bluuebunny/crossref_metadata_2025 huggingface dataset:
18 Clinical features in 104 patients investigated for potential autoimmune encephalitis at a London teaching hospital after presenting with psychotic symptoms
Authors: Morrin Hamilton , Pollak Thomas A , Nasir Moneeb
Published: November 2023

Objectives/Aims

The aim of this retrospective study was to describe characteristics and diagnostic outcomes of patients presenting with psychosis to a general hospital who were investigated for possible autoimmune encephalitis (AE).

Methods

Electronic patient records were used to identify patients who had presented with psychosis to a London teaching hospital, were reviewed by neurology, and in whom the diagnosis of autoimmune encephalitis had been considered. Data were collected on clinical features, admission length, investigation results, antibody results, whether immunotherapy was given, whether response was seen to immunotherapy, and final diagnosis. A diagnosis of AE was defined as meeting the Graus criteria for either definite NMDA receptor encephalitis, or definite autoimmune limbic encephalitis. Clinical features were compared between AE (meeting definite criteria) and all other causes of psychosis. Patients with a likely diagnosis of AE (but not meeting definite criteria) were excluded from analyses. Anonymized data were analysed using SPSS28. Subgroup comparisons for categorical variables were conducted using Pearson’s χ2 test.

Results

104 suitable patients were identified as having presented with psychotic symptoms and undergone investigation for AE. Year of presentation ranged from 2010 – 2021. 24 were found to have AE with the most common subtype being NMDA receptor encephalitis (N=14). 80 had psychosis due to other causes, most commonly: primary psychiatric disorders (N=24), suspected AE not meeting definite criteria (N=16), infectious (N=9), and neurodegenerative (N=7). Impaired consciousness (p=0.010) was found to be significantly more common in the AE group compared to the non-AE group. No significant difference in frequency of seizures, speech symptoms, sleep disruption, movement disorders, cognitive dysfunction, autonomic dysregulation, focal neurology, encephalopathy, adverse reaction to antipsychotics, and current/recent tumour was observed. Focused comparison of patients with AE and those with primary psychiatric disorders found significant difference in frequency of impaired cognition (p = 0.009) and encephalopathy (p = 0.007).

Conclusions

Impaired consciousness is seen more frequently in AE compared to other causes of psychosis. In combination with other clinical features this may lend support to a potential diagnosis of AE. Limitations include selection bias from patient screening, and observer bias from medical record retrospective review. There is a need for future prospective longitudinal studies to guide development of clinical guidelines for the detection of AE presenting with psychotic symptoms.
21 How can we collaborate with experts-by-example to improve the ecological validity of computational psychiatry? A pilot study where the experts-by-experience are people with functional neurological disorder (FND) and the overall aim is to understand what leads patients unilaterally to disengage from psychotherapy
Authors: Vuqetrna Elseja , Selai Caroline , Golder Dawn , Moutoussis Michael
Published: November 2023

Background

This project is one component of a larger project which, using computational neuropsychiatry, aims to understand what leads patients unilaterally to disengage from psychotherapy. Computational Neuropsychiatry is a promising new field which has yielded great gains in many areas. However, it has not fulfilled it early promise and it is suggested that one reason is because computational modelling has lacked input from Experts-by experience who can enhance the validity of the model by contributing their personal (real world) insights.

Aims

(i) to assess the feasibility of recruiting a specific group of Experts-by-experience i.e. people with Functional Neurological Disorder (FND) to help us to design and refine a Computational Neuropsychiatry task (ii) to develop guidelines for future recruitment of Experts-by-experience to collaborate on computational neuropsychiatry tasks, drawing on this specific example of people with FND.

