Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. METHODS: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. RESULTS: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury. CONCLUSIONS: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury.

Acute ischemic stroke with a diagnosis of Marfan syndrome: A report of 3 cases in multifaceted settings.

RATIONALE: Marfan syndrome (MFS), which is a dominantly inherited connective tissue disease resulting from a mutation in the FBN1 gene, exhibits variable manifestations affecting the cardiovascular, musculoskeletal, ophthalmologic, and pulmonary systems. Notably, neurologic deficiency, which involves ischemic or hemorrhagic stroke, is a rare but severe manifestation. The safety of rt-PA treatment for ischemic stroke caused by MFS is still under discussion. PATIENT CONCERNS: In the current report, we discuss 3 atypical MFS cases presented as acute ischemic stroke, compared to those exhibiting cardiovascular and musculoskeletal abnormalities. DIAGNOSES: Three patients were diagnosed with acute ischemic stroke accompanied by MFS based on clinical manifestations, imaging examinations, and genetic testings. INTERVENTIONS: The first case underwent intravenous thrombolytic therapy with rt-PA, the second case received antiplatelet therapy, and the third case received anticoagulant therapy and perfusion therapy. OUTCOMES: The neurologic deficiency of all three patients showed improvement upon discharge, and there were no symptoms of recurrence observed during the follow-up period. LESSONS SUBSECTIONS: MFS is a rare etiology in young people with embolic stroke of undetermined source. Physicians should take MFS into consideration when they observe the characteristic symptoms during a consultation. The potential pathogenesis of ischemic stroke secondary to MFS may include cardio-embolism, arterial dissection, and hypoperfusion. Although intravenous thrombolysis is a promising therapy to treat acute ischemic stroke, further examinations should be conducted to rule out contraindications in patients with a suspicion of MFS.

CBF Profile in Computed Tomography Perfusion-Based AutoMIStar Software Predicts Futile Recanalization After Basilar Artery Thrombectomy.

Background: Futile recanalization (FR) remains a significant challenge in patients with acute basilar artery occlusion (BAO) following successful endovascular treatment (EVT). This study aimed to investigate the predictive value of computed tomography perfusion (CTP)-based software (AutoMIStar; Apollo) for FR among BAO patients undergoing EVT. Methods: We analyzed a prospectively maintained database to identify consecutive BAO patients who achieved successful recanalization (modified Thrombolysis in Cerebral Infarction grade ≥ 2b) after EVT between January 2020 and September 2022. Clinical characteristics and imaging parameters from non-contrast CT, CT angiography, and CTP-AutoMIStar were collected for analysis. FR was defined as an unfavorable outcome (modified Rankin Scale score > 3) at 90 days despite successful recanalization. Multivariable stepwise logistic regression analysis was performed to identify independent predictors of FR. Results: Of the 54 patients included in this study, 24 (44.4%) experienced FR. In the univariate analysis, admission National Institutes of Health Stroke Scale score, posterior circulation Acute Stroke Prognosis Early CT Score, Basilar Artery on Computed Tomography Angiography (BATMAN) score, hypoperfusion intensity ratio, and perfusion deficit volume in delay time (DT) > 4 s, DT > 6 s, DT > 8 s, and all cerebral blood flow (CBF) thresholds were associated with FR (all P < 0.05). In the multivariate analysis, perfusion deficit volume in CBF < 35% (adjusted odds ratio [aOR] = 1.105, 95% confidence interval [CI]: 1.004-1.215; P = 0.040) and BATMAN score (aOR = 0.662, 95% CI: 0.455-0.964; P = 0.031) remained independent predictors of FR. Conclusion: Perfusion deficit volume in CBF < 35% on CTP-AutoMIStar imaging maps and BATMAN score are independent predictors of FR after EVT in BAO patients. There is a significant positive correlation between perfusion deficit volume in CBF < 35% and the occurrence of FR.

A Principal Component Regression-Based Electrophysiological Study of Patients with Severe Infections.

