The Diagnostic Accuracy of Transcranial Color-Coded Doppler Ultrasound Technique in Stratifying Intracranial Cerebral Artery Stenoses in Cerebrovascular Disease Patients: A Systematic Review and Meta-Analysis.

The early and accurate stratification of intracranial cerebral artery stenosis (ICAS) is critical to inform treatment management and enhance the prognostic outcomes in patients with cerebrovascular disease (CVD). Digital subtraction angiography (DSA) is an invasive and expensive procedure but is the gold standard for the diagnosis of ICAS. Over recent years, transcranial color-coded Doppler ultrasound (TCCD) has been suggested to be a useful imaging method for accurately diagnosing ICAS. However, the diagnostic accuracy of TCCD in stratifying ICASs among patients with CVD remains unclear. Therefore, this systematic review and meta-analysis aimed at evaluating the diagnostic accuracy of TCCD in the stratification of intracranial steno-occlusions among CVD patients. A total of six databases-Embase, CINAHL, Medline, PubMed, Google Scholar, and Web of Science (core collection)-were searched for studies that assessed the diagnostic accuracy of TCCD in stratifying ICASs. The meta-analysis was performed using Meta-DiSc 1.4. The Quality Assessment of Diagnostic Accuracy Studies tool version 2 (QUADAS-2) assessed the risk of bias. Eighteen studies met all of the eligibility criteria. TCCD exhibited a high pooled diagnostic accuracy in stratifying intracranial steno-occlusions in patients presenting with CVD when compared to DSA as a reference standard (sensitivity = 90%; specificity = 87%; AUC = 97%). Additionally, the ultrasound parameters peak systolic velocity (PSV) and mean flow velocity (MFV) yielded a comparable diagnostic accuracy of "AUC = 0.96". In conclusion, TCCD could be a noble, safe, and accurate alternative imaging technique to DSA that can provide useful diagnostic information in stratifying intracranial steno-occlusions in patients presenting with CVD. TCCD should be considered in clinical cases where access to DSA is limited.

Serum phosphorus concentration and its association with the degree and pattern of intracranial arterial calcification.

BACKGROUND AND AIM: The aim of this study was to determine whether the serum phosphorus concentrations (SPC) are associated with the degree and pattern of intracranial arterial calcification (IAC) in patients with normal renal function or mild-moderate renal impairment. METHODS AND RESULTS: A total of 513 patients were enrolled in this study. The degree of IAC measured by IAC scores was evaluated on non-contrast head computed tomography (CT) images and IAC was classified as intimal or medial calcification. Study participants were classified according to IAC degrees (mild, moderate and severe) and patterns (intimal and medial calcification). A multivariate regression model was used to assess the independent relationship of SPC with IAC scores and patterns. Of 513 study participants (mean [SD] age, 68.3 [10.3] years; 246 females [48%]), the mean SPC was 1.07 ± 0.17 mmol/L and IAC scores was 4.0 (3.0-5.0). Multivariate analysis showed that higher serum phosphorus was a significant risk factor for moderate/severe IAC in both patients with eGFR ≥60 ml/min/1.73 m2 (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01-1.59; P < 0.05) and eGFR <60 ml/min/1.73 m2 (OR, 1.92; 95% CI, 1.04-3.57; P < 0.05), when those with mild IAC were considered as the reference group. However, higher SPC was associated with an increased odds of medial calcification only in patients with eGFR <60 ml/min/1.73 m2 (OR, 1.67; 95% CI, 1.08 to 2.61). CONCLUSIONS: High levels of serum phosphorus were positively correlated with the degree of IAC, and this significant effect on medial IAC was only present in patients with impaired renal function (eGFR <60 ml/min/1.73 m2).

Preparation of Emamectin Benzoate·Hexaflumuron Granules Based on Response Surface Methodology.