Methods

The Experts-by-experience were recruited from amongst the membership of the charity FND Hope International, the first and only global charity for people with Functional Neurological Disorder. We held four group meetings on zoom. The meetings had a number of themes including (i) education e.g. what is computational neuropsychiatry?, (ii) the political and cultural context e.g. how collaboration with Experts-by-experience can reduce power inequalities in medical research (iii) the process e.g. an enquiry into how best to engage Experts-by-experience (iv) catharsis e.g. an opportunity for the participants to contribute both as representatives or advocates of the wider group of people with FND and as themselves i.e. sharing their unique personal experience. Two of the researchers who convened the groups (CS & MM) took extensive notes during the meetings and these notes were the raw data.

Analysis

The data were transcribed and analysed using qualitative data analysis methods i.e. to identify and code the key themes.

Results

Our experts-by-experience were intrigued by the computational neuropsychiatry task and by the contextual background i.e. how people with FND can be empowered to collaborate on and to co-facilitate clinical research. They contributed ideas on how people with FND can input. They shared their personal stories of their interaction with healthcare professionals, both positive and less successful experiences including ruptures in the therapeutic alliance and times when they had decided unilaterally to disengage from therapy. Key themes emerging e.g. the (crucial) need to take time to develop trust and forge a strong (collaborative) working alliance will be used to develop guidelines for future research collaboration with Experts-by experience.
Autism and neurodiversity: a new paradigm
Authors: Fletcher-Watson Sue
Published: November 2023

Sue Fletcher-Watson holds a Personal Chair in Developmental Psychology at the University of Edinburgh, and is Director of the Salvesen Mindroom Research Centre. She is interested in how children grow and learn, with a particular focus on development, neurodiversity and autism across the lifespan. Her work draws on rigorous methods from psychology and applies these to questions with clinical, educational and societal impact. She strives to achieve meaningful partnerships with community representatives and to support neurodivergent leadership in research. She is an advocate for open science and good citizenship in research, and serves as Co-Director of Research Ethics for the College of Medicine and Veterinary Medicine.

Neurodiversity is a simple, incontrovertible scientific fact, and yet the implications of this concept are both profound and radical. In this talk I will briefly examine how we have attempted to define, diagnose and support autistic people to date, showing the failings of these approaches. I will then go on to define neurodiversity and three core tenets of the neurodiversity paradigm. I will directly address some of the myths around neurodiversity, drawing on the work of prominent neurodivergent scholars to provide a solid basis for understanding. In the second half of the talk, I will then explore the potential of a neurodiversity paradigm to improve how we identify and provide support to autistic people. I will work through the implications of neurodiversity for clinical diagnostic and therapeutic practice, including a specific rebuttal of concerns that the neurodiversity movement is aligned with an anti-psychiatry position. I will ask: what would neurodiversity-affirmative services look like? And why and how should we create them?
Implementing survival analysis to capture stochastic characteristics of saturation flow rate considering the impacts of adverse road-weather conditions
Authors: Hirose Ryutaro , Mehran Babak , Pani Agnivesh , Omrani Reza , Sahu Prasanta
Published: November 2023

Saturation flow rate (SFR) variations were analyzed using the video data collected at a signalized intersection in Winnipeg, Canada, to investigate the implications of adverse road-weather (RW) conditions for SFR distributions and characteristics. Survival analysis was implemented to develop stochastic SFR distribution functions considering censored data and a statistical analysis method was developed for determining the optimal critical vehicle (CV) for measurement of saturation headway. The analysis findings suggest that adverse RW conditions decrease SFR significantly and moves CV to the front of the queue while having little impact on SFR considering heavy vehicles. Furthermore, the findings imply that the conventional SFR estimation method overestimates the probability of saturation at a given flow rate. The proposed analysis method reveals stochastic characteristics of SFR and provides a method to estimate SFR distributions under different RW conditions, which is essential for improving the operation of signalized intersections, particularly in cold regions.
Non-exotic traversable wormholes in $$f\left( R,T_{ab}T^{ab}\right) $$ gravity
Authors: Luís Rosa João , Ganiyeva Nailya , Lobo Francisco S. N.
Published: November 2023

