bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell transcriptomic atlas throughout anti-BCMA CAR-T therapy in patients with multiple myeloma
Authors: Xia Yuan , Zhao Qian , Shen Xuxing , Jin Yuanyuan , Wang Jing , Zhu Jianfeng , Chen Lijuan
Published: November 2023

Introduction

The emergence of chimeric antigen receptor (CAR)-T therapy targeting B cell maturation antigen (BCMA) has improved the prognosis of patients with multiple myeloma (MM); however, the majority of patients eventually experience relapse.

Methods

In this study, employing the latest single-cell RNA sequencing technology, we examined 24 bone marrow or peripheral blood samples collected throughout the course of anti-BCMA CAR-T therapy, analyzing a total of 59,725 bone marrow cells and 72,479 peripheral blood cells.

Results

Our findings reveal that tumor cells in relapsed patient exhibit higher expression levels of HSP90B1 and HSPA5, and demonstrate significantly enriched pathways regarding endoplasmic reticulum stress and unfolded protein response. In the analysis of T cells, we observed that patient with impaired effector function and increased expression of immune checkpoints in endogenous T cell are more susceptible to relapse. Notably, T cells from both the bone marrow microenvironment and peripheral blood share highly similar biological characteristics.

Discussion

Overall, this study provides a comprehensive atlas of endogenous immune cells, particularly in the relatively long term, after CAR-T therapy. It offers clinical evidence for a deeper understanding of the internal environment post CAR-T treatment and for identifying mechanisms underlying relapse.
Human leukocyte immunoglobulin-like receptors in health and disease
Authors: Redondo-García Silvia , Barritt Christopher , Papagregoriou Charys , Yeboah Muchaala , Frendeus Björn , Cragg Mark S. , Roghanian Ali
Published: November 2023

Human leukocyte immunoglobulin (Ig)-like receptors (LILR) are a family of 11 innate immunomodulatory receptors, primarily expressed on lymphoid and myeloid cells. LILRs are either activating (LILRA) or inhibitory (LILRB) depending on their associated signalling domains (D). With the exception of the soluble LILRA3, LILRAs mediate immune activation, while LILRB1-5 primarily inhibit immune responses and mediate tolerance. Abnormal expression and function of LILRs is associated with a range of pathologies, including immune insufficiency (infection and malignancy) and overt immune responses (autoimmunity and alloresponses), suggesting LILRs may be excellent candidates for targeted immunotherapies. This review will discuss the biology and clinical relevance of this extensive family of immune receptors and will summarise the recent developments in targeting LILRs in disease settings, such as cancer, with an update on the clinical trials investigating the therapeutic targeting of these receptors.
Case Report: Gene expression profiling of COVID-19 vaccination-related lymphadenopathies reveals evidence of a dominantly extrafollicular immune response
Authors: Menter Thomas , Zinner Carl P. , Berger Christoph T. , Went Philip , Tzankov Alexandar
Published: November 2023

mRNA-based vaccines against SARS-CoV-2 have been proven to be very efficient in preventing severe COVID-19. Temporary lymphadenopathy (LA) has been observed as a common adverse event following immunization. Here we describe a case series of three female patients with prominent local to generalized LA after SARS-CoV-2 mRNA-1273 vaccination, which led to lymph node biopsy due to the suspicion of lymphoma or metastasis. All three patients morphologically showed similar patterns of follicular hyperplasia and especially extrafollicular blast activation. Two of the three patients only had short-lasting humoral immune responses to the vaccination. Gene expression profiling (GEP) using the HTG Immune response panel revealed that all three patients clustered together and clearly differed from the GEP-patterns of COVID-19, infectious mononucleosis and non-specific follicular hyperplasia. The closest similarities were seen with lymph nodes showing extrafollicular activation of B-blasts as well as hemophagocytosis. The GEP of the vaccination-induced LA was reminiscent of an immune response with little potential of immunologic memory. mRNA-1273 vaccination-induced LA may to a certain extend reflect disordered immune response with potentially poor immunologic memory in affected individuals.
Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection
Authors: Kim Kwang H. , Park Donghwan , Cho Soo Young , Cho Yejin , Lee Buhyun , Jeong Haengdueng , Lee Yura , Lee Yourim , Nam Ki Taek
Published: November 2023

Macrophages are highly heterogeneous immune cells with a role in maintaining tissue homeostasis, especially in activating the defense response to bacterial infection. Using flow cytometric and single-cell RNA-sequencing analyses of peritoneal cells, we here show that small peritoneal macrophage and immature macrophage populations are enriched in histamine-deficient (Hdc-/-) mice, characterized by a CD11bmiF4/80loCCR2+MHCIIhi and CD11bloF4/80miTHBS1+IL-1α+ phenotype, respectively. Molecular characterization revealed that immature macrophages represent an abnormally differentiated form of large peritoneal macrophages with strong inflammatory properties. Furthermore, deficiency in histamine signaling resulted in significant impairment of the phagocytic activity of peritoneal macrophage populations, conferring high susceptibility to bacterial infection. Collectively, this study reveals the importance of histamine signaling in macrophage differentiation at the molecular level to maintain tissue homeostasis, offering a potential therapeutic target for bacterial infection-mediated diseases.
Initial investigation on the feasibility of porcine red blood cells from genetically modified pigs as an alternative to human red blood cells for transfusion
Authors: Park Sangkeun , Lee Haneulnari , Park Eun Mi , Roh Juhye , Kang Pul Ip , Shim Joohyun , Choi Kimyung , Kang Hee Jung
Published: November 2023

