The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

Environmental toxicology of bisphenol A: Mechanistic insights and clinical implications on the neuroendocrine system.

Bisphenol A (BPA) is a widely used environmental estrogen found in a variety of products, including food packaging, canned goods, baby bottle soothers, reusable cups, medical devices, tableware, dental sealants, and other consumer goods. This substance has been found to have detrimental effects on both the environment and human health, particularly on the reproductive, immune, embryonic development, nervous, endocrine, and respiratory systems. This paper aims to provide a comprehensive review of the effects of BPA on the neuroendocrine system, with a primary focus on its impact on the brain, neurons, oligodendrocytes, neural stem cell proliferation, DNA damage, and behavioral development. Additionally, the review explores the clinical implications of BPA, specifically examining its role in the onset and progression of various diseases associated with the neuroendocrine metabolic system. By delving into the mechanistic analysis and clinical implications, this review aims to serve as a valuable resource for studying the impacts of BPA exposure on organisms.

BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases.

Subcellular organelles dysfunction is implicated in various diseases, including metabolic diseases, neurodegenerative diseases, cancer, and cardiovascular diseases. BAM15, a selective mitochondrial uncoupler, has emerged as a promising therapeutic agent due to its ability to enhance mitochondrial respiration and metabolic flexibility. By disrupting the coupling between electron transport and ATP synthesis, BAM15 dissipates the proton gradient, leading to increased mitochondrial respiration and energy expenditure. This review provides a comprehensive overview of BAM15, including its mechanism of action and potential therapeutic applications in diverse disease contexts. BAM15 has shown promise in obesity by increasing energy expenditure and reducing fat accumulation. In diabetes, it improves glycemic control and reverses insulin resistance. Additionally, BAM15 has potential in non-alcoholic fatty liver disease, sepsis, and cardiovascular diseases by mitigating oxidative stress, modulating inflammatory responses, and promoting cardioprotection. The safety profile of BAM15 is encouraging, with minimal adverse effects and remarkable tolerability. However, challenges such as its high lipophilicity and the need for alternative delivery methods need to be addressed. Further research is necessary to fully understand the therapeutic potential of BAM15 and optimize its application in clinical settings.

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling.

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Optimizing glycation control in diabetes: An integrated approach for inhibiting nonenzymatic glycation reactions of biological macromolecules.

Diabetes is a multifactorial disorder that increases mortality and disability due to its complications. A key driver of these complications is nonenzymatic glycation, which generates advanced glycation end-products (AGEs) that impair tissue function. Therefore, effective nonenzymatic glycation prevention and control strategies are urgently needed. This review comprehensively describes the molecular mechanisms and pathological consequences of nonenzymatic glycation in diabetes and outlines various anti-glycation strategies, such as lowering plasma glucose, interfering with the glycation reaction, and degrading early and late glycation products. Diet, exercise, and hypoglycemic medications can reduce the onset of high glucose at the source. Glucose or amino acid analogs such as flavonoids, lysine and aminoguanidine competitively bind to proteins or glucose to block the initial nonenzymatic glycation reaction. In addition, deglycation enzymes such as amadoriase, fructosamine-3-kinase, parkinson's disease protein, glutamine amidotransferase-like class 1 domain-containing 3A and terminal FraB deglycase can eliminate existing nonenzymatic glycation products. These strategies involve nutritional, pharmacological, and enzymatic interventions that target different stages of nonenzymatic glycation. This review also emphasizes the therapeutic potential of anti-glycation drugs for preventing and treating diabetes complications.

Identification of Potential Indicators for Survival in Patients with Thyroid Cancer Based on Expression of FAM3 Members.

Thyroid cancer (THCA) is a common head and neck malignancy. The family with sequence similarity 3 (FAM3) is a cytokine-like gene family with four members, which is presumed to participate in the development of many cancer types. However, the expression patterns of FAM3s in THCA and their prognostic values, have not yet been established. We investigated differential expressions of FAM3 mRNA and protein in THCA, then validated the findings for FAM3B by immunohistochemistry. We also investigated survival data with respect to FAM3 expression patterns in patients with THCA. FAM3s information regarding their relationships with clinical pathological parameters were obtained and FAM3 mutations were assessed. KEGG and GO pathway regarding FAM3C were obtained using online databases. To investigate potential correlations between FAM3s and immune cell infiltration, we investigated the roles of FAM3s in immune cells of patients with THCA. The mRNA expression of FAM3C were significantly elevated in THCA tissues; high expression levels of FAM3C protein were also observed in THCA tissues. A significant association between the pathological stage and the expression of FAM3C was found in patients with THCA. Patients with THCA who had high mRNA expression levels of FAM3C exhibited significantly more favorable prognosis, compared with patients who had low mRNA expression levels of FAM3C. Overall, FAM3C may play vital roles in the pathogenesis and development of THCA, and these findings constitute novel insights for biomarkers of immunotherapeutic targeted agents and may aid in the identification of prognostic biomarkers for THCA.