In this work we analyze traversable wormhole spacetimes in the framework of a covariant generalization of Einstein’s General Relativity known as energy–momentum squared gravity, or $$f\left( R,{\mathcal {T}}\right) $$

f

R
,
T

gravity, where R is the Ricci scalar, $${\mathcal {T}}=T_{ab}T^{ab}$$

T
=

T

ab

T

ab

, and $$T_{ab}$$

T

ab

is the energy–momentum tensor. Considering a linear $$f\left( R,{\mathcal {T}}\right) =R+\gamma {\mathcal {T}}$$

f

R
,
T

=
R
+
γ
T

form, we show that a wide variety of wormhole solutions for which the matter fields satisfy all the energy conditions, namely the null, weak, strong and dominant energy conditions, exist in this framework, without the necessity for a fine-tuning of the free parameters that describe the model. Due to the complexity of the field equations these solutions are obtained through an analytical recursive algorithm. A drawback of the solutions obtained is that they are not naturally localized, and thus a matching with an external vacuum is required. For that purpose, we derive the junction conditions for the theory, and we prove that a matching between two spacetimes must always be smooth, i.e., no thin-shells are allowed at the boundary. Finally, we use these junction conditions to match the interior wormhole spacetime to an exterior vacuum described by the Schwarzschild solution, thus obtaining traversable localized static and spherically symmetric wormhole solutions satisfying all energy conditions for the whole spacetime range. We also prove that the methods outlined in this work can be straightforwardly generalized to more complicated dependencies of the action in $${\mathcal {T}}$$
T
, as long as crossed terms between R and $${\mathcal {T}}$$
T
are absent.
Quantum and Approximation Algorithms for Maximum Witnesses of Boolean Matrix Products
Authors: Kowaluk Mirosław , Lingas Andrzej
Published: November 2023

The problem of finding maximum (or minimum) witnesses of the Boolean product of two Boolean matrices (MW for short) has a number of important applications, in particular the all-pairs lowest common ancestor (LCA) problem in directed acyclic graphs (dags). The best known upper time-bound on the MW problem for [Formula: see text] Boolean matrices of the form [Formula: see text] has not been substantially improved since 2006. In order to obtain faster algorithms for this problem, we study quantum algorithms for MW and approximation algorithms for MW (in the classical computational model). Some of our quantum algorithms are input or output sensitive. Our fastest quantum algorithm for the MW problem, and consequently for the related problems, runs in time [Formula: see text], where [Formula: see text] satisfies the equation [Formula: see text] and [Formula: see text] is the exponent of the multiplication of an [Formula: see text] matrix by an [Formula: see text] matrix. Next, we consider a relaxed version of the MW problem (in the classical model) asking for reporting a witness of bounded rank (the maximum witness has rank 1) for each non-zero entry of the matrix product. First, by adapting the fastest known algorithm for maximum witnesses, we obtain an algorithm for the relaxed problem that reports for each non-zero entry of the product matrix a witness of rank at most [Formula: see text] in time [Formula: see text] Then, by reducing the relaxed problem to the so called [Formula: see text]-witness problem, we provide an algorithm that reports for each non-zero entry [Formula: see text] of the product matrix [Formula: see text] a witness of rank [Formula: see text], where [Formula: see text] is the number of witnesses for [Formula: see text], with high probability. The algorithm runs in [Formula: see text] time, where [Formula: see text].
Alzheimer’s Disease Evaluation Through Visual Explainability by Means of Convolutional Neural Networks
Authors: Mercaldo Francesco , Di Giammarco Marcello , Ravelli Fabrizio , Martinelli Fabio , Santone Antonella , Cesarelli Mario
Published: November 2023