The decline in blood donation rates and the ongoing shortage of blood products pose significant challenges to medical societies. One potential solution is to use porcine red blood cells (pRBCs) from genetically modified pigs as an alternative to human red blood cells (hRBCs). However, adverse immunological reactions remain a significant obstacle to their use. This study aimed to evaluate the compatibility of diverse genetically modified pRBCs with human serum. We acquired human complement-competent serum, complement 7 (C7)-deficient serum, and hRBCs from all ABO blood types. Additionally, we used leftover clinical samples from health checkups for further evaluation. pRBCs were collected from wild-type (WT) and genetically modified pigs: triple knockout (TKO), quadruple KO (QKO), and TKO/hCD55.hCD39 knockin (hCD55.hCD39KI). The extent of C3 deposition on RBCs was measured using flow cytometry after incubation in C7-deficient serum diluted in Ca++-enriched or Ca++-depleted and Mg++-enriched buffers. The binding of immunoglobulin (Ig) M/IgG antibody to RBCs after incubation in ABO-type human serum was evaluated using flow cytometry. Naïve human serum- or sensitized monkey serum-mediated hemolysis was also evaluated. Phagocytosis was assessed by incubating labeled RBCs with the human monocytic cell line THP-1 and measurement by flow cytometry. All three genetic modifications significantly improved the compatibility of pRBCs with human serum relative to that of WT pRBCs. The extent of IgM/IgG binding to genetically modified pRBCs was lower than that of WT pRBCs and similar to that of O-type hRBCs. Total and alternative pathway complement activation in all three genetically modified pRBCs was significantly weaker than that in WT pRBCs and did not differ from that in O-type hRBCs. The extent of serum-mediated hemolysis and phagocytosis of these genetically modified pRBCs was low and similar to that of O-type hRBCs. Sensitized monkey serum-mediated hemolysis in QKO and TKO/hCD55.hCD39KI pRBCs was higher than in O-type hRBCs but lower than in TKO pRBCs. The elimination of porcine carbohydrate antigens in genetically modified pigs significantly enhanced pRBC compatibility with naïve human sera, which was comparable to that of O-type hRBCs. These findings provide valuable insights into the development of pRBCs as potential alternatives to hRBCs.
Attention vs. accessibility: the role of different cue types for non-canonical sentence production in German
Authors: Dolscheid Sarah , Penke Martina
Published: November 2023

Introduction

There is evidence of close links between the allocation of attention and the production of language. For instance, while speakers commonly produce active sentences when they describe an event with an agent acting on a patient, this preference can shift once the patient is in the spotlight of attention (e.g., by means of a brief attentional cue preceding the patient). In this case, speakers are more prone to produce non-canonical sentences such as passives. Critically, however, whereas attentional cueing is particularly effective for speakers of English, it has proven less effective for speakers of languages like German that differ from English in terms of case-marking and word order flexibility. This observation begs the question of how German speakers respond to alternative cue types that differ in the conceptual and lexical information they provide. In the current study, we address this question by directly comparing the effect of different cue types on sentence production.

Methods

German-speaking participants were asked to describe transitive event scenes while their eye gaze was monitored via eye tracking. Prior to scene onset, participants saw one of three different cue types: a short attentional cue preceding the patient character, a long attentional cue, or a centrally presented pre-view of the patient (referential cue).

Results and discussion

Our results demonstrate that different cue types led to differences in speakers' propensity to produce passives. Critically, referential cueing was more effective than attentional cueing in increasing German speakers' rate of passive production, contra to what has previously been reported for English speakers. At the same time, the cues resulted in different viewing behavior, demonstrating that an increase in visual attention does not necessarily go hand in hand with an increase in passivization. Consequently, our findings show that a direct link between the allocation of attention and speakers' structural choices may not always be licensed.
Inhibition of oil tea anthracnose by natural product extracts from Bacillus and Pseudoalteromonas isolates from mangrove soil
Authors: Fei Liwang , Xu Xiaowen , Feng Jinying , Hao Lingyun
Published: November 2023

