BDNF-VGF Pathway Aggravates Incision Induced Acute Postoperative Pain via Upregulating the Neuroinflammation in Dorsal Root Ganglia.

Approximately one-third of postoperative patients are troubled by postoperative pain. Effective treatments are still lacking. The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF)-VGF (non-acronymic) in dorsal root ganglia (DRG) in postoperative pain. Pain behaviors were assessed through measurements of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). Transcriptome analysis was conducted to identify potential targets associated with postoperative pain. Western blotting, immunofluorescence, and ELISA were employed to further detect macrophage activation as well as the expression of BDNF, VGF, TNF-α, IL-1ß, and IL-6. Results showed that plantar incision induced both mechanical and thermal hyperalgesia. Transcriptome analysis suggested that plantar incision caused upregulation of BDNF and VGF. The expressions of BDNF and VGF were upregulated in isolectin B4-positive (IB4+) and calcitonin gene-related peptide-positive (CGRP+) neurons, rather than neurofilament 200-positive (NF200+) neurons. The activation of BDNF-VGF pathway upregulated expression of IL-6, TNF-α, and IL-1ß and promoted the activation of macrophages. In conclusion, BDNF-VGF pathway aggravates acute postoperative pain by promoting macrophage activation and pro-inflammatory cytokine production, which may provide a new target for the treatment of postoperative pain.

Synthesis of triazole AD-1 derivatives and its mechanism of mediating DNA damage of ROS in lung cancer cells.

Based on the significant biological activities and the remarkable physical and chemical properties of 1H-1,2,3-triazole pharmacophore, we herein adopted the strategy of click chemistry to combine the triazole fragment and the unique scaffold of 25-OCH3-PPD (AD-1) to design a series of potent compounds inducing apoptosis and DNA damage. The anti-proliferative effect was verified by MTT assay and colony formation assay. DNA double-stand breaks (DSBs) were obtained by observing the nuclear focus formation and the protein expression of γ-H2AX. Cell cycle arrest was evaluated by the cycle-related proteins such as CDK2, CDK4, CDK6, Cyclin D1 and P21. Apoptosis was assessed by flow cytometry, mitochondrial membrane potential (MMP) detection and the expression of apoptosis-related proteins. Reactive oxygen species (ROS) generation was measured with 2', 7'-dichlorofluorescein diacetate (DCFH-DA) staining. According to SAR analysis, the most potent compound 6a exhibited great inhibitory effect against A549 cells, which IC50 value of 2.84 ± 0.68 µM. Furthermore, 6a remarkably induced DNA damage, cell cycle arrest and apoptosis in A549 cells. 6a treatment increased the levels of ROS. Network pharmacology and molecular docking predicted the potential signaling pathways and ligand-receptor interactions, and the results of western blotting showed that 6a inhibited the PI3K/Akt/Bcl-2 signaling pathway by decreasing PI3K and Bcl-2 and total level of Akt expression, while Bax and Cyt c were increasing in 6a-treated A549 cells. As mentioned above, 6a has a potent inhibitory effect in A549 cells through induction of DNA damage, apoptosis via ROS generation and modulation of PI3K/Akt/Bcl-2 signaling pathway.

Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.

Carbazole-based mitochondria-targeted fluorescent probes for in vivo viscosity and cyanide detection in cells and zebrafish.

Cells of most eukaryotic species contain mitochondria, which play a role in physiological processes such as cellular senescence, metabolism, and autophagy. Viscosity is considered a key marker for many illnesses and is involved in several crucial physiological processes. Cyanide (CN-) can target cytochrome-c oxidase, disrupting the mitochondrial electron transport chain and causing cell death through asphyxiation. In this study, a fluorescent probe named HL-1, which targets mitochondria and measures viscosity and CN- levels, was designed and synthesized. HL-1 is viscosity-sensitive, with a linear correlation coefficient of up to 0.992. In addition, HL-1 was found to change color substantially during a nucleophilic addition reaction with CN-, which has a low detection limit of 47 nM. HL-1 not only detects viscosity and exogenous CN- in SKOV-3 cells and zebrafish but also monitors viscosity changes during mitochondrial autophagy in real time. Furthermore, HL-1 has been used successfully to monitor changes in mitochondrial membrane potential during apoptosis. Endogenous CN- in plant samples was quantified. HL-1 provides new ideas for studying viscosity and CN-.