Background and Objective: Alzheimer’s disease is nowadays the most common cause of dementia. It is a degenerative neurological pathology affecting the brain, progressively leading the patient to a state of total dependence, thus creating a very complex and difficult situation for the family that has to assist him/her. Early diagnosis is a primary objective and constitutes the hope of being able to intervene in the development phase of the disease. Methods: In this paper, a method to automatically detect the presence of Alzheimer’s disease, by exploiting deep learning, is proposed. Five different convolutional neural networks are considered: ALEX_NET, VGG16, FAB_CONVNET, STANDARD_CNN and FCNN. The first two networks are state-of-the-art models, while the last three are designed by authors. We classify brain images into one of the following classes: non-demented, very mild demented and mild demented. Moreover, we highlight on the image the areas symptomatic of Alzheimer presence, thus providing a visual explanation behind the model diagnosis. Results: The experimental analysis, conducted on more than 6000 magnetic resonance images, demonstrated the effectiveness of the proposed neural networks in the comparison with the state-of-the-art models in Alzheimer’s disease diagnosis and localization. The best results in terms of metrics are the best with STANDARD_CNN and FCNN with accuracy, precision and recall between 98% and 95%. Excellent results also from a qualitative point of view are obtained with the Grad-CAM for localization and visual explainability. Conclusions: The analysis of the heatmaps produced by the Grad-CAM algorithm shows that in almost all cases the heatmaps highlight regions such as ventricles and cerebral cortex. Future work will focus on the realization of a network capable of analyzing the three anatomical views simultaneously.
Quantum-inspired Probabilistic Database Corruption Detection
Authors: Salazar Roberto
Published: November 2023

A crucial problem of machine learning is the management of unclean probabilistic databases. We approach this problem by applying recent results and methods from quantum information to detect a specific class of database corruption. We present a quantifier of the global corruption of the probabilistic database and show its relationship with detection protocols based on generalized Bell inequalities. Furthermore, we show a relation between the noise generating the corruption and information encoded in the database schema. Finally, we discuss how our work indicates a way to export quantum information results to study noise in probabilistic databases.
A KNETSCH PROPOSITION AND A DUE PROCESS FOR THE EVALUATION OF MINING PROJECTS IN ECOLOGICALLY SENSITIVE AREAS: AN ILLUSTRATION THROUGH TWO AUSTRALIAN CASE STUDIES
Authors: LODHI IFTHIKAR A. , THAMPAPILLAI DODO J.
Published: November 2023

Drawn on some Knetsch observations, this paper illustrates a due process for the economic evaluation of mining projects that impact sensitive and irreversible ecological assets. Towards this end, two case studies of coal mining projects in Australia are considered — one on the Liverpool Plains in New South Wales and the other on the Galilee Basin in Central Queensland. The adverse environmental and social externalities of these projects are well known — especially the impacts on the Gunnedah and the Great Artesian Basins. Notwithstanding these impacts, which are exceedingly difficult to value, private financial analyses demonstrate significant revenue gains. Mining firms find such gains difficult to ignore. Nevertheless, economic analyses illustrate that the net benefits to Australia are possibly absent even without accounting for the costs of environmental social externalities. Given that the property rights of the mineral reserves are vested with the State, the Resource Rent Tax (RRT) becomes a legitimate fiscal policy tool. The paper argues that the assessment of mining decisions must account for the depreciation of the Mineral asset. When this depreciation is measured alongside the Hartwick–Rule, the mining projects demonstrate monetary viability only when the RRT is enforced and is invested in its entirety on options that generate annual returns in excess of 3% to 4%. If recognized, the costs of environmental and social externalities could readily wipe out this, and for that matter any, monetary viability owing to the irreversible nature of the natural social endowments.
Plane vortex pairs, colorful structures and low-lying Dirac modes
Authors: Hosseini Nejad Seyed Mohsen
Published: November 2023

In this paper, we investigate the influence of topological charges on nonstable zero and near-zero modes of the single uni-color plane vortex pairs. We combine the uni-color plane vortices with the spherical vortex and also construct the plane vortex pairs with two colorful vortices. The stability of zero and near-zero modes is analyzed where various boundary conditions for the fermions are checked. In addition, plane vortex pairs may show the role of the topological charges for changing the chirality of fermions. The results clearly indicate characteristic properties for spontaneous chiral symmetry breaking.
Open charm mesons and charmonium states in magnetized strange hadronic medium at finite temperature
Authors: Mishra Amruta
Published: November 2023

