bluuebunny/crossref_metadata_2025 huggingface dataset:
LW-5 DENDRITIC CELL IMMUNOTHERAPY FOR MALIGNANT GLIOMA: RESEARCH HISTORY FOR 25 YEARS AND THE FUTURE PROSPECTS
Authors: Akasaki Yasuharu , Kikuchi Tetsuro , Tnaka Toshihide , Murayama Yuichi
Published: December 2022

We started a research of dendritic cell (DC) immunotherapy for malignant glioma in late 1997, and were continuing the clinical study for more than 20 years with making several improvements of methods. The presenter has been participating in this research from its inception, and has continued to conduct research as the life's work. We will present research history and the future prospects. Autologous cultured tumor cells were established from tumor tissue obtained from a surgery of patient with malignant glioma in our hospital. Mature DCs were induced from autologous peripheral blood mononuclear cells (PBMC), and were fused with the established tumor cells. Cell manufacturing performed at a cell processing facility (CPF) maintained and managed by our university. Before 2004, the tumor-fused DCs (TFDC) were co-administrated with rIL-12. Since 2014, TFDCs were stimulated with Poly(I:C) and IL-10-siRNA in order to increase IL-12 secretion levels of them. Since 2014, PBMCs were collected by the apheresis method. Since 2006, the TFDC immunotherapy was combined with temozolomide (TMZ) chemotherapy. 111 cases were enrolled in the clinical study. The TFDC-immunotherapy was combined with the TMZ chemotherapy in 88 cases enrolled after 2006. No serious problem was confirmed in the cell manufacturing. The therapeutic effect in this study will be compared with a historical control that were the cases of malignant glioma treated with a standard therapy at the other affiliated hospitals at the same period. The results will be reported in the presentation. The safety and efficacy of this treatment were confirmed in the previous study. We would like to establish a provision system of the TFDCs by use of our CPF by preparing product uniformity, transport safety, preservation methods, etc., and aim to expand the hospitals that can perform this immunotherapy.
LW-6 OKAYAMA ROSAI HOSPITAL GLIOMA SUPPORT CENTER INITIATIVES
Authors: Adachi Yoshiaki
Published: December 2022

For glioblastoma, which is a rare and intractable disease, it is necessary to speed up the development and verification of new treatment methods through nationwide clinical trials by consolidating cases in the High Volume Center. Okayama University-related facilities have consolidated glioblastoma cases at Okayama University Hospital and are actively conducting high-precision surgery, genetic analysis, and clinical trials. On the other hand, there are cases where it is difficult to continue treatment at university hospitals, such as dissemination cases and poor Performance Status cases. In order to respond to this need with One Stop, we established the Okayama Rosai Hospital Glioma Support Center. We provide seamless support for postoperative radiation chemotherapy, rehabilitation, maintenance chemotherapy, alternating current electric field therapy, best supportive care, and end-of-life support including backward coordination. The goal is not to make glioblastoma patients and their families “cancer refugees” but to provide QOL-oriented treatment until the end within the comprehensive regional care system. We will report on the results of 29 cases of glioblastoma intervention from May 2013 to August 2022 and future issues.
LW-8 TREATMENT STRATEGY FOR OLIGODENDROGLIOMAS WITH NEOADJUVANT STRATEGY AND STAGED RESECTION UTILIZING THEIR CHEMOTHERAPEUTIC RESPONSIVENESS
Authors: Sasaki Hikaru , Kanazawa Tokunori , Kitamura Yohei , Nakaya Masato , Fujiwara Hirokazu , Kimura Tokuhiro , Nakae Shunsuke , Ohba Shigeo , Nishiyama Yuya , Toda Masahiro , Yoshida Kazunari , Hirose Yuichi
Published: December 2022

Background

In glioma surgery, both of functional preservation and maximal safe resection are critical, however, neoadjuvant strategy has never been used because of difficulty of tissue sampling without craniotomy.

Method

In Keio University Hospital, oligodendrogliomas, i.e., diffuse gliomas with IDH mutation and 1p/19q codeletion, with incomplete initial resection have been treated by upfront chemotherapy and subsequent resection after tumor volume decrease (second look resection, SLR) since 2006 (J Neurooncol 124:127-35, 2015). At first, initial radiotherapy was prescribed immediately after chemotherapy or SLR only for the cases with aggressive clinical course or subarachnoid infiltration, however, cases with residual FLAIR abnormality after upfront chemotherapy or SLR were also subjected to initial radiotherapy since 2018. Cases 1) with IDH mutation and 1p/19q codeletion, and 2) without history of either chemotherapy or radiotherapy, and 3) treated with upfront chemotherapy and subsequent resection strategy, were included.