This study investigates the potential of natural products derived from two mangrove soil bacteria, GP521A and GP3R5, in anthracnose management in oil tea. Based on 16s rDNA sequencing, GP521A and GP3R5 were identified as Bacillus velezensis and Pseudoalteromonas caenipelagi, respectively. Both bacteria showed strong antagonistic effects towards multiple fungal pathogens on dual cultural plates. The ethyl acetate extracts of fermentation cultures of GP521A (FEGP5) and GP3R5 (FEGP3) significantly inhibited mycelial growth of both Colletotrichum camelliae MC171, C. fructicola CF-1 and Pyricularia oryzae P131 at 100 and 200 μg/mL, respectively. Furthermore, FEGP5 and FEGP3 significantly inhibited conidiation, conidial germination and appressorial formation in C. camelliae MC171 at 50 μg/mL, with stronger inhibitory effects observed in the latter. On detached oil tea leaves, 100 μg/mL of FEGP5 and FEGP3 resulted in ~ 98.0% and 97.5% reduction in diseased areas, respectively, when applied before MC171 inoculation, whereas the reduction was approximately 55.0% and 77.6%, respectively, in the curative treatments. In fresh fruits, both extracts also significantly inhibited disease development, either in preventative or curative treatments. Moreover, FEGP5 and FEGP3 demonstrated significantly lower aquatic toxicity than prochloraz at the same concentrations towards a commonly used bioindicator, Artemia salina. In conclusion, this study demonstrates the potential of marine microbes derived natural products in development of environmentally compatible biopesticides to control anthracnose in oil tea.
A comparative study of the efficacy of instrument-assisted soft tissue mobilization and massage techniques in patients with patellofemoral joint pain
Authors: Liu Yang , Wang Yidan
Published: November 2023

Purpose

The aim of this study was to compare the clinical efficacy of instrument-assisted soft tissue mobilization (IASTM) and manipulative therapy Tui-na techniques in the treatment of patients with patellofemoral joint pain syndrome, and to evaluate their impact on pain relief, functional improvement, and joint range of motion.

Methods

In this study, 25 patients with patellofemoral pain syndrome were enrolled, comprising of an intervention group of 13 patients who received IASTM treatment and a control group of 12 patients who received Tui-na manipulation therapy. The treatment cycle lasted for 4 weeks, featuring two interventions per week. Before treatment, the visual analog pain scale (VAS) of the knee, Lysholm score of the knee, modified Thomas test (MTT), and maximum isometric strength of the extensor muscles of the lower limbs were measured and recorded for both groups. After the first and last treatments, the aforementioned indexes were reassessed, and the maximum isometric muscle strength of the lower extremity extensors was measured only after 4 weeks of treatment had been completed.

Results

There was no significant difference in the basic information of the two intervention groups (p > 0. 05). After the first treatment and 4 weeks of treatment, the Lysholm score in both groups significantly improved (p < 0. 05), indicating that both interventions can improve the function of patients’ lower limbs. However, the Lysholm score in the IASTM group significantly increased compared with that of the massage group after 4 weeks of treatment, indicating that its improvement in functional performance is superior. Both groups showed significant improvement in knee joint pain after the first treatment and 4 weeks of treatment (p < 0. 05), with the IASTM group having a lower VAS score and better pain improvement after 4 weeks of treatment. The strength of the two intervention groups significantly increased after the maximum isometric muscle strength test of the lower limb extensor muscles before and after 4 weeks of treatment (p < 0. 05). After the MTT test, the extension angle, deviation angle, and hip abduction angle of the tested legs in the two intervention groups were significantly reduced (p < 0. 001), indicating an improvement in lower limb joint mobility.

Conclusion

Instrument-assisted soft tissue mobilization treatment and Tui-na manipulation therapy significantly reduced pain, improved knee flexibility, and increased range of motion of the lower extremity in patients with PFPS. However, IASTM treatment significantly improved pain and function and sustained pain in the short to medium-term post-trial period.

Clinical trial registration

www.isrctn.com, ISRCTN88098928
Thermal titration molecular dynamics (TTMD): shedding light on the stability of RNA-small molecule complexes
Authors: Dodaro Andrea , Pavan Matteo , Menin Silvia , Salmaso Veronica , Sturlese Mattia , Moro Stefano
Published: November 2023

Ribonucleic acids are gradually becoming relevant players among putative drug targets, thanks to the increasing amount of structural data exploitable for the rational design of selective and potent binders that can modulate their activity. Mainly, this information allows employing different computational techniques for predicting how well would a ribonucleic-targeting agent fit within the active site of its target macromolecule. Due to some intrinsic peculiarities of complexes involving nucleic acids, such as structural plasticity, surface charge distribution, and solvent-mediated interactions, the application of routinely adopted methodologies like molecular docking is challenged by scoring inaccuracies, while more physically rigorous methods such as molecular dynamics require long simulation times which hamper their conformational sampling capabilities. In the present work, we present the first application of Thermal Titration Molecular Dynamics (TTMD), a recently developed method for the qualitative estimation of unbinding kinetics, to characterize RNA-ligand complexes. In this article, we explored its applicability as a post-docking refinement tool on RNA in complex with small molecules, highlighting the capability of this method to identify the native binding mode among a set of decoys across various pharmaceutically relevant test cases.
Modeling of cerebellar transcranial electrical stimulation effects on hand tremor in Parkinson’s disease
Authors: Rahimi Soraya , Towhidkhah Farzad , Baghdadi Golnaz , Forogh Bijan , Saadat Payam , Soleimani Ghazaleh , Habibi Seyed Amirhassan
Published: November 2023

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder with different motor and neurocognitive symptoms. Tremor is a well-known symptom of this disease. Increasing evidence suggested that the cerebellum may substantially contribute to tremors as a clinical symptom of PD. However, the theoretical foundations behind these observations are not yet fully understood.

