bluuebunny/crossref_metadata_2025 huggingface dataset:
Marked skewing of entire T-cell memory compartment occurs only in a minority of CMV-infected individuals and is unrelated to the degree of memory subset skewing among CMV-specific T-cells
Authors: Fuhrmann Stephan , Reus Bernhard , Frey Oliver , Pera Alejandra , Picker Louis J. , Kern Florian
Published: October 2023

Background

Chronic CMV infection drives the clonal expansion and accumulation of terminally differentiated, dysfunctional CMV-specific T-cells. CMV infection also appears to accelerate the differentiation of non-CMV-specific T-cells; however, the extent of this phenomenon is unclear.

Methods

The distribution of CD4 and CD8 T-cells into four memory subsets determined by CD45RA and CCR7 expression was analyzed in 96 CMV-infected (CMV+) and 81 CMV-uninfected (CMV-) older individuals. In CMV+ individuals, the distribution of IFN-γ producing CMV-specific T-cells into the same subsets was analyzed following stimulation with 16 different CMV antigens using flowcytometry (intracellular cytokine staining). We used previously published results to extrapolate the relative size of the entire CMV-specific CD4 and CD8 T-cell response from the summated response to selected antigens. The T-cell memory subset distribution across all CMV antigen-induced responses (weighted mean) was then used to calculate memory subset proportions (in % of CD4 or CD8 T-cells) of CMV-specific and non-CMV-specific T-cells. These were compared to the corresponding proportions in CMV- individuals.

Results

Only a minority (20%–30%) of CMV+ individuals displayed overall proportions of terminally differentiated T-cell memory subsets above an upper outlier boundary defined in CMV- individuals. The calculated proportions of these subsets among non-CMV-specific T-cells in CMV+ individuals also exceeded the corresponding proportions in CMV- people, suggesting that their differentiation could be CMV-driven. In CMV+ people showing overall subset distributions within the outlier limits, the memory subset distributions of non-CMV-specific T-cells were more like those in CMV- people. Logistic regression revealed that CMV infection, age, and sex all had significant effects on one or more of the non-CMV-specific CD4 or CD8 T-cell memory subsets in CMV+ individuals, with CMV infection showing the strongest effect overall. Surprisingly, except for the CD45RA-/CCR7- CD4 T-cell subset, we only found weak correlations between corresponding memory subset proportions among all T-cells and CMV-specific T-cells.

Conclusion

Our analysis supports an effect of CMV infection on non-CMV-specific T-cells; however, it is limited to a minority of individuals and not closely related to the degree of memory subset differentiation of CMV-specific T-cells. We propose that unknown predisposing factors might determine to what extent CMV infection affects non-CMV-specific T-cell differentiation.
SOCS-JAK-STAT inhibitors and SOCS mimetics as treatment options for autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis
Authors: Pandey Rahul , Bakay Marina , Hakonarson Hakon
Published: October 2023

Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.
Case Report: Autoimmune encephalitis and other neurological syndromes with rare neuronal surface antibody in children after hematopoietic stem cell transplantation
Authors: Zhang Ming-min , Wang Jing , Sun Dan , Wang Jing-xuan , Zhang Jun-hong , Xu Jia-wei
Published: October 2023

Introduction

Neuronal surface antibody syndromes (NSAS) encompass a growing set of autoimmune neurological disorders, with their predominant clinical presentation being autoimmune encephalitis (AE). The most extensively documented form within NSAS is anti-N-methyl-D-aspartate receptor (NMDAR) autoimmunity. In contrast, other NSAS, such as anti-metabotropic glutamate receptor-5 (mGluR5) autoimmunity, are less common and less comprehensively characterized, particularly in pediatric cases.

Case description

In this instance, we present the case of a 7-year-old girl who exhibited abnormal behaviors following hematopoietic stem cell transplantation (HSCT). She received a diagnosis of anti-mGluR5 AE, and her Electroencephalogram (EEG) displayed an increased number of generalized slow waves during wakefulness. Treatment involved intravenous administration of gamma globulin and methylprednisolone, followed by oral prednisone tablets. Levetiracetam was introduced as an antiepileptic therapy during the pulse steroid therapy. Notably, the abnormal behaviors exhibited significant improvement after treatment.

Conclusions

To the best of our knowledge, this is the first report of rare pediatric NSAS involving anti-mGluR5 AE following HSCT. Enhancing our understanding and characterization of this condition may facilitate its recognition and treatment in children. Serum antibody testing could enable early identification and treatment of anti-mGluR5 AE.
Ankylosing spondylitis and psychiatric disorders in European population: a Mendelian randomization study
Authors: Zuo Huifang , Li Min-Min
Published: October 2023

Background

Epidemiologic evidence has demonstrated a correlation between ankylosing spondylitis and psychiatric disorders. However, little is known about the common genetics and causality of this association. This study aimed to investigate the common genetics and causality between ankylosing spondylitis (AS) and psychiatric disorders.