Results

Thirty nine cases of oligodendroglioma have been treated with the above strategy since 2006. Tumor volume decrease following upfront chemotherapy was 30-35% (median), and 19 tumors underwent SLR. Among the total 39 cases, PFS and OS after initiation of upfront chemotherapy were 81 months and not reached, respectively, and were 64 months and not reached, respectively, among the 32 cases with deferred radiotherapy. Importantly, the majority of tumor recurrence occurred at the residual FLAIR abnormality following upfront chemotherapy.

Conclusions

Treatment of oligodendrogliomas utilizing neoadjuvant strategy enables 1) decrease of resection volume as compared with initial maximal safe resection, 2) more precise resection, 3) confirmation of the necessity of initial radiotherapy based on the observed efficacy of chemotherapy. Moreover, the study also suggested that 4) invasion front of oligodendroglioma likely withdraw by alkylating agents, and 5) cases with residual FLAIR abnormality following chemotherapy may be appropriate subjects for initial radiotherapy.
LW-10 PRECLINICAL THERAPEUTIC TESTING FOR BRAIN TUMOR USING PATIENT-DERIVED XENOGRAFT (PDX) MODEL
Authors: Hashizume Rintaro
Published: December 2022

I have been working on the brain tumor research about 20 years in the United State. My primary research interests in understanding of the mechanisms of genetic and epigenetic regulation that promote tumor development and progression, and identify novel therapeutic targets for the treatment of human brain cancer. For these purposes, I have developed many unique patient-derived xenograft (PDX) models for human brain tumors in the brains of immunocompromised mice. This animal model system has been shown to better preserve tumor characteristics, as manifested in patients, than tumor cell propagation in cell culture. In association with the development of these models, my laboratory utilizes numerous techniques to investigate brain tumor growth and response to novel agents that are administered singularly or in combinations, including with radiation. My laboratory employs the latest genomic/epigenomic technologies to identify novel genetic and epigenetics alteration that would reveal rational therapeutic targets, and test the anti-tumor activity of the therapeutics using PDX mouse model including diffuse intrinsic pontine glioma (DIPG) harboring histone H3 gene mutation (H3K27M). We have investigated the role of H3K27M mutations and histone modifications, and preclinical therapeutic testing in DIPG PDX models. In addition to the molecular targeted therapy, we recently implement AI machine learning approach and emerging patient genomic data to discover more effective and less toxic candidates from billions of compounds for brain tumor therapy. Moreover, we investigate new drug delivery systems to bypass the blood-brain barrier using convection-enhanced delivery and intranasal delivery. My long-term goal of my work further tests the efficacy of my approach preclinically and, if validated, move this therapeutic approach to clinical trial. In the meeting, I will present current advances in experimental therapeutics in my laboratory.
IL-1 TERT PROMOTER C228T MUTATION IN NEURAL PROGENITORS CONFERS GROWTH ADVANTAGE FOLLOWING TELOMERE SHORTENING IN VIVO
Authors: Furnari Frank , Miki Shunichiro , Koga Tomoyuki , Mckinney Andrew M , Parisian Alison D , Tadokoro Takahiro , Vadla Raghavendra , Masala Martin , Hevner Robert F , Costello Joseph F
Published: December 2022

Heterozygous TERT (Telomerase reverse transcriptase) promoter mutations (TPMs) facilitate TERT expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this mutation is one of the earliest events in gliomagenesis, however no appropriate human models have been engineered to study the role of this mutation in the initiation of these tumors. To address this, we established GBM models by introducing the heterozygous TPM in human induced pluripotent stem cells (hiPSCs) using a two-step targeting approach in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, and EGFRvIII overexpression. Orthotopic injection of neuronal precursor cells (NPCs) derived from hiPSCs with TPM into immunodeficient mice did not enhance tumorigenesis compared to TERT promoter wild type (TPW) NPCs at initial in vivo passage which we attribute to relatively long telomeres. We further show that the TPM mutation recruited GA-Binding Protein (GABPA) and engendered low-level TERT expression, resulting in enhanced tumorigenesis upon secondary passage and maintenance of short telomere length as has been reported in human GBM. RNA sequencing of harvested tumors grown as secondary spheres demonstrated upregulated proliferation and mitosis pathway signatures in TPM cells, consistent with their increased in vitro proliferation relative to TPW counterparts. Finally, when secondary TPM and TPW sphere cultures were reinjected into mice, only the TPM led to tumor formation. In summary, our novel GBM model illustrates a growth advantage imparted by heterozygous TPMs in the context of GBM driver mutations relative to isogenic controls, and thereby allows for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.
IL-2 TUMOR TREATING FIELDS: IMPROVING THE ODDS FOR PATIENTS WITH GLIOBLASTOMA
Authors: Hottinger Andreas F
Published: December 2022

