial to study the impact of an eyeglasses promotion program in rural China on the mental health of myopic primary school students. Three measures of mental health are used: learning anxiety, physical anxiety, and scores on the Mental Health Test (MHT). Our empirical analysis showed that on average, the treatment has small and insignificant for learning anxiety and MHT, and a small but significant reduction in physical anxiety. However, subgroup analysis reveals that myopic students who study more intensively see their learning anxiety and physical anxiety reduced after being provided with eyeglasses. In contrast, students with the lower study intensity suffer a rise in learning anxiety after receiving eyeglasses. A potential mechanism for the differing impacts is the increase in teasing reported among low study-intensity students that does not occur for high study-intensity students. Care should be taken to maximize the benefits and minimize the costs of in-school vision programs.
Smoking during pregnancy increases chemerin expression in neonatal tissue

What is the central question of this study? Is chemerin, an adipokine implicated in obesity, increased in neonates following in utero cigarette smoke exposure. What is the main finding and its importance? Chemerin mRNA expression was increased and chemerin DNA methylation was decreased in babies born to mothers who smoked during pregnancy. These data provide a potential mechanism that may be mediating the increased obesity risk in individuals that are born to mothers who smoked during pregnancy.
Synbiotic combination of prebiotic grape pomace extract and probiotic Lactobacillus sp. reduced important intestinal inflammatory markers and in-depth signalling mediators in lipopolysaccharide-treated Caco-2 cells

Abstract Inflammatory bowel diseases (IBD) are a major problem for public health, with an increased incidence and impact on life quality. The effect of pre- and probiotic combination has been less studied in IBD. Using genomic and proteomic array technologies, this study examined the efficacy of a new combination of natural alternatives: prebiotics (grape pomace extract, GP) and probiotics (lactobacilli mixture, Lb mix) on inflammation and intracellular signalling routes in a cellular model of inflammation. Caco-2 cells challenged with lipopolysaccharide (LPS) for 4 h were treated with GP extract (50 μg/ml gallic acid equivalent) and Lb combination (3 × 108 colony-forming units/ml total Lb) for 24 h. The profile expressions of forty key inflammatory markers and twenty-six signalling kinases were analysed. Other markers involved in inflammation were also investigated (NF-κB/RELA, Nrf2, aryl hydrocarbon receptor, Cyp1A1, Cyp1B1); 57·5 and 60 % of investigated genes and proteins, respectively, were down-regulated by the synbiotic combination. Relevant cytokines and chemokines involved in response to microbial infection and inflammation were reduced under the level induced by LPS treatment and toward the unchallenged control. As expected, the reduction effect seems to imply mitogen-activated protein kinase and NF-κB pathway. Most of the signalling molecules activated by LPS were decreased by GP extract and Lb mix. Our study indicates that the synbiotic combination of GP extract and Lactobacillus sp. mixture exerted anti-inflammatory properties, which are able to decrease the majority of inflammatory genes, their proteins and associated signalling markers. Due to protective role of GP compounds on lactobacilli probiotic, this synbiotic combination might serve as a promising adjunctive therapy in intestinal inflammations.
Random-Effects Meta-analysis: Summarizing Evidence With Caveats

Questions involving medical therapies are often studied more than once. For example, numerous clinical trials have been conducted comparing opioids with placebos or nonopioid analgesics in the treatment of chronic pain. In the December 18, 2018, issue of JAMA, Busse et al1 evaluated the evidence on opioid efficacy from 96 randomized clinical trials and, as part of that work, used random-effects meta-analysis to synthesize results from 42 randomized clinical trials on the difference in pain reduction among patients taking opioids vs placebo using a 10-cm visual analog scale (Figure 2 in Busse et al). 1 Meta-analysis is the process of quantitatively combining study results into a single summary estimate and is a foundational tool for evidence-based medicine. Random-effects meta-analysis is the most common approach.
Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models

Purpose: Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy. Experimental Design: DNA damage and changes in cell signaling following in vitro prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line–derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies. Results: Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment in vitro, resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively. Conclusions: Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies.
Desired Features of a Digital Technology Tool for Self-Management of Well-Being in a Nonclinical Sample of Young People: Qualitative Study

Background Adaptive coping behaviors can improve well-being for young people experiencing life stressors, while maladaptive coping can increase vulnerability to mental health problems in youth and into adulthood. Young people could potentially benefit from the use of digital technology tools to enhance their coping skills and overcome barriers in help-seeking behaviors. However, little is known about the desired digital technology use for self-management of well-being among young people in the general population. Objective This is a small, qualitative study aimed at exploring what young people desire from digital technology tools for the self-management of their well-being. Methods Young people aged 12-18 years were recruited from the general community to take part in semistructured interviews. Recorded data from the interviews were transcribed and analyzed using inductive thematic analysis. Results In total, 14 participants were recruited and completed the study, with a mean age of 14.6 years (female n=3). None of the participants reported using any digital tools specifically designed to manage well-being. However, as indicated through the emerged themes, young people used digital technology to reduce their stress levels and manage their mood, mainly through games, music, and videos. Overall, identified themes showed that young people were keen on using such tools and desired certain facets and features of an ideal tool for self-management of well-being. Themes related to these facets indicated what young people felt a tool should do to improve well-being, including being immersed in a stress-free environment, being uplifting, and that such a tool would direct them to resources based on their needs. The feature-based themes suggested that young people wanted the tool to be flexible and enable engagement with others while also being sensitive to privacy. Conclusions The young people interviewed in this study did not report engaging with digital technology specialized to improving well-being but instead used media already accessed in their daily lives in order to self-manage their psychological states. As a result, the variety of coping strategies reported and digital tools used was limited to the resources that were already being used for recreational and social purposes. These findings contribute to the scarce research into young people’s preferred use of digital technology tools for the self-management of their well-being. However, this was a small-scale study and the current participant sample is not representative of the general youth population. Therefore, the results are only tentative and warrant further investigation.