Objective: Severe infections can lead to neuromyopathy in critically ill patients, resulting in limb weakness and difficulty in weaning from a ventilator. This study aims to assess the electrophysiological test results in patients with severe infection and their correlation with severity scores (APACHE II and SOFA). Methods: Thirty-one patients with severe infection in the EICU were prospectively studied. Factor analysis and principal component regression were applied to develop linear models of electrophysiological diagnostic outcomes with APACHE II and SOFA scores for the entire patient cohort, the younger group (age<55) cohort, and the older group (age>55) cohort of patients with severe infections, respectively. Results: Among patients with a severe infection in the EICU, the proportion of patients without critical neuromyopathy with more than 50% F-wave presence in the median, ulnar, and tibial nerves (64.9%, 56.8%, 48.6%, respectively) was significantly higher than in the group with critical neuromyopathy (52.1%, 35.4%, 29.2%, respectively.), and the proportion of patients with critical neuromyopathy who did not elicit the three types of F wave was significantly higher in the cohort of patients with critical neuromyopathy (40.5%, 32.4%, 35.1%, respectively.) were significantly higher than in the cohort of patients without critical illness (18.8%, 12.5%, 20.8%, respectively). In addition, on average, patients with critical neuromyopathy had a much lower CMAP for the median nerve (wrist, elbow) (2.4, 1.88, respectively) (4.3, 3.9, respectively in undiagnosed cohort), ulnar nerve (wrist, elbow) (2.4, 1.88, respectively) (5.65, 5.4, respectively in undiagnosed cohort), and tibial nerve(ankle, popliteal fossa) (2.7, 1.57, respectively)(6.55, 5.3, respectively in undiagnosed cohort) nerves than patients without critical neuromyopathy, and showed more non-elicitation, which was not seen in the cohort of patients without critical neuromyopathy. The CMAP returned to normal in the cohort of patients without critical neuromyopathy. Therefore, with respect to our selected electrophysiological parameters, the two patient groups showed significant differences in terms of the specific values and statistical analysis (Table 1). Through factor analysis and principal component regression, we found that CMAP and F-wave were highly correlated with APACHE II and SOFA scores, and the correlation between the electrophysiological wave spectrum and the two scores was further quantified by principal component regression. Conclusion: Electrophysiological spectroscopy can serve as an early warning for the development of neuromuscular disease in EICU patients. Abnormal electrophysiological diagnosis prior to actual neuromuscular abnormalities and its subsequent return to normal can help identify high-risk patients and implement early interventions.

A region of suppressed recombination misleads neoavian phylogenomics.

Genomes are typically mosaics of regions with different evolutionary histories. When speciation events are closely spaced in time, recombination makes the regions sharing the same history small, and the evolutionary history changes rapidly as we move along the genome. When examining rapid radiations such as the early diversification of Neoaves 66 Mya, typically no consistent history is observed across segments exceeding kilobases of the genome. Here, we report an exception. We found that a 21-Mb region in avian genomes, mapped to chicken chromosome 4, shows an extremely strong and discordance-free signal for a history different from that of the inferred species tree. Such a strong discordance-free signal, indicative of suppressed recombination across many millions of base pairs, is not observed elsewhere in the genome for any deep avian relationships. Although long regions with suppressed recombination have been documented in recently diverged species, our results pertain to relationships dating circa 65 Mya. We provide evidence that this strong signal may be due to an ancient rearrangement that blocked recombination and remained polymorphic for several million years prior to fixation. We show that the presence of this region has misled previous phylogenomic efforts with lower taxon sampling, showing the interplay between taxon and locus sampling. We predict that similar ancient rearrangements may confound phylogenetic analyses in other clades, pointing to a need for new analytical models that incorporate the possibility of such events.

Gold Nanoparticle Delivery of Glut1 SiRNA Facilitates Glucose Starvation Therapy in Lung Cancer.

Glucose transporter protein-1 (Glut1), is highly expressed in many cancer types and plays a crucial role in cancer progression through enhanced glucose transport. Its overexpression is associated with aggressive tumor behavior and poor prognosis. Herein, the nucleic acids modified gold nanoparticles (AuNPs) was synthesized to deliver small interfering RNA (siRNA) against Glut1 by microRNA 21 (miR-21) triggers toehold-mediated strand displacement reaction for lung cancer starvation therapy. Overexpression of miR-21 triggers toehold-mediated strand displacement, releasing the siRNA to knockdown of Glut1 in cancer cell instead of normal cell. Furthermore, the glucose oxidase-like activity of the AuNPs accelerates intracellular glucose consumption, promoting cancer cell starvation. The engineered AuNPs@anti-miR-21/siGlut1 complex inhibits cancer cell proliferation, xenograft tumor growth and promotes apoptosis through glucose starvation and ROS cascade signaling, underscoring its potential as an effective therapeutic strategy for lung cancer.