Tumor treating fields (TTFields) is a novel, noninvasive regional antimitotic treatment modality approved for use in newly diagnosed glioblastoma (GBM). Nowadays, it is an integral part of the standard management of GBM. TTFields therapy delivers intermediate frequency (100-300 kHz), low intensity (1-3 V/cm), alternating electric fields to the tumor using transducer arrays placed on the scalp. TTFields disrupt mitotic spindle formation, block cell division and disrupt intracellular constituents, inducing apoptosis, autophagy and immune mediated cell death, as well as impairment of cell migration and DNA repair. A phase III trial of TTFields therapy in combination with maintenance temozolomide has established that TTFields are associated with minimal toxicity and result in a significant improvement of progression free survival and overall survival. Importantly, it also significantly increases the percentage of long-term survivors while maintaining the quality of life of the patients. Recent work has focused on a number of key parameters to better understand which patients are most likely to benefit from this new therapeutic approach. In this presentation, we will review the basics of TTFields therapy and the available clinical evidence that justify its use in GBM. We will also discuss how to best integrate this novel therapeutic approach in the current management of patients with newly diagnosed and progressing glioblastoma, highlighting how this was performed in the Swiss Institutions. We will also review and discuss recent work that analyzed the pertinence of TTFields in specific subgroups of patients, analyze patterns of progression under TTFields and discuss ongoing translational and clinical research.
IL-3 DISCONNECTING BRAIN TUMOR NETWORKS FOR IMPROVED THERAPIES
Authors: Winkler Frank
Published: December 2022

Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for very effective brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma growth(Venkataramani et al., Nature 2019) and invasion (Venkataramani et al., Cell 2022). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed.
IL-4 CHALLENGES FOR MANAGEMENT OF PRIMARY CNS LYMPHOMA
Authors: Nagane Motoo
Published: December 2022

Primary central nervous system lymphoma (PCNSL) affects primarily elderly patients and comprises 5% of all primary brain tumors with predominant histology of diffuse large B-cell lymphoma (DLBCL). Whole brain radiotherapy (WBRT) does not provide durable remission, rather is deeply involved in development of leukoencephalopathy with delayed neurotoxicity, especially in elderly patients. BBB-penetrating high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapies have been extensively explored and have shown high activities as induction regimens, followed by consolidation therapies such as high-dose chemotherapy with autologous stem-cell transplant (HDC/ASCT). Recent progress in understanding molecular pathogenesis of PCNSL has shed light on developing novel molecular targeted therapies against key signaling molecules such as Bruton’s tyrosine kinase (BTK) and pathways leading to constitutive activation of NF-kB signaling. In this lecture, standard of care for PCNSL with its molecular landscape and issues to be pursuit to further improve outcome of PCNSL treatment will be discussed.
IL-5 Targeted Therapies for Nervous System Tumors – Progress, Pitfalls, and Prospects
Authors: Batchelor Tracy
Published: December 2022

The molecular genetic understanding of nervous system tumors has expanded rapidly offering insight into potentially targetable oncogenic driver alterations. In monogenic tumor susceptibility syndromes such as tuberous sclerosis, neurofibromatosis type 1, and von Hippel Lindau syndrome targeted drugs have demonstrated efficacy and are now approved in the United States for the treatment of subependymal giant cell astrocytoma, plexiform neurofibroma, and hemangioblastoma, respectively. Some genetic alterations like BRAF V600E mutations or neurotrophic receptor tyrosine kinase (NTRK) fusions, occur across multiple cancers, including certain types of gliomas. Dabrafenib in combination with trametinib is approved for use in gliomas that harbor BRAF V600E mutations and larotrectinib is approved in gliomas that harbor certain NTRK fusions. In pediatric low-grade astrocytoma, one of the most common solid tumors of childhood, BRAF truncation-fusion events may render these tumors susceptible to tovorafenib, a type 2 RAF inhibitor, which is under study in clinical trials. Mutations in the isocitrate dehydrogenase (IDH) gene occur in the majority of low-grade and anaplastic gliomas, create specific metabolic vulnerabilities, and several IDH-mutant targeting strategies are under investigation. Glioblastoma is characterized by intratumoral molecular heterogeneity so strategies that target single genetic alterations may not be as effective as in other types of gliomas although a number of novel targeted strategies have been advanced to clinical trials. Other types of nervous system tumors such as medulloblastoma, meningioma, primary central nervous system diffuse large B-cell lymphoma, and craniopharyngioma harbor targetable genetic alterations and clinical trials are ongoing. Finally, metastatic brain tumors may harbor targetable genetic alterations that may differ from the primary site of cancer highlighting the importance of biopsy and molecular analysis of the brain metastases in order to enroll patients in clinical trials of targeted therapies.
The Personality Divide Between Citizens and Politicians: The Case of the Four Largest Spanish Parties
Authors: Galais Carol , Coller Xavier
Published: December 2022