Methods

In this study, a computational model is proposed to consider the role of the cerebellum and to show the effectiveness of cerebellar transcranial alternating current stimulation (tACS) on the rest tremor in participants with PD. The proposed model consists of the cortex, cerebellum, spinal circuit-muscular system (SC-MS), and basal ganglia blocks as the most critical parts of the brain, which are involved in generating rest tremors. The cortex, cerebellum, and SC-MS blocks were modeled using Van der Pol oscillators that interacted through synchronization procedures. Basal ganglia are considered as a regulator of the coupling weights defined between oscillators. In order to evaluate the global behavior of the model, we applied tACS on the cerebellum of fifteen PD patients for 15 min at each patient’s peak frequency of their rest tremors. A tri-axial accelerometer recorded rest tremors before, during, and after the tACS.

Results and Discussion

The simulation of the model provides a suggestion for the possible role of the cerebellum on rest tremors and how cerebellar tACS can affect these tremors. Results of human experiments also showed that the online and offline effects of cerebellar tACS could lead to the reduction of rest tremors significantly by about %76 and %68, respectively. Our findings suggest that the cerebellar tACS could serve as a reliable, therapeutic technique to suppress the PD tremor.
X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study
Authors: Wang Kai-Wen , Yuan Yu-Xin , Zhu Bin , Zhang Yi , Wei Yi-Fang , Meng Fan-Shuo , Zhang Shun , Wang Jing-Xuan , Zhou Ji-Yuan ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2023

Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disease with high heritability. Compared to autosomes, a higher proportion of disorder-associated genes on X chromosome are expressed in the brain. However, only a few studies focused on the identification of the susceptibility loci for AD on X chromosome.

Methods

Using the data from the Alzheimer’s Disease Neuroimaging Initiative Study, we conducted an X chromosome-wide association study between 16 AD quantitative biomarkers and 19,692 single nucleotide polymorphisms (SNPs) based on both the cross-sectional and longitudinal studies.

Results

We identified 15 SNPs statistically significantly associated with different quantitative biomarkers of the AD. For the cross-sectional study, six SNPs (rs5927116, rs4596772, rs5929538, rs2213488, rs5920524, and rs5945306) are located in or near to six genes DMD, TBX22, LOC101928437, TENM1, SPANXN1, and ZFP92, which have been reported to be associated with schizophrenia or neuropsychiatric diseases in literature. For the longitudinal study, four SNPs (rs4829868, rs5931111, rs6540385, and rs763320) are included in or near to two genes RAC1P4 and AFF2, which have been demonstrated to be associated with brain development or intellectual disability in literature, while the functional annotations of other five novel SNPs (rs12157031, rs428303, rs5953487, rs10284107, and rs5955016) have not been found.

Discussion

15 SNPs were found statistically significantly associated with the quantitative biomarkers of the AD. Follow-up study in molecular genetics is needed to verify whether they are indeed related to AD. The findings in this article expand our understanding of the role of the X chromosome in exploring disease susceptibility, introduce new insights into the molecular genetics behind the AD, and may provide a mechanistic clue to further AD-related studies.
Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target
Authors: Pal Ranu , Hui Dongwei , Menchen Heather , Zhao Huiping , Mozziconacci Olivier , Wilkins Heather , Blagg Brian S. J. , Schöneich Christian , Swerdlow Russell H. , Michaelis Mary L. , Michaelis Elias K.
Published: November 2023

A feature of most neurodegenerative diseases is the presence of “mis-folded proteins” that form aggregates, suggesting suboptimal activity of neuronal molecular chaperones. Heat shock protein 90 (Hsp90) is the master regulator of cell responses to “proteotoxic” stresses. Some Hsp90 modulators activate cascades leading to upregulation of additional chaperones. Novobiocin is a modulator at the C-terminal ATP-binding site of Hsp90. Of several novobiocin analogs synthesized and tested for protection against amyloid beta (Aβ)-induced neuronal death, “KU-32” was the most potent in protecting primary neurons, but did not increase expression of other chaperones believed to help clear misfolded proteins. However, KU-32 reversed Aβ-induced superoxide formation, activated Complex I of the electron transfer chain in mitochondria, and blocked the Aβ-induced inhibition of Complex I in neuroblastoma cells. A mechanism for these effects of KU-32 on mitochondrial metabolism appeared to be the inhibition of pyruvate dehydrogenase kinase (PDHK), both in isolated brain mitochondria and in SH-SY5Y cells. PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Aβ25-35-induced cell injury similarly to KU-32. Inhibition of PDHK in neurons would lead to activation of the PDH complex, increased acetyl-CoA generation, stimulation of the tricarboxylic acid cycle and Complex I in the electron transfer chain, and enhanced oxidative phosphorylation. A focus of future studies may be on the potential value of PDHK as a target in AD therapy.
Spatiotemporal analysis of 3D human iPSC-derived neural networks using a 3D multi-electrode array
Authors: Lam Doris , Enright Heather A. , Cadena Jose , George Vivek Kurien , Soscia David A. , Tooker Angela C. , Triplett Michael , Peters Sandra K. G. , Karande Piyush , Ladd Alexander , Bogguri Chandrakumar , Wheeler Elizabeth K. , Fischer Nicholas O.
Published: November 2023