In order to obtain particles with an optimal loading rate and encapsulation efficiency and to explore the effects of sodium alginate, carboxymethyl chitosan, and bentonite on the particle loading rate and encapsulation rate, the preparation parameters of particles were optimized by the response surface method. A series of particles with constantly changing components were prepared, and the particle loading rate and encapsulation rate were determined. The release experiment of granules in different mass release media was implemented, and the optimal loading rate and encapsulation efficiency of particles were used to control the fall armyworm (FAW). The results showed that when the amount of sodium alginate was 1.83%, that of carboxymethyl chitosan was 0.41% and that of bentonite was 0.37%. The maximum theoretical value based on the response surface simulation was 92.63%, and the actual value at this ratio was 91.61%, which was 98.90% of the theoretical value. The release assay indicated that the mechanism of particle release in 2, 4, and 6 mL of the release medium was non-Fickian diffusion, and the controlled mechanism in 25 mL of the medium was Fickian diffusion. The beads were spread directly into maize leaf whorls in field production; at 14 days after application, the efficacy reached 91.28-98.82%. The combination of emamectin benzoate and hexaflumuron granules has a good control effect on the FAW.

S-Adenosyl-l-Methionine Alleviates the Senescence of MSCs Through the PI3K/AKT/FOXO3a Signaling Pathway.

Cellular senescence significantly affects the proliferative and differentiation capacities of mesenchymal stem cells (MSCs). Identifying key regulators of senescence and exploring potential intervention strategies, including drug-based approaches, are active areas of research. In this context, S-adenosyl-l-methionine (SAM), a critical intermediate in sulfur amino acid metabolism, emerges as a promising candidate for mitigating MSC senescence. In a hydrogen peroxide-induced MSC aging model (100 µM for 2 hours), SAM (50 and 100 µM) was revealed to alleviate the senescence of MSCs, and also attenuated the level of reactive oxygen species and enhanced the adipogenic and osteogenic differentiation in senescent MSCs. In a premature aging mouse model (subcutaneously injected with 150 mg/kg/day d-galactose in the neck and back for 7 weeks), SAM (30 mg/kg/day by gavage for 5 weeks) was shown to delay the overall aging process while increasing the number and thickness of bone trabeculae in the distal femur. Mechanistically, activation of PI3K/AKT signaling and increased phosphorylation of forkhead box O3 (FOXO3a) was proved to be associated with the antisenescence role of SAM. These findings highlight that the PI3K/AKT/FOXO3a axis in MSCs could play a crucial role in MSCs senescence and suggest that SAM may be a potential therapeutic drug for MSCs senescence and related diseases.

Associations of combined lifestyle index with migraine prevalence and headache frequency: a cross-sectional study from the MECH-HK study.

BACKGROUND: Prior research has shown that individual lifestyles were associated with migraine. Yet, few studies focused on combined lifestyles, particularly in Chinese populations. This cross-sectional study aimed to investigate the relationships of a combined lifestyle index with migraine in Hong Kong Chinese women. METHODS: Baseline data from a cohort study named Migraine Exposures and Cardiovascular Health in Hong Kong Chinese Women (MECH-HK) were used for analysis. In total 3510 women aged 55.2 ± 9.1 years were included. The combined lifestyle index comprised eight lifestyle factors: smoking, physical activity, sleep, stress, fatigue, diet, body mass index, and alcohol. Each component was attributed a point of 0 (unhealthy) or 1 (healthy). The overall index was the sum of these points, ranging from 0 (the least healthy) to 8 points (the healthiest). Migraine was diagnosed by the International Classification of Headache Disorders 3rd edition. Additionally, for women with migraine, the data on migraine attack frequency (attacks/month) was collected. RESULTS: A total of 357 women with migraine (10.2%) were identified. The prevalence of migraine for the 0-3-point, 4-point, 5-point, 6-point, and 7-8-point groups were 18.0% (162/899), 10.9% (86/788), 6.6% (51/776), 6.0% (38/636), and 4.9% (20/411), respectively. In the most-adjusted model, compared to the 0-3-point group, the odds ratios and 95% confidence intervals for the 4-point, 5-point, 6-point, and 7-8-point groups were 0.57 (0.43-0.75), 0.33 (0.24-0.46), 0.30 (0.21-0.44), and 0.25 (0.15-0.41), respectively (all p < 0.001). For each component, migraine was significantly associated with sleep, stress, fatigue, and diet; but was unrelated to smoking, physical activity, body mass index, and alcohol. Among women with migraine, per point increase in the combined lifestyle index was associated with a reduced migraine attack frequency (ß = - 0.55; 95% confidence interval = - 0.82, - 0.28; p < 0.001). CONCLUSIONS: A combined lifestyle index was inversely associated with migraine and migraine attack frequency in Hong Kong Chinese women. Adhering to a healthy lifestyle pattern might be beneficial to the prevention of migraine attacks. Conversely, it is also plausible that women with migraine might have a less healthy lifestyle pattern compared to those without headaches.