Despite the alleged increasing importance given to politicians’ personalities, the similarities and differences between citizens and politicians regarding their personality traits have been insufficiently studied. This research analyses the personality similarities and differences between citizens and politicians in Spain across party allegiances and ideologies. For this, we use two representative surveys for citizens and MPs. Our results show that Spanish politicians are a more homogeneous population—regarding their personality traits—than Spanish citizens, and that Spanish MPs are more sociable and imaginative and less lazy and artistic than the average citizen, which is consistent with a ‘politician’s personality’.
Toward a systems view on RNA-binding proteins and associated RNAs in plants: Guilt by association
Authors: Mateos Julieta L , Staiger Dorothee
Published: December 2022

RNA-binding proteins (RBPs) have a broad impact on most biochemical, physiological, and developmental processes in a plant’s life. RBPs engage in an on-off relationship with their RNA partners, accompanying virtually every stage in RNA processing and function. While the function of a plethora of RBPs in plant development and stress responses has been described, we are lacking a systems-level understanding of components in RNA-based regulation. Novel techniques have substantially enlarged the compendium of proteins with experimental evidence for binding to RNAs in the cell, the RNA-binding proteome. Furthermore, ribonomics methods have been adapted for use in plants to profile the in vivo binding repertoire of RBPs genome-wide. Here, we discuss how recent technological achievements have provided novel insights into the mode of action of plant RBPs at a genome-wide scale. Furthermore, we touch upon two emerging topics, the connection of RBPs to phase separation in the cell and to extracellular RNAs. Finally, we define open questions to be addressed to move toward an integrated understanding of RBP function.
Calcyclin-binding protein-promoted degradation of MdFRUCTOKINASE2 regulates sugar homeostasis in apple
Authors: Su Jing , Jiao Tiantian , Liu Xi , Zhu Lingcheng , Ma Baiquan , Ma Fengwang , Li Mingjun
Published: December 2022

Fructokinase (FRK) activates fructose through phosphorylation, which sends the activated fructose into primary metabolism and regulates fructose signaling capabilities in plants. The apple (Malus × domestica) FRK gene MdFRK2 shows especially high affinity to fructose, and its overexpression decreases fructose levels in the leaves of young plants. However, in the current study of mature plants, fruits of transgenic apple trees overexpressing MdFRK2 accumulated a higher level of fructose than wild-type (WT) fruits (at both young and mature stages). Transgenic apple trees with high mRNA MdFRK2 expression showed no significant differences in MdFRK2 protein abundance or FRK enzyme activity compared to WT in mature leaves, young fruits, and mature fruits. Immunoprecipitation–mass spectrometry analysis identified an skp1, cullin, F-box (SCF) E3 ubiquitin ligase, calcyclin-binding protein (CacyBP), that interacted with MdFRK2. RNA-sequencing analysis provided evidence for ubiquitin-mediated post-transcriptional regulation of MdFRK2 protein for the maintenance of fructose homeostasis in mature leaves and fruits. Further analyses suggested an MdCacyBP–MdFRK2 regulatory module, in which MdCacyBP interacts with and ubiquitinates MdFRK2 to facilitate its degradation by the 26S proteasome, thus decreasing the FRK enzyme activity to elevate fructose concentration in transgenic apple trees. This result uncovered an important mechanism underlying plant fructose homeostasis in different organs through regulating the MdFRK2 protein level via ubiquitination and degradation. Our study provides usable data for the future improvement of apple flavor and expands our understanding of the molecular mechanisms underlying plant fructose content and signaling regulation.
Fatty acid amide hydrolase and 9-lipoxygenase modulate cotton seedling growth by ethanolamide oxylipin levels
Authors: Arias-Gaguancela Omar , Aziz Mina , Chapman Kent D
Published: December 2022

Polyunsaturated N-acylethanolamines (NAEs) can be hydrolyzed by fatty acid amide hydrolase (FAAH) or oxidized by lipoxygenase (LOX). In Arabidopsis (Arabidopsis thaliana), the 9-LOX product of linoleoylethanolamide, namely, 9-hydroxy linoleoylethanolamide (9-NAE-HOD), is reported to negatively regulate seedling development during secondary dormancy. In upland cotton (Gossypium hirsutum L.), six putative FAAH genes (from two diverged groups) and six potential 9-LOX genes are present; however, their involvement in 9-NAE-HOD metabolism and its regulation of seedling development remain unexplored. Here, we report that in cotton plants, two specific FAAH isoforms (GhFAAH Ib and GhFAAH IIb) are needed for hydrolysis of certain endogenous NAEs. Virus-induced gene silencing (VIGS) of either or both FAAHs led to reduced seedling growth and this coincided with reduced amidohydrolase activities and elevated quantities of endogenous 9-NAE-HOD. Transcripts of GhLOX21 were consistently elevated in FAAH-silenced tissues, and co-silencing of GhLOX21 and GhFAAH (Ib and/or IIb) led to reversal of seedling growth to normal levels (comparable with no silencing). This was concomitant with reductions in the levels of 9-NAE-HOD, but not of 13-NAE-HOD. Pharmacological experiments corroborated the genetic and biochemical evidence, demonstrating that direct application of 9-NAE-HOD, but not 13-NAE-HOD or their corresponding free fatty acid oxylipins, inhibited the growth of cotton seedlings. Additionally, VIGS of GhLOX21 in cotton lines overexpressing AtFAAH exhibited enhanced growth and no detectable 9-NAE-HOD. Altogether, we conclude that the growth of cotton seedlings involves fine-tuning of 9-NAE-HOD levels via FAAH-mediated hydrolysis and LOX-mediated production, expanding the mechanistic understanding of plant growth modulation by NAE oxylipins to a perennial crop species.
The staphylococcal biofilm protein Aap mediates cell–cell adhesion through mechanically distinct homophilic and lectin interactions
Authors: Wang Can , Chantraine Constance , Viljoen Albertus , Herr Andrew B , Fey Paul D , Horswill Alexander R , Mathelié-Guinlet Marion , Dufrêne Yves F
Published: December 2022