Integrated multi-omics analyses reveal effects of empagliflozin on intestinal homeostasis in high-fat-diet mice.

Obesity has become a global epidemic, associated with several chronic complications. The intestinal microbiome is a critical regulator of metabolic homeostasis and obesity. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has putative anti-obesity effects. In this study, we used multi-omics analysis to determine whether empagliflozin regulates metabolism in an obese host through the intestinal microbiota. Compared with obese mice, the empagliflozin-treated mice had a higher species diversity of gut microbiota, characterized by a reduction in the Firmicutes/Bacteroides ratio. Metabolomic analysis unambiguously identified 1,065 small molecules with empagliflozin affecting metabolites mainly enriched in amino acid metabolism, such as tryptophan metabolism. RNA sequencing results showed that immunoglobulin A and peroxisome proliferator-activated receptor signaling pathways in the intestinal immune network were activated after empagliflozin treatment. This integrative analysis highlighted that empagliflozin maintains intestinal homeostasis by modulating gut microbiota diversity and tryptophan metabolism. This will inform the development of therapies for obesity based on host-microbe interactions.

The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes.

Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.

Human cytomegalovirus infection is associated with stroke in women: the US National Health and Nutrition Examination Survey 1999-2004.

BACKGROUND: Increasing evidence indicated that infection factors play important roles in stroke development. Human cytomegalovirus (HCMV) infection was positively associated with atherosclerosis and hypertension which are stroke risk factors. Therefore, we aimed to explore the relationship between HCMV infection and stroke using the data of US National Health and Nutrition Examination Survey (NHANES). METHODS: We analysed data on 2844 men and 3257 women in the NHANES 1999-2004. We included participants aged 20-49 years who had valid data on HCMV infection and stroke. RESULTS: 54.1% of participants had serological evidence of HCMV infection and 0.8% of them had a previous diagnosis of stroke. There were ethnic differences in the prevalence of HCMV seropositivity (p<0.001). There was no significant association between HCMV seropositivity and stroke in men in any of the models. In women, HCMV seropositivity was associated with stroke before adjustment (OR=3.45, 95% CI 1.09 to 10.95, p=0.036). After adjusting for race/ethnicity, the association remained significant (OR=4.40, 95% CI 1.37 to 14.09, p=0.014). After further adjustment for body mass index, diabetes, hypercholesterolaemia, hypertension, alcohol consumption, smoking and physical activity, the association still existed (OR=3.58, 95% CI 1.14 to 11.25, p=0.030). The association was significant consistently in adjusted model for age (OR=3.39, 95% CI 1.08 to 10.64, p=0.037). CONCLUSIONS: We found a strong association between HCMV and stroke in women from the nationally representative population-based survey. This provide additional motivation for undertaking the difficult challenge to reduce the prevalence of stroke.

Relationships Between Perivascular Adipose Tissue and Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) are typically asymptomatic, and there is a high mortality rate associated with aneurysm rupture. AAA pathogenesis involves extracellular matrix degradation, vascular smooth muscle cell phenotype switching, inflammation, and oxidative stress. There is increasing evidence of excessive adipocyte accumulation in ruptured AAA walls. These excessive numbers of adipocytes in the vascular wall have been closely linked with AAA progression. Perivascular adipose tissue (PVAT), a unique type of adipose tissue, can be involved in adipocyte accumulation in the AAA wall. PVAT produces various chemokines and adipocytokines around vessels to maintain vascular homeostasis through paracrine and autocrine mechanisms in normal physiological conditions. Nevertheless, PVAT loses its normal function and promotes the progression of vascular diseases in pathological conditions. There is evidence of significantly reduced AAA diameter in vessel walls of removed PVAT. There is a need to highlight the critical roles of cytokines, cells, and microRNA derived from PVAT in the regulation of AAA development. PVAT may constitute an important therapeutic target for the prevention and treatment of AAAs. In this review, we discuss the relationship between PVAT and AAA development; we also highlight the potential for PVAT-derived factors to serve as a therapeutic target in the treatment of AAAs.

The impact of thiamine deficiency and benfotiamine treatment on Nod-like receptor protein-3 inflammasome in microglia.