[Functional peptidomics analysis of Saccharomyces pastorianus protein hydrolysates based on different enzyme treatments].

The aim of this study is to explore differences in the peptidomics of Saccharomyces pastorianus protein hydrolysates treated with different enzymes. Briefly, differences in the peptide fingerprints and active peptides of neutral protease/papain-hydrolyzed S. pastorianus were analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) combined with PEAKS Online 1.7 analysis software, Peptide Ranker, and the BIOPEP database. Compared to traditional databases, the PEAKS Online uses de novo sequencing for analysis to obtain oligopeptides smaller than pentapeptides. It provides more comprehensive data of the peptide sample. In this study, enzymatic hydrolysates of S. pastorianus protein were prepared under the optimum conditions of neutral protease and papain respectively. In total, 7221 and 7062 polypeptides were identified in the hydrolysates of neutral protease and papain, respectively; among these polypeptides, 980 were common to the two enzymes. The 6241 and 6082 unique peptides found in the hydrolysates of neutral protease and papain, respectively, indicated that the peptide fingerprints of the two hydrolysates are quite different. Peptide Ranker predicted that 3013 (41.73%) and 3095 (43.83%) peptides were potentially bioactive in the hydrolysates of neutral protease and papain, respectively. According to the BIOPEP database, neutral protease and papain contained 295 and 357 active peptides, respectively; these peptides were mainly composed of angiotensin converting enzyme (ACE) inhibitors and dipeptidyl peptidase IV inhibitors and antioxidant peptides. The number of active peptides in the hydrolysate of papain was higher than that in the hydrolysate of neutral protease, but the total ion intensity of active peptides in the former was lower than that in the latter. This study revealed the influence of protease type on the composition of enzymatic hydrolysates from S. pastorianus protein. The above results provide a reference for the development of functional products of S. pastorianus protein peptides and the high-value utilization of yeast resources.

M2 macrophage polarization: a potential target in pain relief.

Pain imposes a significant urden on patients, affecting them physically, psychologically, and economically. Despite numerous studies on the pathogenesis of pain, its clinical management remains suboptimal, leading to the under-treatment of many pain patients. Recently, research on the role of macrophages in pain processes has been increasing, offering potential for novel therapeutic approaches. Macrophages, being indispensable immune cells in the innate immune system, exhibit remarkable diversity and plasticity. However, the majority of research has primarily focused on the contributions of M1 macrophages in promoting pain. During the late stage of tissue damage or inflammatory invasion, M1 macrophages typically transition into M2 macrophages. In recent years, growing evidence has highlighted the role of M2 macrophages in pain relief. In this review, we summarize the mechanisms involved in M2 macrophage polarization and discuss their emerging roles in pain relief. Notably, M2 macrophages appear to be key players in multiple endogenous pathways that promote pain relief. We further analyze potential pathways through which M2 macrophages may alleviate pain.

Genetic polymorphisms are associated with individual susceptibility to dexmedetomidine.

Introduction: Dexmedetomidine (DXM) is widely used as an adjuvant to anesthesia or a sedative medicine, and differences in individual sensitivity to the drug exist. This study aimed to investigate the effect of genetic polymorphisms on these differences. Methods: A total of 112 patients undergoing hand surgery were recruited. DXM 0.5 µg/kg was administered within 10 min and then continuously injected (0.4 µg/kg/h). Narcotrend index, effective dose and onset time of sedation, MAP, and HR were measured. Forty-five single nucleotide polymorphisms (SNPs) were selected for genotype. Results: We observed individual differences in the sedation and hemodynamics induced by DXM. ABCG2 rs2231142, CYP2D6 rs16947, WBP2NL rs5758550, KATP rs141294036, KCNMB1 rs11739136, KCNMA1 rs16934182, ABCC9 rs11046209, ADRA2A rs1800544, and ADRB2 rs1042713 were shown to cause statistically significant (p < 0.05) influence on the individual variation of DXM on sedation and hemodynamics. Moreover, the multiple linear regression analysis indicated sex, BMI, and ADRA2A rs1800544 are statistically related to the effective dose of DXM sedation. Discussion: The evidence suggests that the nine SNPs involved in transport proteins, metabolic enzymes, and target proteins of DXM could explain the individual variability in the sedative and hemodynamic effects of DXM. Therefore, with SNP genotyping, these results could guide personalized medication and promote clinical and surgical management.

Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway.

OBJECTIVE: This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats. METHODS: The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA. RESULTS: APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05). CONCLUSION: EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP. Please cite this article as: Ding YY, Xu F, Wang YF, Han LL, Huang SQ, Zhao S, Ma LL, Zhang TH, Zhao WJ, Chen XD. Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway. J Integr Med. 2023; 21(5): 496-508.

Improving the service quality of cross-border e-commerce: How to understand online consumer reviews from a cultural differences perspective.

Introduction: Cross-border e-commerce (CBEC) consumers come from different countries; thus, cultural differences may affect their evaluations and perceptions of service quality. This paper follows Hofstede's framework as a theoretical anchor to explore how to use online consumer reviews that reflect cultural differences to improve the service quality of CBEC. Methods: First, based on a latent Dirichlet allocation model, 14 service quality issues that consumers are concerned about in CBEC were identified. Second, a generalized ordered logistic regression model was explored to analyze the cultural influences on consumer sentiment orientation. Finally, the effect of each cultural dimension on consumer service quality perception in CBEC was evaluated by employing a binary logistic regression model. Results: The results showed that consumers paid more attention to the service quality of logistics service, customs efficiency and tariff, shopping experience, and so on. Cultural dimensions significantly impacted consumers' emotional tendencies. Moreover, cultural dimensions had significant impacts on consumers' service quality perception (e.g., logistics service, trust in sellers, customs disputes, and cell phone performance). Still, consumers' quality perceptions of some services (e.g., cell phone functions, items as described, logistics package quality, and gifts) were less affected by cultural dimensions. Discussion: Our findings not only provide new perspectives for CBEC consumer behavior studies on quality improvement but also provide practical implications for CBEC enterprises.

Downregulation of cardiac PIASy inhibits Cx43 SUMOylation and ameliorates ventricular arrhythmias in a rat model of myocardial ischemia/reperfusion injury.

BACKGROUND: Dysfunction of the gap junction channel protein connexin 43 (Cx43) contributes to myocardial ischemia/reperfusion (I/R)-induced ventricular arrhythmias. Cx43 can be regulated by small ubiquitin-like modifier (SUMO) modification. Protein inhibitor of activated STAT Y (PIASy) is an E3 SUMO ligase for its target proteins. However, whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown. METHODS: Male Sprague-Dawley rats were infected with PIASy short hairpin ribonucleic acid (shRNA) using recombinant adeno-associated virus subtype 9 (rAAV9). Two weeks later, the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion. Electrocardiogram was recorded to assess arrhythmias. Rat ventricular tissues were collected for molecular biological measurements. RESULTS: Following 45 min of ischemia, QRS duration and QTc intervals statistically significantly increased, but these values decreased after transfecting PIASy shRNA. PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R, as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation, and reduced arrythmia score. In addition, myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation, accompanied by reduced Cx43 phosphorylation and plakophilin 2 (PKP2) expression. Moreover, PIASy downregulation remarkably reduced Cx43 SUMOylation, accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R. CONCLUSION: PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression, thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.

Daytime variation in non-cardiac surgery impacts the recovery after general anesthesia.