The accumulation phase of staphylococcal biofilms relies on both the production of an extracellular polysaccharide matrix and the expression of bacterial surface proteins. A prototypical example of such adhesive proteins is the long multidomain protein Aap (accumulation-associated protein) from Staphylococcus epidermidis, which mediates zinc-dependent homophilic interactions between Aap B-repeat regions through molecular forces that have not been investigated yet. Here, we unravel the remarkable mechanical strength of single Aap–Aap homophilic bonds between living bacteria and we demonstrate that intercellular adhesion also involves sugar binding through the lectin domain of the Aap A region. We find that the mechanical force needed to unfold individual β-sheet-rich G5-E domains from the Aap B-repeat regions is very high, ranging from 300 up to 1,000 pN at high loading rates, indicating these are extremely stable. This high mechanostability provides a means to the cells to form highly adhesive and cohesive biofilms capable of sustaining high physiological shear stress. Importantly, we identify a previously undescribed role of Aap in bacterial–bacterial adhesion, that is, heterophilic sugar binding by a specific lectin domain located in the N-terminal A region, which might be important to establish initial contacts between cells before strong homophilic bonds come into play. This study emphasizes the remarkable mechanical and binding properties of Aap as well as its wide diversity of adhesive functions.
Delocalization and re-entrant localization of flat-band states in non-Hermitian disordered lattice models with flat bands
Authors: Kim Sangbum , Kim Kihong
Published: December 2022

We present a numerical study of Anderson localization in disordered non-Hermitian lattice models with flat bands. Specifically, we consider 1D stub and 2D kagome lattices that have a random scalar potential and a uniform imaginary vector potential and calculate the spectra of the complex energy, the participation ratio, and the winding number as a function of the strength of the imaginary vector potential, h. The flat-band states are found to show a double transition from localized to delocalized and back to localized states with h, in contrast to the dispersive-band states going through a single delocalization transition. When h is sufficiently small, all flat-band states are localized. As h increases above a certain critical value h1, some pairs of flat-band states become delocalized. The participation ratio associated with them increases substantially and their winding numbers become nonzero. As h increases further, more and more flat-band states get delocalized until the fraction of the delocalized states reaches a maximum. For larger h values, a re-entrant localization takes place and, at another critical value h2, all flat-band states return to compact localized states with very small participation ratios and zero winding numbers. This re-entrant localization transition, which is due to the interplay among disorder, non-hermiticity, and the flat band, is a phenomenon occurring in many models having an imaginary vector potential and a flat band simultaneously. We explore the spatial characteristics of the flat-band states by calculating the local density distribution.
Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness
Authors: Jensen Søren B , Sheikh Mashhood A , Akkouh Ibrahim A , Szabo Attila , O’Connell Kevin S , Lekva Tove , Engh John A , Agartz Ingrid , Elvsåshagen Torbjørn , Ormerod Monica B E G , Weibell Melissa A , Johnsen Erik , Kroken Rune A , Melle Ingrid , Drange Ole K , Nærland Terje , Vaaler Arne E , Westlye Lars T , Aukrust Pål , Djurovic Srdjan , Eiel Steen Nils , Andreassen Ole A , Ueland Thor
Published: December 2022

Background and Hypothesis

Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI.

Study Design

We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation.

Study Results

Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4.

Conclusions

Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.
Integration of genome-scale data identifies candidate sleep regulators
Authors: Lee Yin Yeng , Endale Mehari , Wu Gang , Ruben Marc D , Francey Lauren J , Morris Andrew R , Choo Natalie Y , Anafi Ron C , Smith David F , Liu Andrew C , Hogenesch John B
Published: December 2022

Study Objectives

Genetics impacts sleep, yet, the molecular mechanisms underlying sleep regulation remain elusive. In this study, we built machine learning models to predict sleep genes based on their similarity to genes that are known to regulate sleep.

Methods

We trained a prediction model on thousands of published datasets, representing circadian, immune, sleep deprivation, and many other processes, using a manually curated list of 109 sleep genes.