A Comparative Study of Transcranial Color-Coded Doppler (TCCD) and Transcranial Doppler (TCD) Ultrasonography Techniques in Assessing the Intracranial Cerebral Arteries Haemodynamics.

Cerebrovascular disease (CVD) poses a major public health and socio-economic burden worldwide due to its high morbidity and mortality rates. Accurate assessment of cerebral arteries' haemodynamic plays a crucial role in the diagnosis and treatment management of CVD. The study compared a non-imaging transcranial Doppler ultrasound (TCD) and transcranial color-coded Doppler ultrasound (with (cTCCD) and without (ncTCCD)) angle correction in quantifying middle cerebral arteries (MCAs) haemodynamic parameters. A cross-sectional study involving 50 healthy adults aged ≥ 18 years was conducted. The bilateral MCAs were insonated via three trans-temporal windows (TTWs-anterior, middle, and posterior) using TCD, cTCCD, and ncTCCD techniques. The MCA peak systolic velocity (PSV) and mean flow velocity (MFV) were recorded at proximal and distal imaging depths that could be visualised on TCCD with a detectable spectral waveform. A total of 152 measurements were recorded in 41 (82%) subjects with at least one-sided open TTW across the three techniques. The mean PSVs measured using TCD, ncTCCD, and cTCCD were 83 ± 18 cm/s, 81 ± 19 cm/s, and 93 ± 21 cm/s, respectively. There was no significant difference in PSV between TCD and ncTCCD (bias = 2 cm/s, p = 1.000), whereas cTCCD yielded a significantly higher PSV than TCD and ncTCCD (bias = -10 cm/s, p < 0.001; bias = -12 cm/s, p ≤ 0.001, respectively). The bias in MFV between TCD and ncTCCD techniques was (bias = -0.5 cm/s; p = 1.000), whereas cTCCD demonstrated a higher MFV compared to TCD and ncTCCD (bias = -8 cm/s, p < 0.001; bias = -8 cm/s, p ≤ 0.001, respectively). TCCD is a practically applicable imaging technique in assessing MCA blood flow velocities. cTCCD is more accurate and tends to give higher MCA blood flow velocities than non-imaging TCD and ncTCCD techniques. ncTCCD is comparable to non-imaging TCD and should be considered in clinical cases where using both TCD and TCCD measurements is needed.

Preparation and characterization of ι-carrageenan nanocomposite hydrogels with dual anti-HPV and anti-bacterial activities.

Sexually transmitted diseases (STDs) are usually caused by co-infections of bacteria and viruses. However, there is a lack of products that possess both antibacterial and antiviral activities without using chemical drugs. Here, we developed a carrageenan silver nanoparticle composite hydrogel (IC-AgNPs-Gel) based on the antiviral activity of iota carrageenan (IC) and the antibacterial effect of silver nanoparticles (AgNPs) to prevent STDs. IC-AgNPs-Gel showed excellent biocompatibility, hemostasis, antibacterial and antiviral effects. IC-AgNPs-Gel not only effectively prevented S. aureus, E. coli, P. aeruginosa, and C. albicans without using antibiotics, but also significantly inhibited human papilloma virus (HPV)-16 and HPV-6 without using chemotherapy drugs. Moreover, IC-AgNPs-Gel showed the effects of accelerating infected wound healing and reducing inflammation in a rat wound model infected with S. aureus. Therefore, the multifunctional hydrogel shows great potential application prospect in preventing STDs.