BACKGROUND: Circadian rhythm involved with physiology has been reported to affect pharmacokinetics or pharmacodynamics. We hypothesized that circadian variations in physiology disturb anesthesia and eventually affect recovery after anesthesia. METHODS: A retrospective cohort study initially included 107,406 patients (1 June 2016-6 June 2021). Patients were classified into morning or afternoon surgery groups. The primary outcome was daytime variation in PACU (post-anesthesia care unit) recovery time and Steward score. Inverse probability weighting (IPW) approach based on propensity score and univariable/multivariable linear regression were used to estimate this outcome. RESULTS: Of 28,074 patients, 13,418 (48%) patients underwent morning surgeries, and 14,656 (52%) patients underwent afternoon surgeries. LOWESS curves and IPW illustrated daytime variation in PACU recovery time and Steward score. Before adjustment, compared to morning surgery group, afternoon surgery group had less PACU recovery time (median [interquartile range], 57 [46, 70] vs. 54 [43, 66], p < 0.001) and a higher Steward score (5.62 [5.61, 5.63] vs. 5.66 [5.65, 5.67], p < 0.001). After adjustment, compared to morning surgery group, afternoon surgery group had less PACU recovery time (58 [46, 70] vs. 54 [43, 66], p < 0.001). In multivariable linear regression, morning surgery is statistically associated with an increased PACU recovery time (coefficient, -3.20; 95% confidence interval, -3.55 to -2.86).Among non-cardiac surgeries, daytime variation might affect recovery after general anesthesia. These findings indicate that the timing of surgery improves recovery after general anesthesia, with afternoon surgery providing protection.KEY MESSAGESIn this retrospective cohort study of 28,074 participants, the afternoon surgery group has a higher Steward score than the morning surgery group.In multivariable linear regression, morning surgery is statistically associated with an increased PACU recovery time.Among non-cardiac surgeries, daytime variation affects the recovery after general anesthesia, with afternoon surgery providing protection.

Plasma GFAP in Parkinson's disease with cognitive impairment and its potential to predict conversion to dementia.

Glial fibrillary acidic protein (GFAP) has been suggested as a biomarker for reactive astrogliosis. We measured the levels of plasma GFAP by Simoa in 60 patients with PD with normal cognition, 63 with mild cognitive impairment (PD-MCI), 24 with dementia (PDD) and 15 healthy controls. A subgroup of patients with PD-MCI (n = 31) was followed up for 4.1 ± 2.3 years. Compared with healthy controls, plasma GFAP levels were elevated in patients with PDD (adjusted P < 0.001) and PD-MCI (adjusted P = 0.013) and were negatively correlated with the Mini Mental State Examination (MMSE) score in PD participants. Plasma GFAP predicted MCI-to-dementia conversion with an AUC of 0.90, higher than NfL, Tau and pTau181. Our results support that plasma GFAP has potential value for distinguishing patients with PDD, and predicting MCI-to-dementia conversion in PD.

The influence of price value on purchase intention among patients with chronic diseases in medical e-commerce during the COVID-19 pandemic in China.

Background: During the COVID-19 pandemic, medical e-commerce (MEC) has provided a way for patients with chronic diseases to purchase drugs online to maintain social distancing, decrease the risk of infection and community transmission, and relieve the burden on medical resources. Therefore, research which seeks to elucidate the drivers of purchase intention (PI) among patients with chronic diseases in MEC is vital. This study extended the theory of planned behavior (TPB) by integrating the price value (PV) variable into the original TPB framework and explored the effect of PV on patients' PI in MEC during the coronavirus pandemic. Methods: Empirical data was gathered from 414 Chinese participants. Structural equation modeling was applied to explore the mechanism of chronic patients' PI in MEC. In addition, this study also estimated the moderating effect of gender, income, and region and the mediating role of attitude (ATT), subjective norm (SN), and perceived behavioral control (PBC) between PV and PI. Results: Patients' PI in MEC is significantly affected by ATT, SN, and PBC. PV delivers significant influence on ATT, SN, PBC, and PI, with PV having the strongest effect on ATT. Gender, income, and region can significantly moderate the relationship between PV and ATT. Conclusion: These findings can contribute to design targeted interventions to increase the adoption of MEC for patients with chronic diseases, decrease infection rates, and alleviate the strain on medical resources in the COVID-19 era.

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors.