Complexity of avian evolution revealed by family-level genomes.

Despite tremendous efforts in the past decades, relationships among main avian lineages remain heavily debated without a clear resolution. Discrepancies have been attributed to diversity of species sampled, phylogenetic method and the choice of genomic regions1-3. Here we address these issues by analysing the genomes of 363 bird species4 (218 taxonomic families, 92% of total). Using intergenic regions and coalescent methods, we present a well-supported tree but also a marked degree of discordance. The tree confirms that Neoaves experienced rapid radiation at or near the Cretaceous-Palaeogene boundary. Sufficient loci rather than extensive taxon sampling were more effective in resolving difficult nodes. Remaining recalcitrant nodes involve species that are a challenge to model due to either extreme DNA composition, variable substitution rates, incomplete lineage sorting or complex evolutionary events such as ancient hybridization. Assessment of the effects of different genomic partitions showed high heterogeneity across the genome. We discovered sharp increases in effective population size, substitution rates and relative brain size following the Cretaceous-Palaeogene extinction event, supporting the hypothesis that emerging ecological opportunities catalysed the diversification of modern birds. The resulting phylogenetic estimate offers fresh insights into the rapid radiation of modern birds and provides a taxon-rich backbone tree for future comparative studies.

A NAD(P)H oxidase mimic for catalytic tumor therapy via a deacetylase SIRT7-mediated AKT/GSK3ß pathway.

Nicotinamide adenine dinucleotide (NADH) and its phosphorylated form, NADPH, are essential cofactors that play critical roles in cell functions, influencing antioxidation, reductive biosynthesis, and cellular pathways involved in tumor cell apoptosis and tumorigenesis. However, the use of nanomaterials to consume NAD(P)H and thus bring an impact on signaling pathways in cancer treatment remains understudied. In this study, we employed a salt template method to synthesize a carbon-coated-cobalt composite (C@Co) nanozyme, which exhibited excellent NAD(P)H oxidase (NOX)-like activity and mimicked the reaction mechanism of natural NOX. The C@Co nanozyme efficiently consumed NAD(P)H within cancer cells, leading to increased production of reactive oxygen species (ROS) and a reduction in mitochondrial membrane potential. Meanwhile, the generation of the biologically active cofactor NAD(P)+ promoted the expression of the deacetylase SIRT7, which in turn inhibited the serine/threonine kinase AKT signaling pathway, ultimately promoting apoptosis. This work sheds light on the influence of nanozymes with NOX-like activity on cellular signaling pathways in tumor therapy and demonstrates their promising antitumor effects in a tumor xenograft mouse model. These findings contribute to a better understanding of NAD(P)H manipulation in cancer treatment and suggest the potential of nanozymes as a therapeutic strategy for cancer therapy.

Structural insights into Xanthomonas campestris pv. campestris NAD+ biosynthesis via the NAM salvage pathway.

Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) via the nicotinamide (NAM) salvage pathway. While the structural biochemistry of eukaryote NAMPT has been well studied, the catalysis mechanism of prokaryote NAMPT at the molecular level remains largely unclear. Here, we demonstrated the NAMPT-mediated salvage pathway is functional in the Gram-negative phytopathogenic bacterium Xanthomonas campestris pv. campestris (Xcc) for the synthesis of NAD+, and the enzyme activity of NAMPT in this bacterium is significantly higher than that of human NAMPT in vitro. Our structural analyses of Xcc NAMPT, both in isolation and in complex with either the substrate NAM or the product nicotinamide mononucleotide (NMN), uncovered significant details of substrate recognition. Specifically, we revealed the presence of a NAM binding tunnel that connects the active site, and this tunnel is essential for both catalysis and inhibitor binding. We further demonstrated that NAM binding in the tunnel has a positive cooperative effect with NAM binding in the catalytic site. Additionally, we discovered that phosphorylation of the His residue at position 229 enhances the substrate binding affinity of Xcc NAMPT and is important for its catalytic activity. This work reveals the importance of NAMPT in bacterial NAD+ synthesis and provides insights into the substrate recognition and the catalytic mechanism of bacterial type II phosphoribosyltransferases.