TAM-Hijacked Immunoreaction Rescued by Hypoxia-Pathway-Intervened Strategy for Enhanced Metastatic Cancer Immunotherapy.

Immunotherapy is regarded as a prospective strategy against metastatic cancer. However, tumor-associated macrophages (TAMs), which accumulate in hypoxic tumor microenvironment, reduce the effectiveness of immunotherapy by blocking or "hijacking" the initiation of the immune response. Here, a novel tumor-targeted nanoplatform loaded with hypoxia-pathway-intervened docosahexaenoic acid (DHA) and chemotherapeutic drug carfilzomib (CFZ) is developed, which realizes the rescue of TAM-hijacked immune response and effective metastatic cancer immunotherapy. DHA is conjugated to fucoidan (Fuc) via a reduction cleavable selenylsulfide bond (SSe) for micelle preparation, and CFZ is encapsulated in the hydrophobic cores of micelles. The functionalized nanoplatforms (Fuc─SSe─DHA (FSSeD)-CFZs) induce immunogenic cell death, inhibit hypoxia-inducible factor-1α expression, and improve immunosuppression by TAM suppression. FSSeD-CFZs enhance immune response against primary tumor development and metastasis formation. In brief, the novel rescue strategy for TAM-hijacked immunoreaction by inhibiting hypoxia pathway has the potential and clinically translational significance for enhanced metastatic cancer immunotherapy.

Patterns and Implications of Intracranial Atherosclerosis in Anterior and Posterior Circulation Identified by High-Resolution Vessel Wall Imaging.

INTRODUCTION: Anterior and posterior circulation atheroscleroses differ in vascular risk factors and stroke patterns. Posterior circulation stroke has worse clinical outcomes. However, few studies described the differentiation of plaque features between anterior and posterior circulation atheroscleroses via high-resolution vessel wall imaging (HR-VWI). We aimed to compare the plaque imaging features between anterior and posterior circulations to highlight the relevance of plaque imaging features to clinical events of ischemic stroke. METHODS: Prospective data from a HR-VWI cohort of adult patients with acute ischemic stroke or transient ischemic attack were retrospectively analyzed. Quantitative and qualitative measurements of atherosclerotic plaques along the middle cerebral arteries (MCAs), the basilar artery (BA), and the vertebral arteries (VAs) were conducted on HR-VWI. Vessels with stenotic degrees over 30% were identified on the matched time-of-flight magnetic resonance angiography (TOF-MRA) and visually classified into normal, irregular, stenotic, and occluded. The sensitivity, specificity, positive and negative predictive values for TOF-MRA in detecting abnormal vessels were calculated by using quantification on the basis of HR-VWI findings as the reference standard. RESULTS: One hundred and one patients (median age, 64 years old; 62.4% males) were included in this study. A total of 292 plaques were identified, with 152 in the MCAs, 35 in the BA, and 105 in the VAs. The VAs possessed significantly higher enhancement index (EI) (median 38.37 vs. 18.40, p <0.001), more plaques with positive remodeling (76.2% vs. 57.2%, p = 0.002) and intraplaque hypo-intensity (43.8% vs. 12.5%, p <0.001) than the MCAs. The MCAs presented with more intraplaque hemorrhage (IPH) (20.4% vs. 8.6%, p = 0.014) than the VAs. The sensitivity and specificity of TOF-MRA for evaluating luminal stenosis were 89.0 (82.5-93.4) and 66.7 (24.1-94.0) in anterior circulation, respectively, and were 75.2 (66.7-82.2) and 27.3 (7.3-60.7) in posterior circulation, respectively. CONCLUSION: Our findings might elucidate the clinical events and outcomes in anterior and posterior circulation stroke. Posterior circulation atherosclerosis had higher EI and more plaques with hypo-intensity, suggesting a heavier atherosclerosis burden. Positive remodeling pattern in posterior circulation atherosclerosis might create an impression of "wider" vascular lumen, leading to possible underestimation of atherosclerosis burden of posterior circulation on TOF-MRA as compared to HR-VWI. Besides, anterior circulation atherosclerosis with IPH might be associated with plaque rupture and artery-to-artery embolism. Future studies are needed to verify these findings.