In this paper, we investigate the masses of the pseudoscalar ([Formula: see text]([Formula: see text], [Formula: see text]), [Formula: see text]([Formula: see text], [Formula: see text]) and vector open charm mesons ([Formula: see text]([Formula: see text], [Formula: see text]), [Formula: see text]([Formula: see text], [Formula: see text]) as well as the pseudoscalar ([Formula: see text], [Formula: see text]) and the vector charmonium states ([Formula: see text], [Formula: see text], [Formula: see text]) in the asymmetric hot strange hadronic medium in the presence of strong magnetic fields. In the magnetized medium, the mass modification of open charm mesons due to their interactions with baryons and the scalar fields ([Formula: see text], [Formula: see text], and [Formula: see text]) is investigated in a chiral effective model. Moreover, the charged pseudoscalar meson ([Formula: see text]), as well as the longitudinal component of charged vector meson ([Formula: see text]), experience additional positive mass modifications in the magnetic field due to Landau quantization. The effect of the modification of gluon condensates simulated by the medium change of dilaton field [Formula: see text] on the masses of the charmonia is also calculated in the chiral effective model. The contribution of masses of light quarks is also considered in the modification of gluon condensates. At high temperatures, the magnetically induced modifications of scalar fields significantly reduce the in-medium masses of mesons. The effects of magnetically induced spin mixing between the pseudoscalar and the corresponding vector mesons are incorporated in our study through a phenomenological effective Lagrangian interaction. The spin mixing result in a positive mass shift for the longitudinal component of the vector mesons and a negative mass shift for the pseudoscalar mesons in the presence of the magnetic field. From the obtained in-medium masses of charmonia and open charm mesons, we have also calculated the partial decay widths of [Formula: see text] to [Formula: see text], using a light quark pair creation model, namely, the [Formula: see text] model.
Reducing spheres of genus-2 Heegaard splitting of S3
Authors: Palaparthi Sreekrishna , Panda Swapnendu
Published: November 2023

The Goeritz group of the standard genus-g Heegaard splitting of the three sphere, [Formula: see text], acts on the space of isotopy classes of reducing spheres for this Heegaard splitting. Scharlemann [Automorphisms of the 3-sphere that preserve a genus two Heegaard splitting, Bol. Soc. Mat. Mexicana 10 (2004) 503–514] uses this action to prove that [Formula: see text] is finitely generated. In this paper, we give an algorithm to construct any reducing sphere from a standard reducing sphere for a genus-2 Heegaard splitting of the [Formula: see text]. Using this we give an alternate proof of the finite generation of [Formula: see text] assuming the finite generation of the stabilizer of the standard reducing sphere.
On-chip ESD Protection Design Methodologies by CAD Simulation
Authors: Pan Zijin , Li Xunyu , Hao Weiquan , Miao Runyu , Wang Albert
Published: November 2023

Electrostatic discharge (ESD)
can cause malfunction or failure of
integrated circuits (ICs)
. On-chip ESD protection design is a major IC
design-for-reliability (DfR)
challenge, particularly for complex chips made in advanced technology nodes. Traditional trial-and-error approaches become unacceptable to practical ESD protection designs for advanced ICs. Full-chip ESD protection circuit design optimization, prediction, and verification become essential to advanced chip designs, which highly depends on CAD algorithm and simulation that has been a constant research topic for decades. This paper reviews recent advances in CAD-enabled on-chip ESD protection circuit simulation design technologies and ESD-IC co-design methodologies. Key challenges of ESD CAD design practices are outlined. Practical ESD protection simulation design examples are discussed.
Adaptive decision-making depends on pupil-linked arousal in rats performing tactile discrimination tasks
Authors: Narasimhan Shreya , Schriver Brian J. , Wang Qi
Published: November 2023