Trends in Cognitive Function Before and After Diabetes Onset: The China Health and Retirement Longitudinal Study.

BACKGROUND AND OBJECTIVES: Individuals with prevalent diabetes were known to have a higher risk of dementia and lower cognitive function. However, trends of cognitive function before diabetes and in the short term after new-onset diabetes remain unclear. METHODS: This study included participants without baseline diabetes from the China Health and Retirement Longitudinal Study. Cognitive tests were conducted at baseline (wave 1) and at least one time from wave 2 (2013) to wave 4 (2018). Cognitive function was assessed using a global cognition score which was the summary measure of 4 cognitive tests. A linear mixed model was constructed to fit the trends in cognitive function before and after diabetes onset and the trends among nondiabetes. The threshold of statistical significance was p < 0.05. RESULTS: During the 7-year follow-up, 1,207 (9.7% of 12,422, 59.1 ± 8.6 years, 39.9% male participants) participants developed new-onset diabetes. The cognitive function of both the without diabetes group and the diabetes group declined annually during the follow-up. The annual decline rate of the diabetes group before diabetes onset was similar to that of the without diabetes group during the whole follow-up period. After diabetes onset, participants experienced statistically significant faster cognitive declines in global cognition (-0.023 SD/year; 95% CI -0.043 to -0.004; p = 0.019) and visuospatial abilities test (-0.036 SD/year; -0.061 to -0.011; p = 0.004), but not in tests of episodic memory (-0.018 SD/year; -0.041 to 0.004; p = 0.116), attention and calculation (-0.017 SD/year; -0.037 to 0.003; p = 0.090), or orientation (0.001 SD/year; -0.018 to 0.020; p = 0.894), compared with the cognitive slope before diabetes. In subgroup analysis, compared with those who developed diabetes between 45-54 years, those developing diabetes older (55-64 years, p for interaction = 0.701; 65-74 years, p for interaction = 0.996) did not demonstrate different rates of global cognitive decline after diabetes. DISCUSSION: Individuals experienced faster rate of cognitive decline in a few years after diabetes onset, but not during the prediabetes period. Age did not modify the effect of diabetes on postdiabetes cognitive decline. Efforts in eliminating the adverse impacts on cognition should be started on diagnosis of diabetes.

Gasless robot-assisted transaxillary hemithyroidectomy (RATH): learning curve and complications.

PURPOSE: Gasless robot-assisted transaxillary hemithyroidectomy (RATH) is regarded as an alternative surgical option for thyroid operations. However, the associated steep learning curve is a clinical concern. This study evaluated the learning curve of RATH for surgeons without experience of endoscopic surgery and the early surgical outcomes of RATH. METHODS: We conducted a retrospective study of patients who underwent gasless RATH and conventional hemithyroidectomy (CH) at Sun Yat-sen University Cancer Center, Guangzhou, China, from June 2021 to August 2022. The learning curve and early surgical outcomes of gasless RATH were evaluated. And the early surgical outcomes of gasless RATH were compared to CH. RESULTS: In total, 105 patients who underwent gasless RATH and 104 patients who underwent CH were matched and assessed. The cumulative sum techniques (CUSUM) analysis showed that the peak point of gasless RATH operative time occurred at the 31st case. No clear single peak was identified in the CUSUM plot for drainage amount and blood loss. No significant difference in perioperative complications was observed between these two groups. Moreover, the number of postoperative patients who got sense of thyroid area traction were fewer in the gasless RATH group (n = 11, 10.5%) than in the CH group (n = 32, 30.8%). CONCLUSION: Gasless RATH can be considered as an alternative approach to the conventional open procedure, as it is an easy remote access technique, with shorter learning curves and certain advantage such as less sense of thyroid area traction.