Tai Chi for the prophylaxis of episodic migraine: protocol of a non-inferiority randomized controlled trial with mechanism exploration.

BACKGROUND: Migraine is a complex neurovascular disorder with considerable clinical, social and economic issues. Tai chi has the potential to be an alternative prophylactic treatment for migraine with high safety since the adverse effects and limited efficacy of available medications. AIMS: The proposed study aims to compare the prophylaxis efficacy of 24-week Tai Chi training on migraine attacks with the standard prophylactic medication; and to explore the mechanism of Tai Chi in preventing migraine attacks by analyzing the associations between changes of migraine attacks and changes of neurovascular functions and inflammatory makers. METHOD: This is a two-arm parallel non-inferiority randomized controlled trial. In total 220 Hong Kong Chinese women aged 18-65 years with diagnosis of episodic migraine will be recruited and randomized to either the Tai Chi training group or the standard prophylactic medication group with 1:1 ratio, and receive the 24 weeks of modified 33-short form Yang-style Tai Chi training and the standard prophylactic medications, respectively. A 24-week follow-up will be implemented for both groups. For efficacy examination, the primary outcome was the frequency of migraine attacks measured by the migraine diary; and for the mechanism exploration, the primary outcome was the volume and number of white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI). The measurements will be conducted at the baseline, 24th weeks, and 48th weeks. Linear mixed model will be adopted to comprehensively analyze the changes of variables within and between groups. DISCUSSION: Given the importance of reducing disease burden and financial cost of migraine attacks, the findings of this study will provide new insights regarding the role of Tai Chi in alleviating migraine burden and further shed light on the mechanism action of Tai Chi on preventing headache attacks. TRIAL REGISTRATION: ClinicalTrials.gov NCT05690737. Registered on January 28, 2023.

[Advances in cell nuclear mechanobiology and its regulation mechanisms].

As an important intracellular genetic and regulatory center, the nucleus is not only a terminal effector of intracellular biochemical signals, but also has a significant impact on cell function and phenotype through direct or indirect regulation of nuclear mechanistic cues after the cell senses and responds to mechanical stimuli. The nucleus relies on chromatin-nuclear membrane-cytoskeleton infrastructure to couple signal transduction, and responds to these mechanical stimuli in the intracellular and extracellular physical microenvironments. Changes in the morphological structure of the nucleus are the most intuitive manifestation of this mechanical response cascades and are the basis for the direct response of the nucleus to mechanical stimuli. Based on such relationships of the nucleus with cell behavior and phenotype, abnormal nuclear morphological changes are widely used in clinical practice as disease diagnostic tools. This review article highlights the latest advances in how nuclear morphology responds and adapts to mechanical stimuli. Additionally, this article will shed light on the factors that mechanically regulate nuclear morphology as well as the tumor physio-pathological processes involved in nuclear morphology and the underlying mechanobiological mechanisms. It provides new insights into the mechanisms that nuclear mechanics regulates disease development and its use as a potential target for diagnosis and treatment.