Results

Our predictions fit with prior knowledge of sleep regulation and identified key genes and pathways to pursue in follow-up studies. As an example, we focused on the NF-κB pathway and showed that chronic activation of NF-κB in a genetic mouse model impacted the sleep-wake patterns.

Conclusion

Our study highlights the power of machine learning in integrating prior knowledge and genome-wide data to study genetic regulation of complex behaviors such as sleep.
The memory sources of dreams: serial awakenings across sleep stages and time of night
Authors: Picard-Deland Claudia , Konkoly Karen , Raider Rachel , Paller Ken A , Nielsen Tore , Pigeon Wilfred R , Carr Michelle
Published: December 2022

Memories of waking-life events are incorporated into dreams, but their incorporation is not uniform across a night of sleep. This study aimed to elucidate ways in which such memory sources vary by sleep stage and time of night. Twenty healthy participants (11 F; 24.1 ± 5.7 years) spent a night in the laboratory and were awakened for dream collection approximately 12 times spread across early, middle, and late periods of sleep, while covering all stages of sleep (N1, N2, N3, REM). In the morning, participants identified and dated associated memories of waking-life events for each dream report, when possible. The incorporation of recent memory sources in dreams was more frequent in N1 and REM than in other sleep stages. The incorporation of distant memories from over a week ago, semantic memories not traceable to a single event, and anticipated future events remained stable throughout sleep. In contrast, the relative proportions of recent versus distant memory sources changed across the night, independently of sleep stage, with late-night dreams in all stages having relatively less recent and more remote memory sources than dreams earlier in the night. Qualitatively, dreams tended to repeat similar themes across the night and in different sleep stages. The present findings clarify the temporal course of memory incorporations in dreams, highlighting a specific connection between time of night and the temporal remoteness of memories. We discuss how dream content may, at least in part, reflect the mechanisms of sleep-dependent memory consolidation.
Effect of Tithonia diversifolia (Hemsl.) A. Gray intake on in vivo methane (CH4) emission and milk production in dual-purpose cows in the Colombian Amazonian piedmont
Authors: Rivera Julián Esteban , Villegas Gonzalo , Chará Julian , Durango Sandra G , Romero Miguel A , Verchot Louis
Published: December 2022

The inclusion of Tithonia diversifolia in pasture-based diets is a promising alternative to increase bovine productivity, due to its chemical composition and wide adaptation, but there are few in vivo studies to determine its effect on methane yield and animal production in grazing systems. The objective of this study was to determine the effects of the T. diversifolia inclusion in a basal diet of Brachiaria humidicola on methane (CH4) emissions by enteric fermentation, and on milk yield and quality in dual-purpose cows. The polytunnel technique was used for the determination of methane yield and two diets were evaluated (Diet 1: Brachiaria humidicola 100%; Diet 2: T. diversifolia 15% + B. humidicola 85% dry matter basis) in the moderate rainy and rainy seasons using a cross-over experimental design; milk production was measured by daily milk weighing, and milk quality was determined using a LACTOSCAN analyzer. The inclusion of T. diversifolia did not increase the dry matter intake (P = 0.369), but increased the intake of crude protein and minerals, and reduced fiber intake, resulting in the increased yield of milk and its components in the moderate rainy season (P = 0.012). The inclusion of T. diversifolia reduced the absolute CH4 emissions (P = 0.016), Ym and emission intensity (per unit of fat, protein and kilogram fat and protein corrected milk yields) both in the moderate rainy and rainy seasons (P < 0.05). We conclude that the inclusion of T. diversifolia in the forage feed base in the humid tropics such as the Amazon piedmont can be used as a tool to both mitigate enteric CH4 emissions and to increase animal productivity and hence reduce emissions intensity, and thus reduce pressure on the agricultural frontier in critical areas such as the Amazon.
Comparing the yield and nutritional value of ensiled amaranth (Amaranthus hypochondriacus) cultivars with corn silage (Zea mays) in doublecropping condition
Authors: Hosseini Sayed Ahmad , Rouzbehan Yousef , Fazaeli H , Rezaei Javad
Published: December 2022