Treatment of multisystem inflammatory syndrome in children.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a relatively uncommon but severe pediatric complication, is associated with coronavirus disease 2019 (COVID-19). A variety of treatment approaches, including intravenous immunoglobulins (IVIGs), glucocorticoids (GCs) and biologic agents, such as anakinra and infliximab, have been described for the management of COVID-19-related MIS-C. Anticoagulant therapy is also important. However, a well-developed treatment system has not been established, and many issues remain controversial. Several recently published articles related to the treatment of MIS-C have been released. Hence, in this review, we identified relevant articles published recently and summarized the treatment of MIS-C more comprehensively and systematically. DATA SOURCES: We reviewed the literature on the treatment of MIS-C through 20 September 2023. The PubMed/Medline, Web of Science, EMBASE, and Cochrane Library databases were searched with the combination of the terms "multisystem inflammatory syndrome", "MIS-C", "PIMS-TS", "therapy", "treatment", "drug", "IVIG", "GCs", "intravenous immunoglobulin", "corticosteroids", "biological agent", and "aspirin". RESULTS: The severity of MIS-C varies, and different treatment schemes should be used according to the specific condition. Ongoing research and data collection are vital to better understand the pathophysiology and optimal management of MIS-C. CONCLUSIONS: MIS-C is a disease involving multiple systems and has great heterogeneity. With the accumulation of additional experience, we have garnered fresh insights into its treatment strategies. However, there remains a critical need for greater standardization in treatment protocols, alongside the pressing necessity for more robust and meticulously conducted studies to deepen our understanding of these protocols. Supplementary file1 (MP4 208044 kb).

Association of the Neutrophil-to-Lymphocyte Ratio with 90-Day Functional Outcomes in Patients with Acute Ischemic Stroke.

The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, plays an important role in the inflammatory mechanisms of the pathophysiology and progression of acute ischemic stroke (AIS). The aim of this study was to identify the potential factors associated with functional prognosis in AIS. A total of 303 AIS patients were enrolled in this study; baseline information of each participant, including demographic characteristics, medical history, laboratory data, and 90-day functional outcome, was collected. Multivariate logistic regression analysis revealed that NLR, systolic blood pressure (SBP) and National Institutes of Health Stroke Scale (NIHSS) score were found to be independent factors for poor functional outcomes. Receiver operating characteristic (ROC) curve analysis was performed to estimate the predictive value of the NLR for 90-day functional outcome, with the best predictive cutoff value being 3.06. In the multivariate logistic regression analysis, three models were constructed: Model 1, adjusted for age, sex, SBP, and TOAST classification (AUC = 0.694); Model 2, further adjusted for the NIHSS score at admission (AUC = 0.826); and Model 3, additionally adjusted for the NLR (AUC = 0.829). The NLR at admission was an independent predictor of 90-day prognosis in patients with AIS. The risk factors related to poor 90-day functional outcomes were higher SBP, higher NLR, and a greater NIHSS score.

Relationships between obesity and functional outcome after ischemic stroke: a Mendelian randomization study.

BACKGROUND AND OBJECTIVES: Most previous studies suggested obesity deteriorates the functional outcome after ischemic stroke. But there are researches claiming that obesity is associated with lower mortality, recurrence, and readmission rates, which is known as the obesity paradox. Our current research aimed to investigate the correlation between genetically obesity and the post-stroke outcome with the Mendelian randomization (MR) method. METHODS: The UK Biobank and the GIANT consortium provided instrumental variables for body mass index (BMI, 806,834 individuals) and waist-to-hip ratio (WHR, 697,734 individuals). Data of functional outcome after ischemic stroke were obtained from the Genetics of Ischemic Stroke Functional Outcome network (6012 individuals). Inverse-variance weighted approach was utilized as the primary analyses. Sensitivity analyses involved the utilization of different MR methods. The heterogeneity among genetic variants was assessed by I2 and Q value statistics. RESULTS: In univariable analysis, there was a significant connection between genetic susceptibility to WHR and worse functional outcome (modified Rankin Scale 3) after ischemic stroke (OR [95%CI] = 1.47 [1.07, 2.02], P = 0.016). Genetic liability to BMI and was not associated with post-stroke functional outcome (all P > 0.05). The overall patterns between genetic liability to WHR and functional outcome post-ischemic outcome no longer existed in the multivariable MR analysis after adjusting for BMI (OR [95%CI] = 1.26[0.76,1.67], P = 0.56). CONCLUSION: The current MR study provided evidence that WHR was correlated to unfavorable outcome post-ischemic stroke. Exploring interventions against obesity may potentially improve recovery after ischemic stroke.