Association between Obstructive Sleep Apnea and Intracranial Artery Calcification Stratified by Gender and Body Mass Index: A Hospital-Based Observational Study.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Furthermore, intracranial arterial calcification (IAC) has been validated as a marker for subclinical cerebrovascular disease. However, the relationship between OSA with IAC was less studied compared with its established association with coronary artery calcification. In this study, we aimed to investigate the association between the severity of OSA and the degree of IAC in hospitalized patients without preexisting cardiovascular disease. METHODS: This hospital-based observational study was conducted from June 1, 2017, to May 1, 2019. In total, 901 consecutive patients who underwent head computed tomography scans and portable sleep monitoring were included. On the basis of the apnea-hypopnea index (AHI), patients were divided into four OSA severity groups (normal: AHI <5/h; mild: 5≤ AHI <15/h; moderate: 15≤ AHI <30/h; severe: AHI ≥30/h). Associations of OSA with IAC scores were assessed by using multivariate logistic regression analysis. RESULTS: Of the 901 patients, 484 (53.7%) were men; the mean (SD) age was 66.1 (10.0) years. The non-OSA group included 207 (23.0%) patients; mild OSA, 209 (23.2%); moderate OSA, 235 (26.1%); and severe OSA, 169 (18.8%). Mean IAC scores were higher in the severe OSA group compared with non-, mild, and moderate OSA groups (4.79 vs. 2.58; 4.79 vs. 2.94; 4.79 vs. 3.39; p < 0.001). Multivariate analysis adjusted for confounding factors revealed that only severe OSA was associated with a higher IAC score (odds ratio [OR]: 1.65; 95% confidence interval [CI]: 1.43-1.91; p < 0.001). In stratified analyses by BMI, among participants with a BMI <25 kg/m2, the positive association between AHI values and IAC scores was found in the moderate OSA group (OR: 1.23; 95% CI: 1.05, 1.43; p = 0.01) and the severe OSA group (OR: 1.96; 95% CI: 1.55, 2.48; p < 0.001). When stratified by gender, in women, the positive association was found in the moderate OSA group (adjusted OR: 1.21; 95% CI: 1.02-1.51; p = 0.016) and the severe OSA group (adjusted OR: 1.76; 95% CI: 1.36-2.25; p < 0.001). For the men group, a positive association between IAC scores and AHI was only observed in the severe OSA group. DISCUSSION: These findings suggest that OSA, in particular severe OSA (AHI ≥30), is independently associated with higher IAC scores. Women and no-obesity individuals appeared more susceptible to adverse OSA-related subclinical cerebrovascular disease as measured by IAC scores.

Brachial-ankle pulse wave velocity is associated with intracranial artery calcification in acute stroke patients.

BACKGROUND: Intracranial artery calcification (IAC) is closely associated with cerebrovascular disease. Brachial-ankle pulse wave velocity (baPWV) is a noninvasive method for estimating arterial stiffness, which reflects the stiffness of peripheral arteries. This study aimed to examine the association of baPWV with the presence and degree of IAC in patients with acute ischemic stroke. METHODS: A total of 143 ischemic stroke subjects were recruited. A head computed tomography (CT) scan was used to assess the presence and severity of IAC. The oscillometric method was used to simultaneously measure bilateral brachial and posterior tibial arterial pulse waveforms and arterial BP. Multiple logistic regression analysis was used to identify the independent relationship between baPWV and IAC. RESULTS: 143 subjects were included in this study. The demographic and clinical characteristics of the study population were classified according to the baPWV quartile. A higher prevalence of IAC was noted across increasing baPWV quartiles (Q1: 53 %, Q2: 69 %, Q3: 86 %, Q4: 94 %, P < 0.001). IAC scores were also increased with elevated ccPWV values (1.60 ± 1.71; 2.56 ± 1.99; 3.44 ± 1.91; 4.64 ± 1.58. P < 0.001). After an additional adjustment for age and hypertension, the odds ratio (95 % confidence interval) for the IAC scores was 1.61 (1.06-2.45; P = 0.025) in the top quartile of baPWV compared with those in the lowest quartile. CONCLUSIONS: Arterial stiffness as defined by baPWV was positively associated with the degree of IAC in patients with acute ischemic stroke, suggesting the severity of IAC may also be a marker of peripheral or systemic arterial stiffness.

Endoplasmic reticulum-mitochondrial calcium transport contributes to soft extracellular matrix-triggered mitochondrial dynamics and mitophagy in breast carcinoma cells.