While there is a growing appreciation of three-dimensional (3D) neural tissues (i.e., hydrogel-based, organoids, and spheroids), shown to improve cellular health and network activity to mirror brain-like activity in vivo, functional assessment using current electrophysiology techniques (e.g., planar multi-electrode arrays or patch clamp) has been technically challenging and limited to surface measurements at the bottom or top of the 3D tissue. As next-generation MEAs, specifically 3D MEAs, are being developed to increase the spatial precision across all three dimensions (X, Y, Z), development of improved computational analytical tools to discern region-specific changes within the Z dimension of the 3D tissue is needed. In the present study, we introduce a novel computational analytical pipeline to analyze 3D neural network activity recorded from a “bottom-up” 3D MEA integrated with a 3D hydrogel-based tissue containing human iPSC-derived neurons and primary astrocytes. Over a period of ~6.5 weeks, we describe the development and maturation of 3D neural activity (i.e., features of spiking and bursting activity) within cross sections of the 3D tissue, based on the vertical position of the electrode on the 3D MEA probe, in addition to network activity (identified using synchrony analysis) within and between cross sections. Then, using the sequential addition of postsynaptic receptor antagonists, bicuculline (BIC), 2-amino-5-phosphonovaleric acid (AP-5), and 6-cyano-5-nitroquinoxaline-2,3-dione (CNQX), we demonstrate that networks within and between cross sections of the 3D hydrogel-based tissue show a preference for GABA and/or glutamate synaptic transmission, suggesting differences in the network composition throughout the neural tissue. The ability to monitor the functional dynamics of the entire 3D reconstructed neural tissue is a critical bottleneck; here we demonstrate a computational pipeline that can be implemented in studies to better interpret network activity within an engineered 3D neural tissue and have a better understanding of the modeled organ tissue.
Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease
Authors: Shaikh Ammara , Ahmad Fairus , Teoh Seong Lin , Kumar Jaya , Yahaya Mohamad Fairuz
Published: November 2023

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.
Association between weight status and migraine in the paediatric population: a systematic review and meta-analysis
Authors: Quispe-Vicuña Carlos , Soriano-Moreno David R. , De-Los-Rios-Pinto Abraham , Díaz-Ledesma Luz A. , Fernandez-Guzman Daniel , Pacheco-Barrios Kevin , Alva-Diaz Carlos
Published: November 2023

Introduction

An association between weight status and migraine has been previously reported; however, this relationship has only been studied in adults, not in the paediatric population.

Objective

To evaluate the association between weight status and migraine in the paediatric population.

Methods

We searched PubMed/Medline, Scopus, Web of Science, Ovid Medline, and Embase using a cut-off date of May 2023. We included observational studies that evaluated the association between weight status (underweight, overweight, obese, and excess weight) and migraine in the paediatric population (children and adolescents). Normal weight was the comparator. The outcome was migraine (all types, episodic and chronic). We performed meta-analyses using a random-effects model to estimate the pooled effects for each outcome. Sensitivity analysis was performed based on study design and risk of bias (using the Newcastle–Ottawa Scale). Certainty of evidence was assessed using the GRADE approach.

Results

Eight studies (6 cross-sectional, 1 case-control and 1 cohort) covering 16,556 patients were included. The overall certainty of evidence was very low for the association between overweight, obesity, and excess weight with migraine. In the sensitivity analysis, meta-analyses of studies with a low risk of bias found that the overweight population probably had an increased odds of migraine (OR: 1.70; 95% CI: 1.14 to 2.53; I2 = 32.3%, p = 0.224) and that excess weight may increase the odds of migraine (OR: 1.58; 95% CI: 1.06 to 2.35; I2 = 83.7%, p = 0.002). Additionally, cohort and case-control studies found that obesity probably increases the odds of migraine. No studies analysed the association between underweight and migraine.

Conclusion

The associations between overweight, obesity, excess weight and migraine were uncertain, but studies with better methodological quality reported increased odds. Future longitudinal studies with proper confounding control are needed to disentangle their causal relationship.