Spaco: A comprehensive tool for coloring spatial data at single-cell resolution.

Understanding tissue architecture and niche-specific microenvironments in spatially resolved transcriptomics (SRT) requires in situ annotation and labeling of cells. Effective spatial visualization of these data demands appropriate colorization of numerous cell types. However, current colorization frameworks often inadequately account for the spatial relationships between cell types. This results in perceptual ambiguity in neighboring cells of biological distinct types, particularly in complex environments such as brain or tumor. To address this, we introduce Spaco, a potent tool for spatially aware colorization. Spaco utilizes the Degree of Interlacement metric to construct a weighted graph that evaluates the spatial relationships among different cell types, refining color assignments. Furthermore, Spaco incorporates an adaptive palette selection approach to amplify chromatic distinctions. When benchmarked on four diverse datasets, Spaco outperforms existing solutions, capturing complex spatial relationships and boosting visual clarity. Spaco ensures broad accessibility by accommodating color vision deficiency and offering open-accessible code in both Python and R.

Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.

Neoadjuvant chemoimmunotherapy has emerged as a potential treatment option for resectable head and neck squamous cell carcinoma (HNSCC). In this single-arm phase II trial (NCT04826679), patients with resectable locally advanced HNSCC (T2‒T4, N0‒N3b, M0) received neoadjuvant chemoimmunotherapy with camrelizumab (200 mg), nab-paclitaxel (260 mg/m2), and cisplatin (60 mg/m2) intravenously on day one of each three-week cycle for three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), major pathologic response (MPR), two-year progression-free survival rate, two-year overall survival rate, and toxicities. Here, we report the perioperative outcomes; survival outcomes were not mature at the time of data analysis. Between April 19, 2021 and March 17, 2022, 48 patients were enrolled and received neoadjuvant therapy, 27 of whom proceeded to surgical resection and remaining 21 received non-surgical therapy. The ORR was 89.6% (95% CI: 80.9, 98.2) among 48 patients who completed neoadjuvant therapy. Of the 27 patients who underwent surgery, 17 (63.0%, 95% CI: 44.7, 81.2) achieved a MPR or pCR, with a pCR rate of 55.6% (95% CI: 36.8, 74.3). Treatment-related adverse events of grade 3 or 4 occurred in two patients. This study meets the primary endpoint showing potential efficacy of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin, with an acceptable safety profile, in patients with resectable locally advanced HNSCC.

Analyzing the causal relationship between lipid-lowering drug target genes and epilepsy: a Mendelian randomization study.

Background: Previous research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics. Methods: We used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy. Results: The analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available. Conclusion: The drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.

Fluorophore and nanozyme-functionalized DNA walking: A dual-mode DNA logic biocomputing platform for microRNA sensing in clinical samples.

Inspired by the programmability and modifiability of nucleic acids, point-of-care (POC) diagnostics for nucleic acid target detection is evolving to become more diversified and intelligent. In this study, we introduce a fluorescent and photothermal dual-mode logic biosensing platform that integrates catalytic hairpin assembly (CHA), toehold-mediated stand displacement reaction (SDR) and a DNA walking machine. Dual identification and signal reporting modules are incorporated into DNA circuits, orchestrated by an AND Boolean logic gate operator and magnetic beads (MBs). In the presence of bispecific microRNAs (miRNAs), the AND logic gate activates, driving the DNA walking machine, and facilitating the collection of hairpin DNA stands modified with FAM fluorescent group and CeO2@Au nanoparticles. The CeO2@Au nanoparticles, served as a nanozyme, can oxidize TMB into oxidation TMB (TMBox), enabling a near-infrared (NIR) laser-driven photothermal effect following the magnetic separation of MBs. This versatile platform was employed to differentiate between plasma samples from breast cancer patients, lung cancer patients, and healthy donors. The thermometer-readout transducers, derived from the CeO2@Au@DNA complexes, provided reliable results, further corroborated by fluorescence assays, enhancing the confidence in the diagnostics compared to singular detection method. The dual-mode logic biosensor can be easily customized to various nucleic acid biomarkers and other POC signal readout modalities by adjusting recognition sequences and modification strategies, heralding a promising future in the development of intelligent, flexible diagnostics for POC testing.