Methods

A two-sample Mendelian Randomization (MR) analysis was carried out to confirm causal relationships between ankylosing spondylitis and five mental health conditions including major depressive disorder (MDD), anxiety disorder (AXD), schizophrenia (SCZ), bipolar disorder (BIP), and anorexia nervosa (AN). Genetic instrumental variables associated with exposures and outcomes were derived from the largest available summary statistics of genome-wide association studies (GWAS). Bidirectional causal estimation of MR was primarily obtained using the inverse variance weighting (IVW) method. Other MR methods include MR-Egger regression, Weighted Median Estimator (WME), Weighted Mode, Simple Mode, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO). Sensitivity analyses are conducted to estimate the robustness of MR results.

Results

The findings suggest that AS may be causally responsible for the risk of developing SCZ (OR = 1.18, 95% confidence interval = (1.06, 1.31), P = 2.58 × 10-3) and AN (OR = 1.32, 95% confidence interval = (1.07, 1.64), P = 9.43 × 10-3). In addition, MDD, AXD, SCZ, AN, and BIP were not inversely causally related to AS (all p > 0.05).

Conclusion

Our study provides fresh insights into the relationship between AS and psychiatric disorders (SCZ and AN). Furthermore, it may provide new clues for risk management and preventive interventions for mental disorders in patients with AS.
Characterizing hepatocellular carcinoma stem markers and their corresponding susceptibility to NK-cell based immunotherapy
Authors: Chiang Jason , Chen Po-Chun , Pham Janet , Nguyen Cat-Quynh , Kaur Kawaljit , Raman Steven S. , Jewett Anahid
Published: October 2023

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the fourth-leading cause of all cancer-related deaths around the world. Liver transplantation, surgery, and local ablation are curative therapies for early-stage HCC. However, post-treatment outcomes can vary based on histopathologic stage. Poorly-differentiated HCC are associated with higher rates of tumor progression and lower overall survival compared to well-differentiated HCC after therapy. In this study, we aimed to characterize the cancer stem cell (CSC) profile of histopathologically-proven well and poorly-differentiated HCCs in an in-vitro environment. We characterized the stem-like profile of each type of HCC based on their surface markers and susceptibility to NK cell-mediated cytotoxicity.

Methods

Flow cytometry was used to quantify differential expression of MHC-class I, CD54, and CD44 between well- and poorly-differentiated HCCs. Primary untreated NK cells, IL-2 stimulated primary NK cells, and supercharged (sNK) cell-mediated cytotoxicity was assessed against well- and poorly-differentiated HCCs. IFN-γ supernatant from each respective NK cell experimental arm was also used to induce differentiation of HCCs. Finally, we characterized the temporal NK effector cell cytotoxicity using real-time quantitative analysis of imaging and impedance (eSight study).

Results

Poorly-differentiated HCCs demonstrated low surface expression of MHC-class I and CD54, and high expression of CD44. Treatment of NK cells secreted IFN-γ or IFN-γ cytokine induced differentiation in HCCs. Poorly-differentiated HCCs in comparison to well-differentiated HCC were more susceptible to NK cell-mediated cytotoxicity in primary NK cells, IL-2 stimulated primary NK cells, and sNK cells. sNK cells induced significantly higher cytotoxicity against well-differentiated HCCs in comparison to untreated or IL-2-stimulated primary NK cells. These findings were recapitulated with real-time quantitative imaging analysis.

Conclusions

Poorly-differentiated HCCs were found to have surface marker patterns of CSCs, making them highly susceptible to NK cell-based immunotherapy. NK-cell based therapy can potentially be leveraged as a neoadjuvant or adjuvant therapy in poorly-differentiated HCCs. Supercharged NK cells, which can be rapidly expanded to therapeutic levels, are uniquely capable of lysing both poorly- and well-differentiated HCCs. This finding suggests that sNK cells not only exhibit enhanced features against NK cells’ targets but also are capable of activating T cells to induce cytotoxicity against well-differentiated HCCs with high expression of MHC class I.
Leptin favors imbalance of antigen-specific CD4+ T-cells associated with severity of cat allergy
Authors: Vollmer Carolina , Dias Aleida , Sales Marisa , Sacramento Priscila M. , Silva Júlio Cesar , Oyamada Hugo A. A. , Linhares Ulisses C. , Gupta Sudhir , Kasahara Taissa M. , Bento Cleonice A. M.
Published: October 2023

Introduction

Obesity can complicate IgE-mediated allergic diseases. In the present study, we aimed to investigate the ability of obesity-related concentrations of leptin to modulate the in vitro effector and regulatory Fel d1-specific CD4+ T-cell subsets in patients allergic to cat, considered the third most common cause of respiratory allergy in humans.

Methods

For this study, plasma and peripheral blood mononuclear cells (PBMC) from 30 cat-allergic patients with mild, moderate and severe respiratory symptoms were obtained. The PBMC cultures were stimulated with Fel d1 antigen (10 µg/mL) in the presence or absence of obesity-related leptin dose (50 ηg/mL). After 6 days, the levels of cytokines and IgE in the supernatants were evaluated by multiplex and ELISA, respectively. The frequency of different non-follicular (CXCR5-) and follicular (CXCR5+) Fel d1-specific CD4+ T cell subsets was determined by flow cytometry. The plasma levels of leptin and IgE anti-cat titers were evaluated by ELISA and ImmunoCAP, respectively.