Although mitochondrial morphology and function are considered to be closely related to matrix stiffness-driven tumor progression, it remains poorly understood how extracellular matrix (ECM) stiffness affects mitochondrial dynamics and mitophagy. Here, we found that soft substrate triggered calcium transport by increasing endoplasmic reticulum (ER) calcium release and mitochondrial (MITO) calcium uptake. ER-MITO calcium transport promoted the recruitment of dynamin-related protein 1 (Drp1) to mitochondria and phosphorylation at the serine 616 site, which induced mitochondrial fragmentation and Parkin/PINK1-mediated mitophagy. Furthermore, in vivo experiments demonstrated that soft ECM enhanced calcium levels in tumor tissue, Drp1 activity was required for soft ECM-induced mitochondrial dynamics impairment, and inhibition of Drp1 activity enhanced soft ECM-induced tumor necrosis. In conclusion, we revealed a new mechanism whereby ER-MITO calcium transport regulated mitochondrial dynamics and mitophagy through Drp1 translocation in response to soft substrates. These findings provide valuable insights into ECM stiffness as a potential target for antitumor therapy. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and mitochondrial dynamics by using polyacrylamide (PAA) substrates to simulate the stages of breast cancer or BAPN to reduce tumor tissue stiffness. The results elucidated that soft substrate triggered the recruitment of DRP1 and subsequent mitochondrial fission and mitophagy by ER-MITO calcium transport. Furthermore, mitophagy partly attenuated soft ECM-mediated tumor tissue necrosis and contributed to tumor survival in vivo. Our discoveries revealed the molecular mechanisms by which mechanical stimulation regulates mitochondrial dynamics, providing valuable insights into ECM stiffness as a target for anti-tumor approaches, which could be beneficial for both biomechanics research and clinical applications.

Photothermal and Acid-Responsive Fucoidan-CuS Bubble Pump Microneedles for Combined CDT/PTT/CT Treatment of Melanoma.

Transdermal cancer therapy faces great challenges in clinical practice due to the low drug transdermal efficiency and the unsatisfactory effect of monotherapy. Herein, we develop a novel bubble pump microneedle system (BPMN-CuS/DOX) by embedding sodium bicarbonate (NaHCO3) into hyaluronic acid microneedles (MNs) loaded with fucoidan-based copper sulfide nanoparticles (Fuc-CuS NPs) and doxorubicin (DOX). BPMN-CuS/DOX can generate CO2 bubbles triggered by an acidic tumor microenvironment for deep and rapid intradermal drug delivery. Fuc-CuS NPs exhibit excellent photothermal effect and Fenton-like catalytic activity, producing more reactive oxygen species (ROS) by photothermal therapy (PTT) and chemodynamic therapy (CDT), which enhances the antitumor efficacy of DOX and reduces the dosage of its chemotherapy (CT). Simultaneously, DOX increases intracellular hydrogen peroxide (H2O2) supplementation and promotes the sustained production of ROS. BPMN-CuS/DOX significantly inhibits melanoma both in vitro and in vivo by the combination of CDT, PTT, and CT. In short, our study significantly enhances the effectiveness of transdermal drug delivery by constructing BPMNs and provides a promising novel strategy for transdermal cancer treatment with multiple therapies.

The correlation between medial pattern of intracranial arterial calcification and white matter hyperintensities.