BACKGROUND: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. METHODS: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. RESULTS: This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. CONCLUSIONS: These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

Dual-response near-infrared fluorescent probe for detecting cyanide and mitochondrial viscosity and its application in bioimaging.

Viscosity has a significant impact on aerobic respiration in mitochondria. Many foods contain cyanide (CN-) and can cause serious toxicity when consumed in excess. This study discusses the design and synthesis of a dual-response coumarin-based near-infrared fluorescent probe (CCB) for the simultaneous detection of mitochondrial viscosity and CN-. CCB and viscosity have a strong log-linear relationship with a correlation coefficient of 0.997. Additionally, CN- detection can be visualized using a colorimetric method with a detection limit as low as 0.22 µM. Test strips were prepared to facilitate CN- detection in plants. Additional studies have shown the remarkable biocompatibility of CCB, which may be used for real time detection of exogenous CN- and intracellular mitochondrial viscosity and in vivo bioimaging of viscosity in mice. The probe is crucial for understanding disorders connected with mitochondrial viscosity and identifying CN- in daily living.

Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane.

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. A total of 151 individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G > C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG, and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G > C and rs2031920 C > T, GABRG1 rs279858 T > C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G > A, and rs1801394 A > G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that 9 single nucleotide polymorphisms in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane.

In Vivo 18 F-Florzolotau Tau Positron Emission Tomography Imaging in Parkinson's Disease Dementia.

BACKGROUND: Tau pathology is observed during autopsy in many patients with Parkinson's disease dementia (PDD). Positron emission tomography (PET) imaging using the tracer 18 F-florzolotau has the potential to capture tau accumulation in the living brain. OBJECTIVE: The aim was to describe the results of 18 F-florzolotau PET/CT (computed tomography) imaging in patients with PDD. METHODS: Ten patients with PDD, 9 with Parkinson's disease with normal cognition (PD-NC), and 9 age-matched healthy controls (HCs) were enrolled. Clinical assessments and 18 F-florzolotau PET/CT imaging were performed. RESULTS: 18 F-Florzolotau uptake was significantly higher in the cortical regions of patients with PDD compared with both PD-NC and HCs, especially in the temporal lobe. Notably, 18 F-florzolotau uptake in the occipital lobe of patients with PDD showed a significant correlation with cognitive impairment as reflected by Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: 18 F-Florzolotau PET imaging can effectively capture the occurrence of tau pathology in patients with PDD, which was also linked to MMSE scores. © 2022 International Parkinson and Movement Disorder Society.

Prediction of axillary lymph node pathological complete response to neoadjuvant therapy using nomogram and machine learning methods.

Purpose: To determine the feasibility of predicting the rate of an axillary lymph node pathological complete response (apCR) using nomogram and machine learning methods. Methods: A total of 247 patients with early breast cancer (eBC), who underwent neoadjuvant therapy (NAT) were included retrospectively. We compared pre- and post-NAT ultrasound information and calculated the maximum diameter change of the primary lesion (MDCPL): [(pre-NAT maximum diameter of primary lesion - post-NAT maximum diameter of preoperative primary lesion)/pre-NAT maximum diameter of primary lesion] and described the lymph node score (LNS) (1): unclear border (2), irregular morphology (3), absence of hilum (4), visible vascularity (5), cortical thickness, and (6) aspect ratio <2. Each description counted as 1 point. Logistic regression analyses were used to assess apCR independent predictors to create nomogram. The area under the curve (AUC) of the receiver operating characteristic curve as well as calibration curves were employed to assess the nomogram's performance. In machine learning, data were trained and validated by random forest (RF) following Pycharm software and five-fold cross-validation analysis. Results: The mean age of enrolled patients was 50.4 ± 10.2 years. MDCPL (odds ratio [OR], 1.013; 95% confidence interval [CI], 1.002-1.024; p=0.018), LNS changes (pre-NAT LNS - post-NAT LNS; OR, 2.790; 95% CI, 1.190-6.544; p=0.018), N stage (OR, 0.496; 95% CI, 0.269-0.915; p=0.025), and HER2 status (OR, 2.244; 95% CI, 1.147-4.392; p=0.018) were independent predictors of apCR. The AUCs of the nomogram were 0.74 (95% CI, 0.68-0.81) and 0.76 (95% CI, 0.63-0.90) for training and validation sets, respectively. In RF model, the maximum diameter of the primary lesion, axillary lymph node, and LNS in each cycle, estrogen receptor status, progesterone receptor status, HER2, Ki67, and T and N stages were included in the training set. The final validation set had an AUC value of 0.85 (95% CI, 0.74-0.87). Conclusion: Both nomogram and machine learning methods can predict apCR well. Nomogram is simple and practical, and shows high operability. Machine learning makes better use of a patient's clinicopathological information. These prediction models can assist surgeons in deciding on a reasonable strategy for axillary surgery.