Results and conclusions

Fel d1 induced both IgE production and release of cytokines related to Th2, Th9 and Th17 cell phenotypes. Feld1 was more efficient in increasing the frequency of TFHIL-21- cells positive for IL-4, IL-5 and IL-13 than TFHIL-21+ cell subsets. Leptin favored the expansion Th2-like and Th9-like cells and TFHIL-21- cells positive for IL-4, IL-5 and IL-13, but reduced the proportion of conventional (Treg/Tr-1) and follicular (TFR) regulatory CD4+ T-cell subsets expressing or not CD39 marker. Finally, many of the imbalances between Fel d1-specific CD4+ T-cells were also correlated with plasma leptin and anti-Fel d1 IgE titers. In summary, hyperleptinemia should negatively impact on the severity of cat allergies by favoring the expansion of pathogenic Fel d1-specific CD4+ T-cell phenotypes and damaging the functional status of regulatory CD4+ T-cell subsets.
Photoprotective responses of three intertidal Antarctic macroalgae to short-term temperature stress
Authors: Sáez Claudio A. , Troncoso Macarena , Navarrete Camilo , Rodríguez-Rojas Fernanda , Navarro Nelso , Trabal Andrés , Lavergne Céline , Pardo Diego , Brown Murray T. , Gómez Iván , Figueroa Félix L. , Celis-Plá Paula S. M.
Published: October 2023

The Antarctic Peninsula is experiencing one of the highest warming rates globally. In polar regions, macroalgae thrive under extreme environmental conditions, which could worsen because of future climate change scenarios, including increased ultraviolet exposure, extremely low light availability, and fluctuating temperatures, particularly in the intertidal zones. To investigate the potential role of photoprotective and antioxidant mechanisms in response to future increases in sea surface temperatures caused by climate change, we conducted laboratory experiments using three intertidal macroalgae model species: Adenocystis utricularis (Ochrophyta, Phaeophyceae), Pyropia endiviifolia (Rhodophyta, Bangiophyceae), and Monostroma hariotii (Chlorophyta, Ulvophyceae). These algae were collected in Punta Artigas (King George Island, Antarctica) and acclimated at 2°C for 48 h. They were then assessed in laboratory experiments for up to 5 days under two treatments: (1) control conditions at 2°C and (2) elevated tem.perature conditions at 8°C, representing the most negative increment in SSTs estimated by the end of the 21st century. Carbon, nitrogen, pigments (chlorophylls and carotenoids), mycosporine-like amino acids (MAAs), and phenolic compounds were quantified after 3 and 5 days of exposure. For M. hariotii, elevated temperatures led to an increase in the C/N ratio, total antioxidant capacity, and levels of nitrogen, total carotenoids, chlorophyll-a, pigments (chlorophyll-b and violaxanthin), and phenolic compounds. For A. utricularis, elevated temperatures led to elevated C/N ratio and levels of chlorophyll-a and carotenoids (fucoxanthin and β-carotene). For P. endiviifolia, elevated temperatures resulted in elevated levels of carotenoids (lutein and β-carotene), phenolic compounds, and MAAs (porphyra-334, shinorine, and palythine). Thus, our study suggests that increasing water temperatures due to global warming can enhance the photoprotective abilities of three Antarctic intertidal macroalgae (M. hariotii, A. utricularis, and P. endiviifolia), with each species showing specific responses.
Sr/Ca in shells of laboratory-grown bivalves (Arctica islandica) serves as a proxy for water temperature – implications for (paleo)environmental research?
Authors: Brosset Cornélia , Höche Nils , Witbaard Rob , Nishida Kozue , Shirai Kotaro , Mertz-Kraus Regina , Schöne Bernd R.
Published: October 2023

Seawater temperature is an essential quantity for paleoclimatological and paleoecological studies. A potential archive that can provide century-long, temporally well-constrained and high-resolution temperature proxy data is available in the form of bivalve shells. However, the number of well-accepted and robust temperature proxies contained in shells is limited to stable oxygen isotopes and carbonate clumped isotopes. Many studies have therefore investigated the possibility to reconstruct temperature from element/Ca properties, specifically Sr/Ca ratios in case of aragonitic shells. As demonstrated here, in agreement with thermodynamic expectations and the lattice strain model, shell Sr/Ca of laboratory-grown Arctica islandica specimens is strongly positively coupled to water temperature. If ultrastructure-related bias is mathematically eliminated, up to 75% of the variability in shell Sr/Ca data can be explained by water temperature. However, in field-grown specimens, this relationship is superimposed by other environmental variables that can hardly be quantified and mathematically eliminated. The explained variability of Sr/Ca is reduced to merely 26% and the prediction uncertainty too large for reliable temperature estimates. Most likely, the equable, less biased conditions in the laboratory resulted in the production of a more uniform shell ultrastructure (with larger and more elongated biomineral units) which in turn was associated with less variable Sr/Ca values and a stronger link to water temperature. Without a detailed understanding and quantification of the factors controlling ultrastructural variations in field-grown bivalves, it remains impossible to employ shell Sr/Ca of wild A. islandica specimens for precise temperature estimates, merely a qualitative temperature reconstruction seems feasible.
Reduction of experimental ocular axial elongation by neuregulin-1 antibody
Authors: Shi Xu Han , Dong Li , Zhang Rui Heng , Zhou Wen Da , Li Yi Fan , Wu Hao Tian , Li He Yan , Yu Chu Yao , Li Yi Tong , Wang Ya Xing , Jonas Jost B. , Wei Wen Bin
Published: October 2023

Background

Since the mechanisms underlying myopic axial elongation have remained unclear, we examined the effect of neuregulin-1 (NRG-1), an epidermal growth factor family member, on myopic axial elongation.