Perceptual decision-making is a dynamic cognitive process and is shaped by many factors. However, the extent to which changes in sensory environment result in adaptive decision-making remains poorly understood. Our data provided new experimental evidence demonstrating that the rats were able to adaptively modify their decision criterion to maximize water reward in response to changes in the statistics of the sensory environment. Furthermore, the adaptive decision-making is dependent on pupil-linked arousal.
Photobiomodulation Can Enhance Stem Cell Viability in Cochlea with Auditory Neuropathy but Does Not Restore Hearing
Authors: Chang So-Young , Kim Eunjeong , Carpena Nathaniel T. , Lee Jae-Hun , Kim Doo Hee , Lee Min Young
Published: November 2023

Sensorineural hearing loss is very difficult to treat. Currently, one of the techniques used for hearing rehabilitation is a cochlear implant that can transform sound into electrical signals instead of inner ear hair cells. However, the prognosis remains very poor if sufficient auditory nerve cells are not secured. In this study, the effect of mouse embryonic stem cells (mESC) and photobiomodulation (PBM) combined treatment on auditory function and auditory nerve cells in a secondary neuropathy animal model was investigated. To confirm the engraftment of stem cells in vitro, cochlear explants were treated with kanamycin (KM) to mimic nerve damage and then cocultured with GFP-mESC. GFP-mESCs were observed to have attached and integrated into the explanted samples. An animal model for secondary neurodegeneration was achieved by KM treatment and was treated by a combination therapy of GFP-mESC and NIR-PBM at 8 weeks of KM treatment. Hearing recovery by functional testing using auditory brain stem response (ABR) and eABR was measured as well as morphological changes and epifluorescence analysis were conducted after 2 weeks of combination therapy. KM treatment elevated the hearing threshold at 70–80 dB and even after the combination treatment with GFP-mESC and PBM was applied, the auditory function was not restored. In addition, the stem cells transplanted into cochlea has exponentially increased due to PBM treatment although did not produce any malignancy. This study confirmed that the combined treatment with mESC and PBM could not improve hearing or increase the response of the auditory nerve. Nevertheless, it is noteworthy in this study that the cells are distributed in most cochlear tissues and the proliferation of stem cells was very active in animals irradiated with PBM compared to other groups wherein the stem cells had disappeared immediately after transplantation or existed for only a short period of time.
Supplementary Table 2 from SETD2 Deficiency Confers Sensitivity to Dual Inhibition of DNA Methylation and PARP in Kidney Cancer
Authors: Zhou Xinyi , Sekino Yohei , Li Hong-Tao , Fu Guanghou , Yang Zhi , Zhao Shuqing , Gujar Hemant , Zu Xiongbing , Weisenberger Daniel J. , Gill Inderbir S. , Tulpule Varsha , D’souza Anishka , Quinn David I. , Han Bo , Liang Gangning
Published: November 2023

Supplementary Table 2
Supplementary Table 1 from SETD2 Deficiency Confers Sensitivity to Dual Inhibition of DNA Methylation and PARP in Kidney Cancer
Authors: Zhou Xinyi , Sekino Yohei , Li Hong-Tao , Fu Guanghou , Yang Zhi , Zhao Shuqing , Gujar Hemant , Zu Xiongbing , Weisenberger Daniel J. , Gill Inderbir S. , Tulpule Varsha , D’souza Anishka , Quinn David I. , Han Bo , Liang Gangning
Published: November 2023

Supplementary Table 1
Supplementary Figure legends from SETD2 Deficiency Confers Sensitivity to Dual Inhibition of DNA Methylation and PARP in Kidney Cancer
Authors: Zhou Xinyi , Sekino Yohei , Li Hong-Tao , Fu Guanghou , Yang Zhi , Zhao Shuqing , Gujar Hemant , Zu Xiongbing , Weisenberger Daniel J. , Gill Inderbir S. , Tulpule Varsha , D’souza Anishka , Quinn David I. , Han Bo , Liang Gangning
Published: November 2023