BACKGROUND AND AIMS: Despite reported correlations between intracranial arterial calcification (IAC) and white matter hyperintensities (WMH), little is known about the relationship between IAC pattern and WMH. By differentiating intimal and medial IAC, we aimed to investigate the relationship between IAC pattern and WMH. METHODS: Consecutive acute stroke patients were included. IAC pattern was categorized as intimal or medial on plain brain CT. The number of cerebral arteries involved by IAC for each patient was recorded. IAC severity was defined as focal or diffuse. On brain MRI, the burden of WMH was visually graded and classified as absent mild, moderate and severe. Multiple logistic regression was performed to examine the relationship between IAC and WMH. RESULTS: Among 265 patients, intimal IAC was detected in 54.7% patients and medial IAC in 48.5% patients. Diffuse IAC was present in 27.9% patients, all of which were medial. WMH was found in 75.5% patients, including 39.6% patients with mild WMH, 26.0% with moderate WMH, and 9.8% with severe WMH. The severity of medial IAC was correlated with WMH occurrence (p < 0.001). Chi-square linear trend suggested the number of arteries involved by medial IAC (p < 0.001) and the severity of medial IAC (p < 0.001) were correlated with WMH burden. Multiple ordinal logistic regression demonstrated a positive correlation of WMH burden with the number of arteries involved by medial IAC (p < 0.001) and the severity of medial IAC (p < 0.001). CONCLUSIONS: Medial IAC was correlated with WMH. The dose-effect relationship between medial IAC and WMH suggests underlying shared mechanisms of intracranial large artery disease and small vessel disease.

GE11-modified carboxymethyl chitosan micelles to deliver DOX·PD-L1 siRNA complex for combination of ICD and immune escape inhibition against tumor.

Programmed cell death-ligand 1 (PD-L1) small interfering RNA (siRNA) achieves tumor immunotherapy by restoring the immune response of T cells, but the efficacy of PD-1/PD-L1 monotherapy is relatively low. While immunogenic cell death (ICD) can improve the response of most tumors to anti-PD-L1 and enhance tumor immunotherapy. Herein, a targeting peptide GE11-functionalized dual-responsive carboxymethyl chitosan (CMCS) micelle (G-CMssOA) is developed for simultaneous delivery of PD-L1 siRNA and doxorubicin (DOX) in a complex form of DOX·PD-L1 siRNA (D&P). The complex-loaded micelles (G-CMssOA/D&P) have good physiological stability and pH/reduction responsiveness, and improve the intratumoral infiltration of CD4+ and CD8+ T cells, reduce Tregs (TGF-ß), and increase the secretion of immune-stimulatory cytokine (TNF-α). The combination of DOX-induced ICD and PD-L1 siRNA-mediated immune escape inhibition significantly improves anti-tumor immune response and inhibits tumor growth. This complex delivery strategy provides a new approach for effectively delivering siRNA and enhancing anti-tumor immunotherapy.

The correlation between intracranial arterial calcification and the outcome of reperfusion therapy.

OBJECTIVE: Intracranial arterial calcification (IAC) is a risk factor of ischemic stroke. However, the relationship between IAC patterns and clinical outcome of ischemic stroke remains controversial. We aimed to investigate the correlation between IAC patterns and the effects of reperfusion therapy among acute stroke patients. METHODS: Consecutive acute ischemic stroke patients who underwent reperfusion therapy were included. IAC was categorized as intimal or medial. Based on its involvement, IAC was further classified as diffuse or focal. Neurologic dysfunction was assessed by the National Institute of Health stroke scale (NIHSS). Clinical outcome including favorable neurologic outcome (FNO) and early neurologic deterioration (END) were assessed. RESULTS: Of 130 patients, 117 had IAC. Intimal IAC was identified in 74.6% of patients and medial IAC was present in 64.6% of patients. Diffuse IAC was present in 31.5% of patients. All diffuse IACs were medial pattern. Diffuse IAC was associated with higher baseline NIHSS (p = 0.011) and less FNO (p = 0.047). Compared with patients with focal or single diffuse IAC, patients with multiple diffuse IAC had higher baseline NIHSS (p = 0.002) and less FNO (p = 0.024). Multivariable linear regression (p < 0.001) and logistic regression (p = 0.027) suggested that multiple diffuse IAC was associated with higher baseline NIHSS and less FNO. No significant association was found between END and different IAC patterns. INTERPRETATION: Multiple diffuse medial IAC may predict severer neurologic dysfunction and less favorable neurologic outcome after reperfusion therapy in acute stroke patients.