Yield, chemical composition, and fermentation variables were compared for amaranth silages (AMS) from five cultivars (A5, A12, A14, A28, and Maria) and corn (Zea mays; CS). In vitro methane production, organic matter disappearance, microbial protein, ammonia-N concentration, volatile fatty acid levels, cellulolytic bacteria and protozoa populations, and in situ dry matter (DM) and crude protein (CP) degradability were evaluated. All crops were harvested when the plant was at the mid-milk line stage, then chopped, placed in sealed 5 L plastic bags and stored for 60 days. Data analysis was carried out using the PROC MIXED method of SAS with a randomized complete block design. The mean DM forage yield of CS was higher than the average DM yield of the amaranth cultivars (P < 0.001). In comparison with CS, the AMS had higher CP, lignin, ether extract, ash, calcium, phosphorus, magnesium, total phenolics and metabolizable protein (P < 0.001), but had lower DM, neutral detergent fiber, non-fiber carbohydrates, organic matter disappearance, lactic acid (P < 0.01) and in vitro methane production (P = 0.001). The AMS had higher (P < 0.01) pH, ammonia-N concentration, in vitro microbial protein, in situ digestible undegradable protein, and metabolizable protein compared to CS. Overall, in comparison to CS, the amaranths produced a silage of medium-quality.
Identifying high-confidence variants in human cytomegalovirus genomes sequenced from clinical samples
Authors: Camiolo Salvatore , Hughes Joseph , Baldanti Fausto , Furione Milena , Lilleri Daniele , Lombardi Giuseppina , Angelini Micol , Gerna Giuseppe , Zavattoni Maurizio , Davison Andrew J , Suárez Nicolás M
Published: December 2022

Understanding the intrahost evolution of viral populations has implications in pathogenesis, diagnosis, and treatment and has recently made impressive advances from developments in high-throughput sequencing. However, the underlying analyses are very sensitive to sources of bias, error, and artefact in the data, and it is important that these are addressed adequately if robust conclusions are to be drawn. The key factors include (1) determining the number of viral strains present in the sample analysed; (2) monitoring the extent to which the data represent these strains and assessing the quality of these data; (3) dealing with the effects of cross-contamination; and (4) ensuring that the results are reproducible. We investigated these factors by generating sequence datasets, including biological and technical replicates, directly from clinical samples obtained from a small cohort of patients who had been infected congenitally with the herpesvirus human cytomegalovirus, with the aim of developing a strategy for identifying high-confidence intrahost variants. We found that such variants were few in number and typically present in low proportions and concluded that human cytomegalovirus exhibits a very low level of intrahost variability. In addition to clarifying the situation regarding human cytomegalovirus, our strategy has wider applicability to understanding the intrahost variability of other viruses.
Refugees and Housing: Evidence from the Mortgage Market
Authors: Akgündüz Yusuf Emre , Hacıhasanoğlu Yavuz Selim , Yılmaz Fatih
Published: December 2022

This paper investigates the impact of large-scale Syrian refugee inflows on the Turkish housing market. Employing a micro-level data set of the population of mortgaged houses in Türkiye between 2010 and 2017, it identifies the dynamic effects using a difference-in-differences approach. As the regional distribution of Syrian refugees is presumably not exogenous, it is instrumented in the estimations. The instrument is constructed using the distance from Turkish provinces to each Syrian region, while weighting each Syrian region by their population and distance to Türkiye compared to other destination countries. The results show that house prices increased in response to the arrival of Syrian refugees. The effects are mostly driven by low-priced housing and faded after 2014. The results further show that construction permits and sales increased, while the average age of purchased houses declined, indicating an increase in supply that may explain the fading-out effect over time. Finally, the findings provide suggestive evidence that houses that are sold after the arrival of refugees decline in size, which further points to a squeeze in the housing market for natives.
Comparative morphological study of the gnathochilarium of millipedes of the suborder Cambalidea (Juliformia: Spirostreptida) assessed by discrete and morphometric character approaches
Authors: Moretti Iniesta Luiz Felipe , Enghoff Henrik , Bouzan Rodrigo S , Brescovit Antonio D
Published: December 2022

Phylogenetic relationships of the suborder Cambalidea have been a well-known focus of discussion over the past 100 years. The most recent approach to the suborder is based on the morphology of the sexual structure of males and of the gnathochilarium. The phylogenetic interpretation of the gnathochilarium has been especially criticized due to the poorly understood evolution of its components since no hypothesis of homology has been put forward. This work provides a comparative study of characters of the gnathochilarium. Twenty-one characters are proposed and optimized for 34 terminals from the orders Julida and Spirostreptida. Two datasets were analysed on the basis of whether the sclerite duplomentum corresponds to a mentum fused to a promentum or only to an elongated mentum (promentum being absent). Concatenated analyses were performed with both discrete and morphometric characters to verify the variation in shape of the mentum. In all topologies obtained, Cambalidea were recovered as paraphyletic in terms of the suborder Spirostreptidea. Through constrained searches, Cambalidae, Cambalopsidae and Iulomorphidae were not recovered, while Pseudonannolenidae were recovered only when Physiostreptinae were excluded. The morphological evidence indicates the convergence of the gnathochilarium in Spirostreptidea and in some members of Cambalidea, with independent reversions of the promentum.
Usefulness of Intraoperative Arthrography for Postaxial Polysyndactyly of the Foot
Authors: Sakai Yuko , Kawamura Daisuke , Endo Takeshi , Iwasaki Norimasa
Published: December 2022

Background:

Surgery for polydactyly of the foot aims to achieve good cosmesis and improve shoe fitting. An accurate understanding of toe morphology will help to minimize the skin incision or optimize the surgical plan before incision. However, it is difficult to determine the shape of the articular surface using radiographs of children with immature bone. We performed arthrography during surgery for postaxial polydactyly of the foot to assess the cartilaginous structures. The purpose of this study was to investigate the usefulness of arthrography in postaxial polydactyly of the foot.