Supplementary Figure legends
Supplementary Data from PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer
Authors: Ye Huili , Shi Wengui , Yang Jing , Wang Long , Jiang Xiangyan , Zhao Huiming , Qin Long , Qin Junjie , Li Lianshun , Cai Weiwen , Guan Junhong , Yang Hanteng , Zhou Huinian , Yu Zeyuan , Sun Hui , Jiao Zuoyi
Published: November 2023

Supplementary figures and tables.
Table S5 from A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed Antibody–Drug Conjugate for Targeting Melanoma
Authors: Shi Jing , Jiao Tao , Guo Qian , Weng Weining , Ma Linjie , Zhang Qing , Wang Lijun , Zhang Jianjian , Chen Caiwei , Huang Yaling , Wang Mingqiao , Pan Rong , Tang Yanfang , Hu Wenhao , Meng Tao , Liu Shu-Hui , Guo Jun , Kong Yan , Meng Xun
Published: November 2023

PK parapaters in A375 tumor-bearing mice
Supplementary video 1 from Stroma-Mediated Breast Cancer Cell Proliferation Indirectly Drives Chemoresistance by Accelerating Tumor Recovery between Chemotherapy Cycles
Authors: Miroshnychenko Daria , Miti Tatiana , Kumar Pragya , Miller Anna , Laurie Mark , Giraldo Nathalia , Bui Marilyn M. , Altrock Philipp M. , Basanta David , Marusyk Andriy
Published: November 2023

Supplementary video 1
Supplementary Figures from Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling
Authors: Li Zhen , Ning Kang , Zhao Diwei , Zhou Zhaohui , Zhao Junliang , Long Xingbo , Yang Zhenyu , Chen Dong , Cai XinYang , Hong Lexuan , Zhang Luyao , Zhou Fangjian , Wang Jun , Li Yonghong
Published: November 2023

Supplementary Figures
Data from Cross-talk between PARN and EGFR–STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells
Authors: Yin Jinlong , Seo Yoona , Rhim Jiho , Jin Xiong , Kim Tae Hoon , Kim Sung Soo , Hong Jun-Hee , Gwak Ho-Shin , Yoo Heon , Park Jong Bae , Kim Jong Heon
Published: November 2023

Abstract
Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR–STAT3 signaling to support glioblastoma stem cells (GSC). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in patients with glioblastoma, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3′–5′ exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics.
Significance:
A positive feedback loop comprising PARN and EGFR–STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.
Data from PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer
Authors: Ye Huili , Shi Wengui , Yang Jing , Wang Long , Jiang Xiangyan , Zhao Huiming , Qin Long , Qin Junjie , Li Lianshun , Cai Weiwen , Guan Junhong , Yang Hanteng , Zhou Huinian , Yu Zeyuan , Sun Hui , Jiao Zuoyi
Published: November 2023

Abstract
The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU–based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (PICH) as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH.
Significance:
PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.
Data from Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases
Authors: Fan Yibo , Song Shumei , Li Yuan , Dhar Shilpa S. , Jin Jiankang , Yoshimura Katsuhiro , Yao Xiaodan , Wang Ruiping , Scott Ailing W. , Pizzi Melissa Pool , Wu Jingjing , Ma Lang , Calin George A. , Hanash Samir , Wang Linghua , Curran Michael , Ajani Jaffer A.
Published: November 2023

Abstract
The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a “don't eat me” signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that CD47 was highly expressed on malignant PC cells, and elevated CD47 was associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 was significantly associated with diffuse type, poor differentiation, and tumor relapse. Depletion of Gal3 reduced expression of CD47 through inhibition of c-Myc binding to the CD47 promoter. Furthermore, injection of Gal3–deficient tumor cells into either wild-type and Lgals3−/− mice led to a reduction in M2 macrophages and increased T-cell responses compared with Gal3 wild-type tumor cells, indicating that tumor cell–derived Gal3 plays a more important role in GAC progression and phagocytosis than host-derived Gal3. Dual blockade of Gal3 and CD47 collaboratively suppressed tumor growth, increased phagocytosis, repolarized macrophages, and boosted T-cell immune responses. These data uncovered that Gal3 functions together with CD47 to suppress phagocytosis and orchestrate immunosuppression in GAC with PC, which supports exploring a novel combination therapy targeting Gal3 and CD47.
Significance:
Dual inhibition of CD47 and Gal3 enhances tumor cell phagocytosis and reprograms macrophages to overcome the immunosuppressive microenvironment and suppress tumor growth in peritoneal metastasis of gastric adenocarcinoma.
R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: November 2023

RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop–associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription–replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.