Thiamine-dependent processes are critical in cerebral glucose metabolism, it is abnormity induces oxidative stress, inflammation and neurodegeneration. Nod-like receptor protein-3 (NLRP3) inflammasome-mediated inflammation is closely related to neurologic diseases and can be activated by oxidative stress. However, the impact of thiamine deficiency on NLRP3 inflammasome activation remains unknown. In this study, we found that NLRP3 inflammasomes were significantly activated in the microglia of thiamine deficiency mice model. In contrast, benfotiamine dampened inflammation NLRP3 mediated in BV2 cells stimulated with LPS and ATP through reducing mitochondrial reactive oxygen species levels and mitigating autophagy flux defect. These data identify an important role of thiamine metabolism in NLRP3 inflammasome activation, and correcting thiamine metabolism through benfotiamine provides a new therapeutic strategy for NLRP3 inflammasome related neurological, metabolic, and inflammatory diseases.

Comprehensive overview of human serum albumin glycation in diabetes mellitus.

The presence of excess glucose in blood is regarded as a sweet hurt for patients with diabetes. Human serum albumin (HSA) is the most abundant protein in human plasma, which undergoes severe non-enzymatic glycation with glucose in patients with diabetes; this modifies the structure and function of HSA. Furthermore, the advanced glycation end products produced by glycated HSA can cause pathological damage to the human body through various signaling pathways, eventually leading to complications of diabetes. Many potential glycation sites on HSA have different degrees of sensitivity to glucose concentration. This review provides a comprehensive assessment of the in vivo glycation sites of HSA; it also discusses the effects of glycation on the structure and function of HSA. Moreover, it addresses the relationship between HSA glycation and diabetes complications. Finally, it focuses on the value of non-enzymatic glycation of HSA in diabetes-related clinical applications.

Fertility intentions among the working population of Dalian City born between 1980 and 1989.

In October 2015, the Chinese Government announced that the one-child policy had finally been replaced by a universal two-child policy. China's universal two-child policy is highly significant because, for the first time in 36 years, no one in an urban city is restricted to having just one child. This cross-sectional study was conducted to explore future fertility intentions and factors influencing individual reproductive behaviour (whether to have two children) in Dalian City. A total of 1370 respondents were interviewed. The respondents' mean ideal number of children was only 1.73, and urban respondents' sex preference was symmetrical. A total of 19.0% of the respondents were unmarried, 64.5% were married and had childbearing experience and only 6.3% of married respondents had two children. Among the 1370 participants, 30.4% stated that they would have a second child, while 69.6% refused to have a second child in the future. Binary logistic regression analysis (Model 1) showed that the following characteristics were associated with having only one child in the future: being female, being older, having a lower education level, being born in Dalian, having a lower family income and reporting one child as the ideal number of children. Model 2 (comprising only respondents with childbearing experience) showed that respondents who were female, had a lower family income and were unable to obtain additional financial support from parents were more likely to intend to stick at one child. In addition, respondents' ideal number of children and childbearing experiences had a significant influence on future fertility intentions. These results suggest that fertility intentions and reproductive behaviours are still below those needed for replacement level fertility in Dalian City. China's policymakers should pay more attention to these factors (socioeconomic characteristics, economic factors, desired number of children and childbearing experiences) and try to increase individual reproductive behaviour.

Growth differentiation factor 11: a "rejuvenation factor" involved in regulation of age-related diseases?

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor ß superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.

Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer's Mouse Model.

BACKGROUND: Microglia play diverse roles in Alzheimer's disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. OBJECTIVE: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. METHODS: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. RESULTS: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. CONCLUSION: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-ß deposition.

Circular RNA circPHC3 Promotes Cell Death and Apoptosis in Human BMECs After Oxygen Glucose Deprivation via miR-455-5p/TRAF3 Axis in vitro.

OBJECTIVE: Brain microvascular endothelial cells (BMECs) are involved in brain vascular dysfunction in ischemic stroke. Abnormal expression of circular RNAs regulate physiological and pathophysiological processes in the central nervous system. The aim of the present study was to investigate profile circRNAs in human BMECs after oxygen glucose deprivation (OGD), which was an in vitro model of ischemic stroke, and find promising biomarkers in ischemic stroke. METHODS: RNA sequencing (RNA-seq) technology was conducted to analyze the differential expression of circRNAs between BMECs after OGD and non-OGD treated BMECs. RT-qPCR, cell proliferation, cell apoptosis and dual-luciferase assay, and so on, were used to investigate the functions and molecular mechanisms of hsa_circ_0001360 (named circPHC3 in this study) in ischemic stroke. RESULTS: CircPHC3 was highly expressed in human BMECs after OGD. Knockdown of circPHC3 inhibited cell death and apoptosis in human BMECs treated with OGD. Mechanistically, circPHC3 acted as miR-455-5p sponge to activate TRAF3 to promote cell death and apoptosis in human BMECs after OGD. CONCLUSION: In short, circPHC3 promotes cell death and apoptosis in ischemic stroke in vitro model, which might be a novel molecular target for acute cerebrovascular protection.

Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease.

Empagliflozin is a novel type of sodium-glucose cotransporter two inhibitor with diverse beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Although empagliflozin impacts NAFLD by regulating lipid metabolism, the underlying mechanism has not been fully elucidated. In this study, we investigated transcriptional regulation pathways affected by empagliflozin in a mouse model of NAFLD. In this study, NAFLD was established in male C57BL/6J mice by administration of a high-fat diet; it was then treated with empagliflozin and whole transcriptome analysis was conducted. Gene expression levels detected by transcriptome analysis were then verified by quantitative real-time polymerase chain reaction, protein levels detected by Western Blot. Differential expression genes screened from RNA-Seq data were enriched in lipid metabolism and synthesis. The Gene Set Enrichment Analysis (GSEA) results showed decreased lipid synthesis and improved lipid metabolism. Empagliflozin improved NAFLD through enhanced triglyceride transfer, triglyceride lipolysis and microsomal mitochondrial ß-oxidation. This study provides new insights concerning the mechanisms by which sodium-glucose cotransporter two inhibitors impact NAFLD, particularly in terms of liver lipid metabolism. The lipid metabolism-related genes identified in this experiment provide robust evidence for further analyses of the mechanism by which empagliflozin impacts NAFLD.

The Role of DNA Methylation in Ischemic Stroke: A Systematic Review.

Background: Knowledge about the classic risk and protective factors of ischemic stroke is accumulating, but the underlying pathogenesis has not yet been fully understood. As emerging evidence indicates that DNA methylation plays a role in the pathological process of cerebral ischemia, this study aims to summarize the evidence of the association between DNA methylation and ischemic stroke. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials were searched for eligible studies. The results reported by each study were summarized narratively. Results: A total of 20 studies with 7,014 individuals finally met the inclusion criteria. Three studies focused on global methylation, 11 studies on candidate-gene methylation, and six on epigenome-wide methylation analysis. Long-interspersed nuclear element 1 was found to be hypomethylated in stroke cases in two studies. Another 16 studies reported 37 genes that were differentially methylated between stroke cases and controls. Individuals with ischemic stroke were also reported to have higher acceleration in Hanuum 's epigenetic age compared to controls. Conclusion: DNA methylation might be associated with ischemic stroke and play a role in several pathological pathways. It is potentially a promising biomarker for stroke prevention, diagnosis and treatment, but the current evidence is limited by sample size and cross-sectional or retrospective design. Therefore, studies on large asymptomatic populations with the prospective design are needed to validate the current evidence, explore new pathways and identify novel risk/protective loci.

Comprehensive Glycomic Analysis Reveals That Human Serum Albumin Glycation Specifically Affects the Pharmacokinetics and Efficacy of Different Anticoagulant Drugs in Diabetes.

Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.

Time-dependence of NIHSS in predicting functional outcome of patients with acute ischemic stroke treated with intravenous thrombolysis.

OBJECTIVES: The National Institute of Health Stroke Scale (NIHSS) is a predictor for the prognosis of acute ischaemic stroke (AIS) and its prediction is time-dependent. We examined the performance of NIHSS at different timepoints in predicting functional outcome of patients with thrombolysed AIS. METHODS: This prospective study included 269 patients with AIS treated with recombinant tissue plasminogen activator (rt-PA). Unfavourable functional outcome was defined as modified Rankin Scale score 4-6 at 3 months after rt-PA treatment. Receiver operating characteristic curves were used to examine the predictive power of NIHSS score at admission and 2 hours/24 hours/7 days/10 days after rt-PA treatment. Youden's index was used to select the threshold of NIHSS score. Logistic regression was used to estimate the ORs of unfavourable functional outcome for patients with NIHSS score higher than the selected thresholds. RESULTS: The threshold of NIHSS score at admission was 12 (sensitivity: 0.51, specificity: 0.84) with an acceptable predictive power (area under curve [AUC] 0.74) for unfavourable functional outcome. The threshold changed to 5 at 24 hours after rt-PA treatment (sensitivity: 0.83, specificity: 0.65) and remained unchanged afterwards. The predictive power and sensitivity sequentially increased over time and peaked at 10 days after rt-PA treatment (AUC 0.92, sensitivity: 0.85, specificity: 0.80). NIHSS scores higher than the thresholds were associated with elevated risk of unfavourable functional outcome at all timepoints (all p<0.001). CONCLUSIONS: NIHSS is time-dependent in predicting AIS prognosis with increasing predictive power over time. Since patients whose NIHSS score ≥ 12 are likely to have unfavourable functional outcome with rt-PA treatment only, mechanical thrombectomy should be largely taken into consideration for these patients.