Methods

The guinea pigs aged two to three weeks were subjected to bilateral negative lens-induced axial elongation and received weekly intravitreal injections into their right eyes of NRG-1 antibody (doses: 5 μg, n = 8; 10 μg, n = 8, 20 μg, n = 9) or of NRG-1 (doses: 0.05 μg, n = 8; 0.01 μg, n = 9; 0.2 μg, n = 8), underwent only bilateral negative lens-induced axial elongation (myopia control group, n = 10), or underwent no intervention (control group, n = 10). The contralateral eyes received corresponding intravitreal phosphate-buffered solution injections. One week after the last injection, the guinea pigs were sacrificed, the eyeballs were removed, the thicknesses of the retina and sclera were histologically examined, the expression of NRG-1 and downstream signal transduction pathway members (ERK1/2 and PI3K/AKT) and the mRNA expression of NRG-1 in the retina was assessed.

Results

The inter-eye difference in axial length at study end increased (p < 0.001) from the normal control group (−0.02 ± 0.09 mm) and the myopia control group (−0.01 ± 0.09 mm) to the low-dose NRG-1 antibody group (−0.11 ± 0.05 mm), medium-dose NRG-1 antibody group (−0.17 ± 0.07 mm), and high-dose NRG-1 antibody group (−0.28 ± 0.06 mm). The relative expression of NRG-1, ERK1/2, and PI3K/AKT in the retina decreased in a dose-dependent manner from the myopia control group to the NRG-1 antibody groups and the normal control group. The relative NRG-1 mRNA expression in the retina was higher (p < 0.01) in the myopic control group than in the NRG-1 antibody groups and normal control group. Scleral and retinal thickness decreased from the normal control group to the NRG-1 antibody groups to the myopic control group. After intraocular injection of NRG-1 protein, there was a slight dose-dependent increase in the difference in axial length between the right and left eye, however not statistically significantly, from the normal control group (−0.02 ± 0.09 mm) to the high-dose NRG-1 protein group (0.03 ± 0.03 mm; p = 0.12).

Conclusion

Intravitreal NRG-1 antibody application was dose-dependently and time-dependently associated with a reduction in negative lens-induced axial elongation in young guinea pigs.
Integrative analysis of microbiota and metabolomics in chromium-exposed silkworm (Bombyx mori) midguts based on 16S rDNA sequencing and LC/MS metabolomics
Authors: Chen Ya-Zhen , Rong Wan-Tao , Qin Ying-Can , Lu Lin-Yuan , Liu Jing , Li Ming-Jie , Xin Lei , Li Xiao-Dong , Guan De-Long
Published: October 2023

The gut microbiota, a complex ecosystem integral to host wellbeing, is modulated by environmental triggers, including exposure to heavy metals such as chromium. This study aims to comprehensively explore chromium-induced gut microbiota and metabolomic shifts in the quintessential lepidopteran model organism, the silkworm (Bombyx mori). The research deployed 16S rDNA sequence analysis and LC/MS metabolomics in its experimental design, encompassing a control group alongside low (12 g/kg) and high (24 g/kg) feeding chromium dosing regimens. Considerable heterogeneity in microbial diversity resulted between groups. Weissella emerged as potentially resilient to chromium stress, while elevated Propionibacterium was noted in the high chromium treatment group. Differential analysis tools LEfSe and random forest estimation identified key species like like Cupriavidus and unspecified Myxococcales, offering potential avenues for bioremediation. An examination of gut functionality revealed alterations in the KEGG pathways correlated with biosynthesis and degradation, suggesting an adaptive metabolic response to chromium-mediated stress. Further results indicated consequential fallout in the context of metabolomic alterations. These included an uptick in histidine and dihydropyrimidine levels under moderate-dose exposure and a surge of gentisic acid with high-dose chromium exposure. These are critical players in diverse biological processes ranging from energy metabolism and stress response to immune regulation and antioxidative mechanisms. Correlative analyses between bacterial abundance and metabolites mapped noteworthy relationships between marker bacterial species, such as Weissella and Pelomonas, and specific metabolites, emphasizing their roles in enzyme regulation, synaptic processes, and lipid metabolism. Probiotic bacteria showed robust correlations with metabolites implicated in stress response, lipid metabolism, and antioxidant processes. Our study reaffirms the intricate ties between gut microbiota and metabolite profiles and decodes some systemic adaptations under heavy-metal stress. It provides valuable insights into ecological and toxicological aspects of chromium exposure that can potentially influence silkworm resilience.
Comparative secretomic and proteomic analysis reveal multiple defensive strategies developed by Vibrio cholerae against the heavy metal (Cd2+, Ni2+, Pb2+, and Zn2+) stresses
Authors: Zhang Beiyu , Xu Jingjing , Sun Meng , Yu Pan , Ma Yuming , Xie Lu , Chen Lanming
Published: October 2023