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias.

BACKGROUND: Abnormal myocardial Nav1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia-reperfusion (I/R). Protein inhibitor of activated STAT Y (PIASy)-mediated caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to the voltage-gated sodium channel 1.5 (Nav1.5). PIASy activity is increased after myocardial I/R, but it is unclear whether this is attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias. METHODS: Using recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements. RESULTS: PIASy was upregulated by I/R (P < 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane Nav1.5 density (P < 0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart downregulated PIASy after I/R, at both mRNA and protein levels (P < 0.05 vs. Scramble-shRNA + I/R group), decreased SUMO-modified Cav-3 levels, enhanced Cav-3 binding to Nav1.5, and prevented I/R-induced decrease of Nav1.5 and Cav-3 co-localization in the intercalated disc and lateral membrane. PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias, which was reflected by a modest decrease in the duration of ventricular fibrillation (VF; P < 0.05 vs. Scramble-shRNA + I/R group) and a significantly reduced arrhythmia score (P < 0.01 vs. Scramble-shRNA + I/R group). The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia (VT), sustained VT and VF, especially at the time 5-10 min after ischemia (P < 0.05 vs. Scramble-shRNA + IR group). Using in vitro human embryonic kidney 293 T (HEK293T) cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation (H/R), we confirmed that increased PIASy promoted Cav-3 modification by SUMO2/3 and Nav1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Nav1.5 and Cav-3 before and after H/R in HEK293T cells. CONCLUSIONS: I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Nav1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases.

Efficacy and Safety of Pyrotinib in Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: A Multicenter, Retrospective, Real-World Study.

Purpose: Pyrotinib, a novel human epidermal growth factor receptor 2 (HER2)-targeted tyrosine kinase inhibitor (TKI), has led to remarkable survival outcomes in HER2-positive advanced breast cancer (ABC) in clinical trials and was approved for second-line standards of treatment for HER2+ ABC in China. However, the clinical trials could not fully reflect reality of clinical practice, and predictive factors were still lacking. This study aimed to assess the actual efficacy and safety of pyrotinib in HER2+ ABC in real-world setting. Patients and Methods: In this multicenter, retrospective, observational real-world study, we analyzed 171 patients with HER2+ ABC, who received pyrotinib-based treatment from November 2017 to November 2020. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Results: Up to November 30, 2021, the median PFS (mPFS) was 12.0 months for all patients. One hundred and sixty-two patients (94.7%) with measurable lesions had been included in efficacy assessment. The ORR and CBR were 45.1% and 81.5%, respectively. A significantly longer PFS was reported in patients who received pyrotinib as first-line treatment, had the ECOG-PS of 0-1, as well as those who were lapatinib-naive. In addition, multivariable analysis indicated that ECOG-PS of 2-4, positive hormone receptor (HR) status, and presence of visceral metastasis were independent negative predictors of PFS. As far as we know, this study first reported the survival outcome of pyrotinib cross-line treatment, with a mPFS of 5.0 months. All grades of adverse events (AEs) occurred in 171 patients (100%), and the most common AE was diarrhea (86.5%). Conclusion: This study further demonstrated the outstanding efficacy and safety of pyrotinib and reported the potential predictors of survival in HER2+ ABC.