Systematic review registration

PROSPERO, identifier CRD42021271533.
Case report: A patient with Delayed Sleep-Wake Phase Disorder and Optic Nerve Hypoplasia treated with tasimelteon: a case study
Authors: Smieszek Sandra P. , Kaden Alyssa R. , Johnson Caroline E. , Brzezynski Jennifer L. , Xiao Changfu , Polymeropoulos Christos M. , Birznieks Gunther , Emsellem Helene A. , Polymeropoulos Mihael H.
Published: November 2023

We present a case of an adult female diagnosed with Delayed Sleep-Wake Phase Disorder (DSWPD) and Optic Nerve Hypoplasia (ONH), with a confirmed delayed Dim Light Melatonin Onset (DLMO), who reports the inability to fall asleep at their desired bedtime and obtain adequate sleep nightly, despite the ability to have a full night’s sleep when not required to be up at a specific time for societal requirements. The participant was enrolled in an 11-month Open-Label Extension (OLE) following the randomized portion of a clinical study and was successfully treated with tasimelteon. DSWPD symptoms were resolved, and their previously delayed sleep-wake cycle was advanced.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT04652882, identifier NCT04652882.
Mutations of RAS genes identified in acute myeloid leukemia affect glycerophospholipid metabolism pathway
Authors: Liang Tianqi , Kong Yanxiang , Xue Hongman , Wang Wenqing , Li Chunmou , Chen Chun
Published: November 2023

Background

Acute myeloid leukemia (AML) is a malignant disease originating from myeloid hematopoietic stem cells. Recent studies have shown that certain gene mutations promote tumor cell survival and affect the prognosis of patients by affecting metabolic mechanisms in tumor cells. RAS gene mutations are prevalent in AML, and the RAS signaling pathway is closely related to many metabolic pathways. However, the effects of different RAS gene mutations on AML cell metabolism are unclear.

Objectives

The main purpose of this study was to explore the effect of RAS gene mutation on the metabolic pathway of tumor cells.

Methods

In this study, we first used a retrovirus carrying a mutant gene to prepare Ba/F3 cell lines with RAS gene mutations, and then compared full-transcriptome data of Ba/F3 cells before and after RAS gene mutation and found that differentially expressed genes after NRASQ61K and KRASG12V mutation.

Results

We found a total of 1899 differentially expressed genes after NRASQ61K and KRASG12V mutation. 1089 of these genes were involved in metabolic processes, of which 167 genes were enriched in metabolism-related pathways. In metabolism-related pathways, differential genes were associated with the lipid metabolism pathway. Moreover, by comparing groups, we found that the expression of the DGKzeta and PLA2G4A genes in the glycerophospholipid metabolism pathway was significantly upregulated.

Conclusion

In conclusion, our study revealed that RAS gene mutation is closely related to the glycerophospholipid metabolism pathway in Ba/F3 cells, which may contribute to new precision therapy strategies and the development and application of new therapeutic drugs for AML.
The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway
Authors: Papoff Giuliana , Presutti Dario , Fustaino Valentina , Parente Andrea , Calandriello Clelia , Alemà Stefano , Scavizzi Ferdinando , Raspa Marcello , Merlino Giuseppe , Salerno Massimiliano , Bigioni Mario , Binaschi Monica , Ruberti Giovina
Published: November 2023

Background

Lung cancer remains the leading cause of cancer-related death worldwide. Targeted therapies with tyrosine kinase inhibitors (TKIs) result in improvement in survival for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). Unfortunately, most patients who initially respond to EGFR-TKI ultimately develop resistance to therapy, resulting in cancer progression and relapse. Combination therapy is today a common strategy for the treatment of tumors to increase the success rate, improve the outcome and survival of patients, and avoid the selection of resistant cancer cells through the activation of compensatory pathways. In NSCLC, the phosphoinositide-3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been heavily implicated in both tumorigenesis and the progression of disease.

Objectives

In this study, we investigated the efficacy of a PI3K δ-sparing inhibitor, MEN1611, in models of NSCLC sensitive and resistant to EGFR inhibitors (erlotinib and gefitinib) with a wild-type PIK3CA gene.

Methods

We performed functional, biochemical, and immunohistochemistry studies.

Results

We demonstrated good efficacy of MEN1611 in NSCLC devoid of PIK3CA gene mutations but with constitutive activation of the PI3K/AKT pathway and its synergistic effect with gefitinib both in vitro and in vivo.

Conclusions

Overall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system.
News and views on ion channels in cancer: is cancer a channelopathy?
Authors: Bell Damian C. , Leanza Luigi , Gentile Saverio , Sauter Daniel R.
Published: November 2023

Ion channels are key signaling proteins found throughout the body; they are critical in many, wide-ranging physiological processes, from gene expression, sensory perception and processing to the cardiac action potential. When ion channel activity goes awry, for example, via mutation, damage or disrupted homeostasis, the outcome can result in causation, development and/or maintenance of disease. Ion channel dependent diseases have been dubbed channelopathies. Recent studies on the role of ion channels in cancer biology suggest that cancer is one such channelopathy. Many ion channels have now been implicated in the cellular processes that are affected in a multitude of cancers. In the last two decades, the field of ion channel and cancer research has been growing exponentially: a combination of developments in molecular biology, genetics, electrophysiology and automation have driven an explosion in our capabilities to interrogate ion channel pathways; how, why and where they go wrong and therapeutic interventions to correct their pathophysiology in cancer. A review of this vast and rapidly developing field would require a titanic tome to merely dimple the surface of research that has ballooned recently. In lieu of that huge undertaking—for the benefit of both authors and readers - this review discusses select examples of primary, applied and clinical research, aiming to shine a light on some of the more innovative and novel findings that this exciting field is excavating.
Role of peptide–cell surface interactions in cosmetic peptide application
Authors: He Bingwei , Wang Feifei , Qu Liping
Published: November 2023