Vibrio cholerae is a common waterborne pathogen that can cause pandemic cholera in humans. The bacterium with heavy metal-tolerant phenotypes is frequently isolated from aquatic products, however, its tolerance mechanisms remain unclear. In this study, we investigated for the first time the response of such V. cholerae isolates (n = 3) toward the heavy metal (Cd2+, Ni2+, Pb2+, and Zn2+) stresses by comparative secretomic and proteomic analyses. The results showed that sublethal concentrations of the Pb2+ (200 μg/mL), Cd2+ (12.5 μg/mL), and Zn2+ (50 μg/mL) stresses for 2 h significantly decreased the bacterial cell membrane fluidity, but increased cell surface hydrophobicity and inner membrane permeability, whereas the Ni2+ (50 μg/mL) stress increased cell membrane fluidity (p < 0.05). The comparative secretomic and proteomic analysis revealed differentially expressed extracellular and intracellular proteins involved in common metabolic pathways in the V. cholerae isolates to reduce cytotoxicity of the heavy metal stresses, such as biosorption, transportation and effluxing, extracellular sequestration, and intracellular antioxidative defense. Meanwhile, different defensive strategies were also found in the V. cholerae isolates to cope with different heavy metal damage. Remarkably, a number of putative virulence and resistance-associated proteins were produced and/or secreted by the V. cholerae isolates under the heavy metal stresses, suggesting an increased health risk in the aquatic products.
Effects of protective step training on proactive and reactive motor adaptations in Parkinson’s disease patients
Authors: Lockhart Thurmon , Frames Chris , Olson Markey , Moon Seong H. , Peterson Dan , Lieberman Abraham
Published: October 2023

The aim of this study was to investigate to what extent PD affects the ability to walk, respond to balance perturbations in a single training session, and produce acute short-term effects to improve compensatory reactions and control of unperturbed walking stability. Understanding the mechanism of compensation and neuroplasticity to unexpected step perturbation training during walking and static stance can inform treatment of PD by helping to design effective training regimens that remediate fall risk. Current rehabilitation therapies are inadequate at reducing falls in people with Parkinson’s disease (PD). While pharmacologic and surgical treatments have proved largely ineffective in treating postural instability and gait dysfunction in people with PD, studies have demonstrated that therapy specifically focusing on posture, gait, and balance may significantly improve these factors and reduce falls. The primary goal of this study was to assess the effectiveness of a novel and promising intervention therapy (protective step training – i.e., PST) to improve balance and reduce falls in people with PD. A secondary goal was to understand the effects of PST on proactive and reactive feedback responses during stance and gait tasks. Multiple-baseline, repeated measures analyses were performed on the multitude of proactive and reactive performance measures to assess the effects of PST on gait and postural stability parameters. In general, the results indicate that participants with PD were able to use experiences with perturbation training to integrate and adapt feedforward and feedback behaviors to reduce falls. The ability of the participants with PD to adapt to changes in task demands suggests that individuals with PD could benefit from the protective step training to facilitate balance control during rehabilitation.
Motor subtypes and clinical characteristics in sporadic and genetic Parkinson's disease groups: analysis of the PPMI cohort
Authors: Jeong Eun Hye , Lee Jae Yong , Han Sun-Ku , Song Yoo Sung
Published: October 2023

Introduction

The extensive clinical variations observed in Parkinson's disease (PD) pose challenges in early diagnosis and treatment initiation. However, genetic research in PD has significantly transformed the clinical approach to its treatment. Moreover, researchers have adopted a subtyping strategy based on homogeneous clinical symptoms to improve clinical diagnosis and treatment approaches. We conducted a study to explore clinical characteristics in genetic PD groups with motor symptom subtyping.

Methods

Data was driven from the Parkinson's Progression Markers Initiative (PPMI) database. The sporadic PD (sPD) group and the genetic PD group including patients with leucine-rich kinase 2 (LRRK2) or glucosylceramidase β (GBA) mutations were analyzed. Motor subtyping was performed using Movement Disorder Society-Unified Parkinson's disease rating scale (MDS-UPDRS) scores. I-123 FP-CIT SPECT scans were used to calculate specific binding ratios (SBRs) in the caudate and putamen. Clinical symptoms of each group were also compared.

Results

MDS-UPDRS III scores were lower in the LRRK2 group, compared with the GBA and sPD group (P < 0.001), but no significant differences in striatal SBRs. The putaminal SBR value of the LRRK2 group was higher than the sPD group (P < 0.05). Within the GBA group, we observed lower SBR values in the postural instability/gait difficulty (PIGD) subtype GBA group compared to the tremor-dominant (TD) subtype GBA group (P < 0.05). The TD subtype GBA group exhibited superior putaminal SBRs compared to the TD subtype sPD group (P < 0.05). The TD subtype LRRK2 group had better putaminal SBR values (P < 0.001) and MDS-UPDRS Part III scores (P < 0.05) compared to the TD sPD group.

Discussions

Our subtyping approach offers valuable insights into the clinical characteristics and progression of different genetic PD subtypes. To further validate and expand these findings, future research with larger groups and long-term follow-up data is needed. The subtyping strategy based on motor symptoms holds promise in enhancing the diagnosis and treatment of genetic PD.
Transcranial magnetic stimulation and ketamine: implications for combined treatment in depression
Authors: Dębowska Weronika , Więdłocha Magdalena , Dębowska Marta , Kownacka Zuzanna , Marcinowicz Piotr , Szulc Agata
Published: October 2023

Drug-resistant mental disorders, particularly treatment-resistant depression, pose a significant medical and social problem. To address this challenge, modern psychiatry is constantly exploring the use of novel treatment methods, including biological treatments, such as transcranial magnetic stimulation (TMS), and novel rapid-acting antidepressants, such as ketamine. While both TMS and ketamine demonstrate high effectiveness in reducing the severity of depressive symptoms, some patients still do not achieve the desired improvement. Recent literature suggests that combining these two methods may yield even stronger and longer-lasting results. This review aims to consolidate knowledge in this area and elucidate the potential mechanisms of action underlying the increased efficacy of combined treatment, which would provide a foundation for the development and optimization of future treatment protocols.
CT-based dosiomics and radiomics model predicts radiation-induced lymphopenia in nasopharyngeal carcinoma patients
Authors: Huang Qingfang , Yang Chao , Pang Jinmeng , Zeng Biao , Yang Pei , Zhou Rongrong , Wu Haijun , Shen Liangfang , Zhang Rong , Lou Fan , Jin Yi , Abdilim Albert , Jin Hekun , Zhang Zijian , Xie Xiaoxue
Published: October 2023

Purpose

This study aims to develop and validate a model predictive for the incidence of grade 4 radiation-induced lymphopenia (G4RIL), based on dosiomics features and radiomics features from the planning CT of nasopharyngeal carcinoma (NPC) treated by radiation therapy.

Methods

The dataset of 125 NPC patients treated with radiotherapy from August 2018 to March 2019 was randomly divided into two sets—an 85-sample training set and a 40-sample test set. Dosiomics features and radiomics features of the CT image within the skull bone and cervical vertebrae were extracted. A feature selection process of multiple steps was employed to identify the features that most accurately forecast the data and eliminate superfluous or insignificant ones. A support vector machine learning classifier with correction for imbalanced data was trained on the patient dataset for prediction of RIL (positive classifier for G4RIL, negative otherwise). The model’s predictive capability was gauged by gauging its sensitivity (the likelihood of a positive test being administered to patients with G4RIL) and specificity in the test set. The area beneath the ROC curve (AUC) was utilized to explore the association of characteristics with the occurrence of G4RIL.

Results

Three clinical features, three dosiomics features, and three radiomics features exhibited significant correlations with G4RIL. Those features were then used for model construction. The combination model, based on nine robust features, yielded the most impressive results with an ACC value of 0.88 in the test set, while the dosiomics model, with three dosiomics features, had an ACC value of 0.82, the radiomics model, with three radiomics features, had an ACC value of 0.82, and the clinical model, with its initial features, had an ACC value of 0.6 for prediction performance.

Conclusion

The findings show that radiomics and dosiomics features are correlated with the G4RIL of NPC patients. The model incorporating radiomics features and dosiomics features from planning CT can predict the incidence of G4RIL in NPC patients.
Superiorization of projection algorithms for linearly constrained inverse radiotherapy treatment planning
Authors: Barkmann Florian , Censor Yair , Wahl Niklas
Published: October 2023

Objective

We apply the superiorization methodology to the constrained intensity-modulated radiation therapy (IMRT) treatment planning problem. Superiorization combines a feasibility-seeking projection algorithm with objective function reduction: The underlying projection algorithm is perturbed with gradient descent steps to steer the algorithm towards a solution with a lower objective function value compared to one obtained solely through feasibility-seeking.

Approach

Within the open-source inverse planning toolkit matRad, we implement a prototypical algorithmic framework for superiorization using the well-established Agmon, Motzkin, and Schoenberg (AMS) feasibility-seeking projection algorithm and common nonlinear dose optimization objective functions. Based on this prototype, we apply superiorization to intensity-modulated radiation therapy treatment planning and compare it with (i) bare feasibility-seeking (i.e., without any objective function) and (ii) nonlinear constrained optimization using first-order derivatives. For these comparisons, we use the TG119 water phantom, the head-and-neck and the prostate patient of the CORT dataset.

Main results

Bare feasibility-seeking with AMS confirms previous studies, showing it can find solutions that are nearly equivalent to those found by the established piece-wise least-squares optimization approach. The superiorization prototype solved the linearly constrained planning problem with similar dosimetric performance to that of a general-purpose nonlinear constrained optimizer while showing smooth convergence in both constraint proximity and objective function reduction.

Significance

Superiorization is a useful alternative to constrained optimization in radiotherapy inverse treatment planning. Future extensions with other approaches to feasibility-seeking, e.g., with dose-volume constraints and more sophisticated perturbations, may unlock its full potential for high performant inverse treatment planning.
Psychosocial needs of post-radiotherapy cancer survivors and their direct caregivers – a systematic review
Authors: Man Ka Hei , Law Helen Ka-Wai , Tam Shing Yau
Published: October 2023