Significance:

Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription–replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
Supplementary Figure 4 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Lee Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Exome Tumor VAF Distribution Partitioned by Validation Status
Supplementary Figure 2 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Li Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Exome VAF and HaloPlex Tumor VAF
Supplementary Figure 17 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Lee Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Diagram of observed mutated components of the PI3K signaling cascade
Supplementary Figure 16 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Lee Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Diagram of observed mutated components of the MAPK signaling cascade
FIGURE 7 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Li Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Hypermutated patient germline analysis. A, Comparison of trinucleotide sequence contexts of COSMIC signature 6 and HL-513 suggesting a high degree of similarity between the two. B, Summary of the MMR germline mutations identified in HL-513. C, Lolliplot of MSH6 with Lynch syndrome mutations from ClinVar and the HL-513 mutation identified here. ClinVar mutations annotated as pathogenic and associated with Lynch syndrome are shown. The shaded oval highlights the duplication identified in HL-513. Note: mutations are plotted by ProteinPaint (103) according to (left-shifted) genomic coordinates but labeled with their HGVS expressions (right-shifted) from ClinVar explaining the discrepancies in some amino acid positions displayed.
FIGURE 5 from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Li Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

JAK/STAT signaling. A, Diagram of components of the JAK/STAT signaling cascade. Identified SMGs are shown in red; genes mutated in at least one non-hypermutated sample are shown in yellow; genes mutated only in the hypermutated sample (HL-513) are shown in orange. The gene mutation frequency across the cohort is shown as a percent. B, The total number and type of mutation observed are shown. C, Zoomed-in view of the C-terminal region of IL4R, where the observed truncating mutations are located. Also shown is the proximity of identified mutations to an ITIM motif that may impact STAT6 activation.
Data from Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Lee Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: November 2023

Abstract
The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL.
Significance:
Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient.
Intraocular Invasion by Conjunctival Squamous Cell Carcinoma: Clinical Presentation, Histopathological Findings, and Outcome
Authors: Borella Ysé , Lumbroso Livia , Lévy Christine , Gardrat Sophie , Klijanienko Jerzy , Malaise Denis , Dendale Rémi , Cassoux Nathalie , Matet Alexandre
Published: November 2023

Introduction: Intraocular localization of conjunctival squamous cell carcinoma (SCC) is due to scleral or corneal invasion. Herein, we describe the clinical and histopathological findings in four cases of SCC complicated by intraocular invasion, and we review cases reported in the literature and their management. We retrospectively collected and analyzed clinical characteristics, histopathology, management, and follow-up data from 4 patients with conjunctival SCC complicated by intraocular invasion. We reviewed the literature and summarized cases of intraocular invasion by conjunctival SCC reported over the last 30 years. Case Presentations: Two patients presented with intraocular invasion by conjunctival SCC at diagnosis. The two others developed intraocular invasion as recurrence of conjunctival SCC, previously treated with excisional biopsy and adjuvant radiotherapy. All 4 cases had a previous history of conjunctival surgery, but no history of intraocular surgery. Three patients were managed with modified enucleation, including one that required adjuvant orbital radiotherapy. One patient required orbital exenteration. Histopathology analysis showed a well-differentiated conjunctival SCC in all cases. None developed distant localization after at least 2.5-year follow-up. Discussion/Conclusion: Intraocular invasion is a rare complication of conjunctival SCC. Appropriate treatment in a tertiary center and long-term follow-up are highly recommended.