Cosmetic peptides have gained popularity in a wide range of skincare products due to their good biocompatibility, effective anti-oxidative properties, and anti-aging effects. However, low binding between peptides and the cell surface limits the efficacy of functional peptides. In this study, we designed two novel targeting peptide motifs to enhance the interaction between cosmetic peptides and the cell surface, thereby improving their performance for skin health. To achieve this, we optimized the well-known peptide tripeptide-1 (GHK) by separately grafting the integrin αvβ3-binding motif RGD and the chondroitin sulfate (CS)-binding motif sOtx2 onto it, forming two chimeric targeting peptides, RGD-GHK and sOtx2-GHK. Comparative analysis showed that both RGD-GHK and sOtx2-GHK exhibited superior anti-oxidative and anti-apoptotic effects compared to the non-targeting peptide, GHK. Furthermore, RGD-GHK demonstrated exceptional anti-aging activity, and its potential for promoting wound healing and repairing the skin barrier was evaluated in vitro using cells and skin models. In vitro permeation and in vivo adsorption testing confirmed that RGD-GHK achieved a high local concentration in the skin layer, initiating peptide effects and facilitating in vivo wound healing, while maintaining excellent biocompatibility. The enhancement of signaling cosmetic peptides can be attributed to the specific interaction between the binding motif and cell surface components. Consequently, this targeting peptide holds promising potential as a novel functional peptide for application in cosmetics.
Safety profile of intravenous digoxin in Chinese patients with acute heart failure with reduced ejection fraction: a small-scale prospective cohort study
Authors: Liu Xintian , Zhang Haojie , Cheng Wenlin , Fan Qingkun , Lu Zhibing , Zheng Xuan , Zhang Gangcheng
Published: November 2023

Background: Adverse effects of intravenous digoxin vary from patients and disease status, which should be closely monitored.

Aims: To explore the safety profile of intravenous digoxin in acute heart failure with reduced ejection fraction (HFrEF) among Chinese patients.

Methods: A clinical prospective, single-center, single-arm, open-label exploratory clinical trial was performed in patients with acute HFrEF at Wuhan Asia Heart Hospital. A fixed dose of 0.5 mg digoxin was used intravenously once per day for 3 days. The normalized dosage of digoxin (NDD), toxic serum digoxin concentration (SDC), and adverse reactions of intravenous digoxin were recorded.

Results: A total of 40 patients were recruited in the study. The SDC increased from 1.03 ± 0.34 ng/mL to 1.95 ± 0.52 ng/mL during treatment. 50% (20/40) patients reached a toxic SDC of 2.0 ng/mL, and toxic effects were seen in 30% (12/40) patients. Estimated glomerular filtration rate (eGFR) < 60 mL/min [HR: 5.269; 95% CI: 1.905–14.575, p = 0.001], NDD ≥7 μg/kg [HR: 3.028; 95% CI: 1.119–8.194, p = 0.029], and ischemic cardiomyopathy [HR: 2.658; 95% CI: 1.025–6.894, p = 0.044] were independent risk factors for toxic SDC. Toxic SDC was effectively identified [area under the receiver operating characteristic (ROC) curve = 0.85, p < 0.001] using this model, and patients would have a higher risk of toxicity with more risk factors.

Conclusion: Intravenous digoxin of 0.5 mg was safe and effective for initial dose but not suitable for maintenance treatment in Chinese patients with acute HFrEF. Patients who had lower eGFR, received higher NDD, and had ischemic cardiomyopathy should be closely monitored to avoid digoxin toxicity.
Acoustic noise levels and field distribution in 7 T MRI scanners
Authors: Shtrepi Louena , Poggetto Vinicius F. Dal , Durochat Clement , Dubois Marc , Bendahan David , Nistri Fabio , Miniaci Marco , Pugno Nicola Maria , Bosia Federico
Published: November 2023

Acoustic noise production during Magnetic Resonance Imaging is an important source of patient discomfort and leads to verbal communication problems, difficulties in sedation, and hearing impairment. To address these issues, in this paper we present a systematic characterization of the acoustic field distribution in a MRI cavity in a last generation 7 T scanner, in different spatial locations, with and without a phantom head. Analysis and comparison of various MRI sequences like Echo-planar imaging”, “Gradient echo”, “Spin echo” are carried out. Sound pressure levels are measured using standard statistical descriptors (Leq,Lmean, L90, and Lmode) using two prepolarized free-field microphones measuring pressure levels generated inside scanner cavities in a 50 Hz to 10 kHz range. Acoustic eigenmodes of the cavity are derived numerically in finite element simulations and compared to measurements. Equivalent sound pressure levels exceed 85 dB in the range between 500 and 3,000 Hz, and peak levels are consistently above 100 dB, i.e., the noise levels of 7 T scanners are higher than 3T and 1.5 T counterparts. The presence of the phantom head in the MRI scanner leads to increased noise levels (by 5–10 dB) in its vicinity, as a result of reflections occurring between the head and the bore reflective walls. Numerical finite element simulations allow to extrapolate the noise distribution in the entire cavity and to interpret experimental results and indicate that the frequencies at which the highest noise levels occur correspond to azimuthal or radial resonant modes of the MRI cavity, i.e., with a radially and azimuthally varying pressure field. These results can be useful for the design of future acoustic noise mitigation solutions.
Potential oxidative stress related targets of mitochondria-focused therapy of PTSD
Authors: Kmita Hanna , Pinna Graziano , Lushchak Volodymyr I.
Published: November 2023

Post-traumatic stress disorder (PTSD) remains a highly prevalent, under-diagnosed, and under-treated psychiatric disorder that often deteriorates over time, and is highly comorbid with major depressive disorder, suicidality, and substance use disorder. Several biomarkers have been proposed but have yet to be implemented into clinical practice. Treatments, including selective serotonin reuptake inhibitors, are efficacious in only a small number of patients, which underscores the need to develop novel, efficient treatments. Mitochondrial dysfunction resulting from chronic oxidative stress has been linked with both altered neurotransmitter signaling and the inflammatory response. Hereinafter, we discuss mechanisms by which mitochondrial dysfunction may contribute to the development of PTSD symptoms, and how these may even increase PTSD susceptibility. We also highlight possible therapeutic targets to reduce oxidative stress to prevent or treat PTSD symptoms.
ERGPNet: lesion segmentation network for COVID-19 chest X-ray images based on embedded residual convolution and global perception
Authors: Yue Gongtao , Yang Chen , Zhao Zhengyang , An Ziheng , Yang Yongsheng
Published: November 2023

The Segmentation of infected areas from COVID-19 chest X-ray (CXR) images is of great significance for the diagnosis and treatment of patients. However, accurately and effectively segmenting infected areas of CXR images is still challenging due to the inherent ambiguity of CXR images and the cross-scale variations in infected regions. To address these issues, this article proposes a ERGPNet based on embedded residuals and global perception, to segment lesion regions in COVID-19 CXR images. First, aiming at the inherent fuzziness of CXR images, an embedded residual convolution structure is proposed to enhance the ability of internal feature extraction. Second, a global information perception module is constructed to guide the network in generating long-distance information flow, alleviating the interferences of cross-scale variations on the algorithm’s discrimination ability. Finally, the network’s sensitivity to target regions is improved, and the interference of noise information is suppressed through the utilization of parallel spatial and serial channel attention modules. The interactions between each module fully establish the mapping relationship between feature representation and information decision-making and improve the accuracy of lesion segmentation. Extensive experiments on three datasets of COVID-19 CXR images, and the results demonstrate that the proposed method outperforms other state-of-the-art segmentation methods of CXR images.
A sense of connectedness, transcendent experiences, and insights for compassionate action emerge through an international collective labyrinth walk with a shared intention during the COVID-19 pandemic
Authors: McGee Jocelyn Shealy , Katzenmeyer Christine , Boddie Stephanie Clintonia , Meraz Rebecca , Wood Sinai
Published: November 2023

Introduction

Labyrinth walking is an integrative contemplative practice that aims to engage the body, heart, mind, and spirit. In this article, qualitative findings from the first year of a mixed methods study on collective labyrinth walking with a shared intention are described. This form of labyrinth walking is distinct in that it is a social contemplative practice. It expands upon most of the labyrinth walking research to date which has been focused upon the individual. More specifically, practitioners walk labyrinths together in solidarity with the same intention in mind during collective labyrinth walking. This practice can be used locally (i.e. practitioners walk the same labyrinth together for the same reason) or non-locally (i.e. practitioners walk different labyrinths for the same reason together in different locations). The study is unique in that it took place at the height of the COVID-19 pandemic which was a time in recent history that evoked fear, uncertainty, grief, isolation, and disconnectedness for many persons around the world.

Methods

This sample in this study was comprised of 461 participants from 19 countries who collectively walked labyrinths together with a shared intention on World Labyrinth Day 2021. Most participants were women in middle to later life from the United States. Data was collected through an anonymous online survey and analyzed using the qualitative methodology of interpretive phenomenological analysis.

Results

Three predominant themes emerged from practitioners’ narrative accounts of their lived experiences: (1) multiple forms of connectedness (i.e., intrapersonal, interpersonal, transpersonal, labyrinth connection) were cultivated through collective labyrinth walking with a shared intention; (2) practitioners reported qualities associated with “transcendent” experiences during this experience (i.e., boundlessness, ultimacy, transcendence, connectedness, positive emotions); and (3) practitioners had insights for compassionate action.

Discussion

Findings suggest that collective labyrinth walking with a shared intention can contribute to individual and group flourishing during times of distress. Quasi-experimental and experimental research designs are needed to build on this exploratory developmental research and are described in this article.