Radiotherapy is an important modality for cancer treatment. About 50% of cancer patients receive radiotherapy, and one-third of radiotherapy recipients were identified as having unmet psychosocial needs. The unmet psychosocial needs worsen the patient’s quality of life and treatment effectiveness. This review aims to identify the psychosocial needs of post-radiotherapy cancer survivors and their direct caregivers. Systematic research of Embase, Scopus and PubMed was done and 17 studies were selected for analysis. The results show that patients encounter distress and fear due to treatment immobilization and unfamiliarity with procedures respectively. Information provision is a common need raised by patients and caregivers. Patients and caregivers report relationship problems due to affected sexual functions. To facilitate future studies, solutions to each identified psychosocial need are proposed in the discussion based on the 17 selected papers and other supporting literature. This review proposes art therapy to alleviate psychological distress, and pre-treatment information sessions to reinforce information delivery. Creative interventions such as a sexual rehabilitation program are recommended. Future studies are warranted to examine the interventions and thus improve the patients’ and caregivers’ well-being.
The cancer glycocode as a family of diagnostic biomarkers, exemplified by tumor-associated gangliosides
Authors: Nejatie Ali , Yee Samantha S. , Jeter Anna , Saragovi Horacio Uri
Published: October 2023

One unexploited family of cancer biomarkers comprise glycoproteins, carbohydrates, and glycolipids (the Tumor Glycocode).A class of glycolipid cancer biomarkers, the tumor-marker gangliosides (TMGs) are presented here as potential diagnostics for detecting cancer, especially at early stages, as the biological function of TMGs makes them etiological. We propose that a quantitative matrix of the Cancer Biomarker Glycocode and artificial intelligence-driven algorithms will expand the menu of validated cancer biomarkers as a step to resolve some of the challenges in cancer diagnosis, and yield a combination that can identify a specific cancer, in a tissue-agnostic manner especially at early stages, to enable early intervention. Diagnosis is critical to reducing cancer mortality but many cancers lack efficient and effective diagnostic tests, especially for early stage disease. Ideal diagnostic biomarkers are etiological, samples are preferably obtained via non-invasive methods (e.g. liquid biopsy of blood or urine), and are quantitated using assays that yield high diagnostic sensitivity and specificity for efficient diagnosis, prognosis, or predicting response to therapy. Validated biomarkers with these features are rare. While the advent of proteomics and genomics has led to the identification of a multitude of proteins and nucleic acid sequences as cancer biomarkers, relatively few have been approved for clinical use. The use of multiplex arrays and artificial intelligence-driven algorithms offer the option of combining data of known biomarkers; however, for most, the sensitivity and the specificity are below acceptable criteria, and clinical validation has proven difficult. One strategic solution to this problem is to expand the biomarker families beyond those currently exploited. One unexploited family of cancer biomarkers comprise glycoproteins, carbohydrates, and glycolipids (the Tumor Glycocode). Here, we focus on a family of glycolipid cancer biomarkers, the tumor-marker gangliosides (TMGs). We discuss the diagnostic potential of TMGs for detecting cancer, especially at early stages. We include prior studies from the literature to summarize findings for ganglioside quantification, expression, detection, and biological function and its role in various cancers. We highlight the examples of TMGs exhibiting ideal properties of cancer diagnostic biomarkers, and the application of GD2 and GD3 for diagnosis of early stage cancers with high sensitivity and specificity. We propose that a quantitative matrix of the Cancer Biomarker Glycocode and artificial intelligence-driven algorithms will expand the menu of validated cancer biomarkers as a step to resolve some of the challenges in cancer diagnosis, and yield a combination that can identify a specific cancer, in a tissue-agnostic manner especially at early stages, to enable early intervention.
Case Report: Identification of a novel STAT3 mutation in EBV-positive inflammatory follicular dendritic cell sarcoma
Authors: Ramsey Megan C. , Sabatini Peter J. B. , Watson Geoffrey , Chawla Tanya , Ko Michael , Sakhdari Ali
Published: October 2023

EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is an uncommon disease primarily observed in Asia. It is characterized by the development of tumors believed to originate from follicular dendritic cells (FDC). The consistent association between this condition and clonal EBV infection suggests EBV’s involvement as an etiological factor. However, diagnosing EBV+ IFDCS can be challenging due to its morphological variability and diverse immunohistochemical staining patterns. The genetic characteristics of EBV+ IFDCS remain insufficiently understood. To address this knowledge gap, we present a case study of a 47-year-old male patient diagnosed with EBV+ IFDCS. We utilized a Next-generation sequencing (NGS) platform to investigate the genetic profile of the tumor cells. We identified a single pathogenic mutation (G618R) in the STAT3 gene. This finding provides valuable insights into the genetic alterations associated with EBV+ IFDCS and potentially contributes to our understanding of the disease’s pathogenesis.
β-sitosterol alleviates dextran sulfate sodium-induced experimental colitis via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis
Authors: Zhang Di , Ge Fei , Ji Jing , Li Yu-Jing , Zhang Fu-Rong , Wang Shu-Yan , Zhang Shu-Jing , Zhang Dong-Mei , Chen Meng
Published: October 2023

Background: Inflammation-related NLRP3/Caspase-1/GSDMD-mediated pyroptosis is involved in the progression of ulcerative colitis (UC). β-sitosterol (SIT) was reported to have anti-inflammatory effects on experimental colitis, while the regulation of SIT on pyroptosis is unclear. Therefore, the present study aimed to define the protective and healing effects of SIT on dextran sulfate sodium (DSS)-induced experimental UC rats and human epithelial colorectal adenocarcinoma cells (Caco-2) and explore the underlying mechanisms that are responsible for its effects on NLRP3/Caspase-1/GSDMD-mediated pyroptosis in UC.

Methods: UC model rats were established by oral 4% DSS. Following colitis injury, the animals received SIT (doses of 50, 100, and 200 mg/kg) treatment for 2 weeks. For in vitro study, we exposed Caco-2–50 mg/mL DSS with or without SIT (concentrations of 8 and 16 μg/mL). Disease activity index (DAI) and histopathological injury were assessed in vivo. Activation proteins of nuclear factor kappa B (NF-κB) signaling axis, and tight junction-related proteins of zonula occludens-1 (ZO-1) and occludin were detected in colon tissues. TNF-α, IL-1β, and IL-18 in serum and cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Changes in NLRP3/Caspase-1/GSDMD-mediated pyroptosis signaling pathway activation were analyzed both in tissues and cells.

Results: Our findings suggested that SIT treatment attenuated the severity of 4% DSS-induced UC by protecting rats from weight and colon length loss, and macroscopic damage. SIT also reduced proinflammatory factors production (TNF-α, IL-1β, and IL-18) in serum and cell supernatant. Mechanistically, SIT downregulated the expression levels of pyroptosis-related proteins including Caspase-1, cleaved-Caspase-1, NLRP3, GSDMD, and GSDMD-N in colon tissues and Caco-2 cells. Further analysis indicated that SIT maintained the colonic barrier integrity by enhancing the protein expression of ZO-1 and occludin.

Conclusion: We confirmed that SIT exerts protective and therapeutic effects on DSS-induced colitis injury by suppressing NLRP3/Caspase-1/GSDMD-mediated pyroptosis and inflammation response. These findings demonstrated that SIT could be a potential medication for UC treatment.
Big data- and machine learning-based analysis of a global pharmacovigilance database enables the discovery of sex-specific differences in the safety profile of dual IL4/IL13 blockade
Authors: Sharif Kassem , Omar Mahmud , Lahat Adi , Patt Yonatan Shneor , Amital Howard , Zoabi Ghanem , Bragazzi Nicola Luigi , Watad Abdulla
Published: October 2023

Background: Due to its apparent efficacy and safety, dupilumab, a monoclonal antibody that blocks Interleukin 4 (IL-4) and Interleukin 13 (IL-13), has been approved for treating T-helper 2 (Th2) disorders. However, adverse effects like local injection site reactions, conjunctivitis, headaches, and nasopharyngitis have been reported. Sex differences are known to influence both adaptive and innate immune responses and, thus, may have a bearing on the occurrence of these adverse effects. Nevertheless, the literature lacks a comprehensive exploration of this influence, a gap this study aims to bridge.

Materials and Methods: A comprehensive data mining of VigiBase, the World Health Organization (WHO) global pharmacovigilance database which contains case safety reports of adverse drug reactions (ADRs) was performed to test for sex -specific safety response to dual IL4/IL13 blockade by dupilumab. The information component (IC), a measure of the disproportionality of ADR occurrence, was evaluated and compared between males and females to identify potential sexual dimorphism.

Results: Of the 94,065 ADRs recorded in the WHO global pharmacovigilance database, 2,001 (57.4%) were reported among female dupilumab users, and 1,768 (50.7%) were among males. Immune/autoimmune T-helper 1 (Th1)-, innate- and T-helper 17 (Th17)-driven diseases and degenerative ones were consistently reported with a stronger association with Dupilumab in males than females. Some adverse events were more robustly associated with Dupilumab in females.

Conclusion: Dupilumab has an excellent safety profile, even though some ADRs may occur. The risk is higher among male patients, further studies, including ad hoc studies, are needed to establish causality.
“Tranq-dope” overdose and mortality: lethality induced by fentanyl and xylazine
Authors: Smith Mark A. , Biancorosso Samantha L. , Camp Jacob D. , Hailu Salome H. , Johansen Alexandra N. , Morris Mackenzie H. , Carlson Hannah N.
Published: October 2023

Introduction: The recreational use of fentanyl in combination with xylazine (i.e., “tranq-dope”) represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose.

Methods: Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 0.5, 1.0, 1.5, 2.0, and 24 h after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone.

Results: A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. Both drug combinations produced a synergistic interaction as determined via isobolographic analysis. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality.

Discussion: These data provide the first quantification of the lethal effects of “tranq-dope” and suggest that rapid administration of naloxone may be effective at preventing death following overdose.
Broadband acoustic signal enhancement via gradient metamaterials coupled to crystals
Authors: Zhang Sai , Hao Guodong , Zhao Xinsa , Liu Yexin , Han Jianning
Published: October 2023

In this work, a phononic crystal gradient metamaterial structure (PCGMs) is proposed based on the strong wave compression effect coupled with equivalent medium theory to achieve enhancement and directional sensing of weak target acoustic signals. Compared with the conventional gradient structure, PCGMs exhibit superior acoustic enhancement performance and wider range of acoustic response capability. Numerical analysis and experimental validation consistently demonstrate that PCGMs can effectively enhance the target frequency signals in harmonic signals. This study breaks through the detection limit of acoustic sensing systems and provides a great method for engineering applications of weak acoustic signal perception.