Methods:

We included 36 digits of 31 patients (16 males and 15 females), including 5 bilateral cases. The age at surgery ranged from 9 to 75 months (mean, 20 mo). Intraoperative arthrography was performed and all radiographs and arthrograms were reviewed and classified by 3 observers using the Watanabe classification. The absolute percentage agreement between the observers was calculated. The senior author assigned the arthrograms as the reference. The types determined by the other 2 observers using radiographs and arthrograms were compared with the reference.

Results:

Full agreement occurred in 66.7% of the radiographs and in 75% of arthrograms. The mean kappa coefficient was 0.58, indicating fair agreement, between the reference and the radiologic assessment, while it was 0.81, indicating excellent or almost perfect agreement, in the evaluation using arthrograms.

Conclusions:

Intraoperative arthrography is an easy and reliable diagnostic method that can be used to determine the detailed articular shape.

Level of Evidence:

Level III.
Implementing a Standardized Workflow Process to Increase the Palliative Care to Hospice Admission Rate
Authors: Boyd Charissa , DiBartolo Mary C. , Helne D'Jenie , Everett Keith
Published: December 2022

Background:

Palliative care is a precursor for hospice care, an underutilized Medicare benefit that has been shown to improve quality of life, decrease health care costs, and provide expert symptom relief at the end of life.

Local Problem:

Palliative patients transitioning to hospice services were experiencing delays within the admission process.

Purpose:

To determine whether standardizing the workflow process with chart completion leads to increases in the hospice admission rate for palliative care patients transitioning to hospice care.

Methods:

This quality improvement project adapted Kurt Lewin's change theory and the Plan-Do-Study-Act (PDSA) cycle for implementation. Preintervention patient data were collected from May 2021 through August 2021, and postintervention data were collected from September 2021 through December 2021.

Interventions:

Standardization of the workflow process included assigning an urgency level to the hospice referral and deactivation (close) of the electronic medical record (EMR) chart, signaling completion of the workflow process.

Results:

The palliative care to hospice admission rate increased by 11.5% in the postintervention group. The EMR chart deactivation rate increased by 55.3%, which was statistically significant (P ≤ .001).

Conclusions:

The standardized workflow process increased the number of palliative care to hospice admissions and improved the effectiveness of transitioning palliative care patients to hospice services.
Reversible Dementia With Bilateral White Matter Changes Caused by Dural Arteriovenous Fistula
Authors: Zeng Yangqiao , Li Xiaoqin , Chen Wei , Du Juan , Tao Tao
Published: December 2022

Introduction:

Dural arteriovenous fistula (DAVF) is a vascular malformation. Although rare, DAVFs can represent a potentially reversible cause of dementia. Bilateral white matter changes can be detected on the magnetic resonance imaging of patients with DAVFs. Familiarity with symptoms of DAVFs can reduce the incidence of misdiagnosis of dementia syndrome. This study aimed to explore the clinical manifestation, imaging characteristics, and prognosis of dementia with bilateral white matter changes caused by DAVFs.

Case Report:

A 56-year-old man presented with memory deterioration, tinnitus, and weakness in both lower limbs for over 2 months. Magnetic resonance imaging of the brain revealed white matter signal changes in the bilateral ventricles and centrum semiovale, which manifested as low signal on T1-weighted imaging, high signal on T2-weighted imaging, fluid-attenuated inversion recovery, and diffusion-weighted imaging. Digital subtraction angiography revealed DAVFs along the lateral sinus. The patients’ condition improved significantly after endovascular embolization of the DAVFs.

Conclusions:

DAVFs presenting with dementia are rare and cases with bilateral white matter alterations can be easily misdiagnosed as other diseases. If the patient has dementia and bilateral alterations in the white matter, a DAVF should be considered. This type of dementia is reversible and may be associated with venous hypertension caused by arteriovenous fistulas. Early digital subtraction angiography is important to reduce misdiagnoses.
Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT)
Authors: Saksena Annapurna , Jain Ashish , Pack Svetlana D. , Kim Jung , Lee Ina , Tyagi Manoj , Xi Liqiang , Pittaluga Stefania , Raffeld Mark , Jaffe Elaine S.
Published: December 2022

Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma (FL) based on genomic and clinical features. The nature of other extranodal FLs is not well defined. We report 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization forBCL2gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization forBCL2gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealedTNFRSF14as the most frequently mutated gene in 6/10 (60%) cases. No case hadCREBBPorKMT2Dmutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5 y) with a 5-year overall survival of 100%. We conclude that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas.