Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound DD205-291 with high selectivity and potency. DD205-291 showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, DD205-291 exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of DD205-291 at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.

Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling.

Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl2, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl2-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.

The effects of entrepreneurial narrative on entrepreneurial intention: An affective events perspective.

Entrepreneurial narrative has been used in the entrepreneurship education process to develop students' entrepreneurial intention. However, previous research has less knowledge about the mechanisms between entrepreneurial narrative and entrepreneurial intention from an affective events perspective. We explore the effect of entrepreneurial narrative on entrepreneurial intention based on the theory of affective events theory. The sample of this study comprised 348 individuals who participated in entrepreneurship education in China. The results suggest that entrepreneurial narrative have a significant positive impact on college students' entrepreneurial intention. Additionally, the relationship between entrepreneurial narrative and entrepreneurial intention is mediated by entrepreneurial passion, and entrepreneurial support positively moderates the relationship between entrepreneurial passion and entrepreneurial intention.

Clinical decision support system using hierarchical fuzzy diagnosis model for migraine and tension-type headache based on International Classification of Headache Disorders, 3rd edition.

Objective: To determine whether the diagnostic ability of the newly designed hierarchical fuzzy diagnosis method is consistent with that of headache experts for probable migraine (PM) and probable tension-type headache (PTTH). Background: Clinical decision support systems (CDSS) are computer systems designed to help doctors to make clinician decisions by information technology, and have proven to be effective in improving headache diagnosis by making medical knowledge readily available to users in some studies. However, one serious drawback is that the CDSS lacks the ability to deal with some fuzzy boundaries of the headache features utilized in diagnostic criteria, which might be caused by patients' recall bias and subjective bias. Methods: A hybrid mechanism of rule-based reasoning and hierarchical fuzzy diagnosis method based on International Classification of Headache Disorders, 3rd edition (ICHD-3) was designed and then validated by a retrospective study with 325 consecutive patients and a prospective study with 380 patients who were clinically diagnosed with migraine and TTH at the headache clinic of Chinese PLA General Hospital. Results: The results of the diagnostic test in the retrospective study indicated that the fuzzy-based CDSS can be used in the diagnosis of migraine without aura (MO) (sensitivity 97.71%, specificity 100%), TTH (sensitivity 98.57%, specificity 100%), PM (sensitivity 91.25%, specificity 98.75%) and PTTH (sensitivity 90.91%, specificity 99.63%). While in the prospective study, the diagnostic performances were MO (sensitivity 91.62%, specificity 96.52%), TTH (sensitivity 92.17%, specificity 95.47%), PM (sensitivity 85.48%, specificity 98.11%) and PTTH (sensitivity 87.50%, specificity 98.60%). Cohen's kappa values for the consistency test were 0.984 ± 0.018 (MO), 0.991 ± 0.018 (TTH), 0.916 ± 0.051 (PM), 0.932 ± 0.059 (PTTH) in the retrospective study and 0.884 ± 0.047 (MO), 0.870 ± 0.055 (TTH), 0.853 ± 0.073 (PM), 0.827 ± 0.118 (PTTH) in the prospective study, which indicated good consistency with the fuzzy-based CDSS and the gold standard (p < 0.001). Conclusion: We developed a fuzzy-based CDSS performs much more similarly to expert diagnosis and performs better than the routine CDSS method in the diagnosis of migraine and TTH, and it could promote the application of artificial intelligence in the area of headache diagnosis.

EBV-Positive Classic Hodgkin Lymphoma and Primary Nodal T-Cell/NK-Cell Lymphoma Arising in the Background of Follicular Lymphoma.

EBV-positive primary nodal T-cell/NK cell lymphoma (TNKL) is a rare diagnosis with a poor prognosis. No relationship with follicular lymphoma (FL), classic Hodgkin lymphoma (cHL), or other non-Hodgkin lymphomas is established. We describe a case of Epstein-Barr virus (EBV)-positive cHL and EBV-positive primary nodal TNKL in the background of an antecedent FL, with all 3 subtypes identified in a single lymph node biopsy from an immunocompetent patient. Intensive frontline therapy achieved only a temporary response, with subsequent rapid progression associated with hemophagocytic lymphohistiocytosis (HLH). We discuss the relationship of the three lymphoma subtypes and the potential roles of EBV and immune dysregulation as contributing factors to this previously undescribed composite lymphoma.

[Treatment of New Daily Persistent Headache With Esketamine: Report of One Case].

New daily persistent headache (NDPH) is a kind of persistent headache that patients can identify the exact date of the sudden onset.It is one of the rare primary headaches difficult to be cured and may lead to disability,seriously affecting the daily life and work.The exact pathogenesis of NDPH remains unclear,which makes the treatment difficult.Here we report a case of refractory NDPH treated by intravenous injection of esketamine at a sub-anesthetic dose.

Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma.

BACKGROUND: Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability. METHODS: Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA. RESULTS: The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression. CONCLUSIONS: In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.

Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the major histopathological types of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence has shown that micropapillary LUAD is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic LUAD has a relatively better prognosis. However, the novel genetic change and its underlying mechanism in the progression of micropapillary LUAD have not been exactly determined. METHODS: A total of 181 patients with LUAD who underwent surgery at the First Affiliated Hospital of Huzhou University from January 2020 to December 2022 were enrolled. Three predominant lepidic and three predominant micropapillary LUAD tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary LUAD was performed. In addition, the TMEM229A Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the TMEM229A Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of TMEM229A Q200del on NSCLC cell proliferation and migration were also determined. RESULTS: The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1, and PKD1L2 were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The TMEM229A Q200del mutation was only mutated in lepidic LUAD. Additionally, the TMEM229A Q200del mutation had occurred in 16 (8.8%) patients, and not found TMEM229A R76H and M346T mutations in our cohort, while TMEM229A mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the TMEM229A Q200del mutation and clinicopathological characteristics suggested that a lower frequency of the Q200del mutation was significantly associated with positive lymph node metastasis, advanced TNM stage, positive cancer thrombus, and pathological features. Finally, overexpression of TMEM229A Q200del suppressed NSCLC cell proliferation and migration in vitro. Mechanistically, overexpression of TMEM229A and TMEM229A Q200del both reduced the expression level of phosphorylated (p)-ERK and p-AKT (Ser473), and the reduced protein level of p-ERK in the TMEM229A Q200del group was more pronounced compared to the TMEM229A group. CONCLUSION: Our results demonstrated that the TMEM229A Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.

Twinning and 9R Phase Transition Mediated Extraordinary Cold-drawn Deformability in NiCoCrFeMo High-Entropy Alloy.

The production and application of materials are evolving towards the low-dimensional micro-nano scale. Nevertheless, the fabrication of micron-scale alloy fibers remains a challenge. Herein, a novel Ni-Co-Cr-Fe-Mo high-entropy alloy (HEA) fiber with a cold-drawn reduction rate of 99.9995% and a strain (ɛ) of 12.19 is presented without requiring intermediate annealing. The exceptional deformation strain of 11.62 within the fiber leads to extraordinary tensile strengths of 2.8 GPa at room temperature and 3.6 GPa at 123 K. The in-depth investigation of the microstructure of fibers has revealed the cold drawing deformation mechanisms mediated by the synergistic effects of plane defects. Specifically, various geometrically necessary dislocation interfaces, such as dislocation walls and microbands, along with deformation twins and long-period 9R structures, form in response to external stress when ɛ≤2.7. As the strain increases, the saturated layered structure emerges and progressively evolves into a 3D equiaxed crystal. Moreover, the formation and evolution of the 9R structure (i.e., the migration of incoherent twin boundaries), coupled with the interaction of partial dislocations and the role of deformation twins, are crucial factors determining the fiber's plastic response. This work provides a novel approach to discovering new high-strength metallic fibers with excellent deformability through plane defects engineering.

Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

Early dopaminergic replacement treatment initiation benefits motor symptoms in patients with Parkinson's disease.

Background: Parkinson's disease (PD) generally progresses slowly, but it is controversial whether delaying treatment accelerates the progression. Objective: Determine the correlation between the time of dopaminergic replacement treatment initiation and the severity of clinical symptoms in PD, including motor and non-motor symptoms. Methods: PD patients were divided between 155 people who were diagnosed de novo and 165 PD patients receiving dopamine replacement therapy. Basic patient characteristics included gender, age, age at onset, disease duration, and the time of dopaminergic replacement treatment initiation. We used MDS-UPDRS scores to evaluate the severity of motor symptoms and we also used the scale to assess the severity of non-motor symptoms such as cognition, mood, sleep, and quality of life. Results: The mean time between symptom onset and the initiation of drug treatment was 31.0 (22.5) months. After adjusting for age, sex, age at onset, and disease duration, we found that the MDS-Unified Parkinson's Disease Rating Scale (UPDRS)-III score increased faster in the de novo group with a similar disease duration (F = 8.7, p = 0.0034) than the treatment group. The cumulative incidence of progression to H-Y score 3 in de novo PD group over disease duration was 39.7% in 50months and 92.2% in 100 months, while in treated group such cumulative incidence was 15.5% in 50 months, 51.4% in 100 months and 81.5% in 150 months. The cumulative incidence of patients in the de novo PD group was higher than that in the treated group (p = 0.001), suggesting that untreated patients were more likely to progress to the advanced stages. Symptoms onset, the time between symptom onset and treatment initiation, age, sex, and disease duration explained 28.95% of the total variation in the MDS-UPDRS-III score for motor symptoms. In drug-naïve patients, the time between symptom onset and treatment initiation explained 20.1% of the total variation in the MDS-UPDRS-III score for motor symptoms (t = 6.15, p < 0.001). Conclusions: These data in our study showed that early dopaminergic replacement treatment have played a positive role in PD patients, while dopaminergic replacement delayed treatment might be detrimental to motor symptoms and non-motor state of PD patient. Recognizing early stage symptoms of PD and early diagnosis are of great significance to treatment.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Multi-scale analysis of acupuncture mechanisms for motor and sensory cortex activity based on SEEG data.

Acupuncture, a traditional Chinese therapy, is gaining attention for its impact on the brain. While existing electroencephalogram and functional magnetic resonance image research has made significant contributions, this paper utilizes stereo-electroencephalography data for a comprehensive exploration of neurophysiological effects. Employing a multi-scale approach, channel-level analysis reveals notable $\delta $-band activity changes during acupuncture. At the brain region level, acupuncture modulated connectivity between the paracentral lobule and the precentral gyrus. Whole-brain analysis indicates acupuncture's influence on network organization, and enhancing $E_{glob}$ and increased interaction between the motor and sensory cortex. Brain functional reorganization is an important basis for functional recovery or compensation after central nervous system injury. The use of acupuncture to stimulate peripheral nerve trunks, muscle motor points, acupoints, etc., in clinical practice may contribute to the reorganization of brain function. This multi-scale perspective provides diverse insights into acupuncture's effects. Remarkably, this paper pioneers the introduction of stereo-electroencephalography data, advancing our understanding of acupuncture's mechanisms and potential therapeutic benefits in clinical settings.

Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis.

BACKGROUND AND AIM: The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS: Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS: For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.

Association between Body Mass Index and Medication-Overuse Headache among Individuals with Migraine: A Cross-Sectional Study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Unveiling unique alternative splicing responses to low temperature in Zoysia japonica through ZjRTD1.0, a high-quality reference transcript dataset.

Inadequate reference databases in RNA-seq analysis can hinder data utilization and interpretation. In this study, we have successfully constructed a high-quality reference transcript dataset, ZjRTD1.0, for Zoysia japonica, a widely-used turfgrass with exceptional tolerance to various abiotic stress, including low temperatures and salinity. This dataset comprises 113,089 transcripts from 57,143 genes. BUSCO analysis demonstrates exceptional completeness (92.4%) in ZjRTD1.0, with reduced proportions of fragmented (3.3%) and missing (4.3%) orthologs compared to prior datasets. ZjRTD1.0 enables more precise analyses, including transcript quantification and alternative splicing assessments using public datasets, which identified a substantial number of differentially expressed transcripts (DETs) and differential alternative splicing (DAS) events, leading to several novel findings on Z. japonica's responses to abiotic stresses. First, spliceosome gene expression influenced alternative splicing significantly under abiotic stress, with a greater impact observed during low-temperature stress. Then, a significant positive correlation was found between the number of differentially expressed genes (DEGs) encoding protein kinases and the frequency of DAS events, suggesting the role of protein phosphorylation in regulating alternative splicing. Additionally, our results suggest possible involvement of serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in generating inclusion/exclusion isoforms under low-temperature stress. Furthermore, our investigation revealed a significantly enhanced overlap between DEGs and differentially alternatively spliced genes (DASGs) in response to low-temperature stress, suggesting a unique co-regulatory mechanism governing transcription and splicing in the context of low-temperature response. In conclusion, we have proven that ZjRTD1.0 will serve as a reliable and useful resource for future transcriptomic analyses in Z. japonica.