Revolutionizing the battle against locally advanced breast cancer: A comprehensive insight into neoadjuvant radiotherapy.

Breast cancer (BC) constitutes one of the most pervasive malignancies affecting the female population. Despite progressive improvements in diagnostic and therapeutic technologies, leading to an increased detection of early stage BCs, locally advanced breast cancer (LABC) persists as a significant clinical challenge. Owing to its poor overall survival (OS) rate, elevated recurrence rate, and high potential for distant metastasis, LABC prominently impacts the comprehensive efficacy of BC treatments. Radiotherapy, encompassing preoperative, intraoperative, and postoperative modalities, is acknowledged as an effective strategy for mitigating BC metastasis and enhancing survival rates among patients. Nevertheless, the domain of preoperative neoadjuvant radiotherapy (NART) remains conspicuously underexplored in clinical studies. Available research suggests that NART can induce tumor volume reduction, provoke fibrotic changes in tumor and adjacent normal tissues, thereby mitigating intraoperative cancer propagation and enhancing the quality of life for LABC patients. This manuscript seeks to provide a review of contemporary research pertaining to LABC and its preoperative radiotherapy.

Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

Non-invasive transcranial direct-current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se-dependent signalling in rat cerebral ischaemia-reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct-current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen-glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R-insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R-insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality-control signalling, vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4), in OGD/R-insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS- and BtDCS-induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. KEY POINTS: Cathodal bilateral transcranial direct-current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct-current stimulation reduces mitochondria injury and blocks the reduction of vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4) in oxygen-glucose deprivation reoxygenation-insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Evaluation of an algorithm-guided photoplethysmography for atrial fibrillation burden using a smartwatch.

BACKGROUND: Wearable devices based on the PPG algorithm can detect atrial fibrillation (AF) effectively. However, further investigation of its application on long-term, continuous monitoring of AF burden is warranted. METHOD: The performance of a smartwatch with continuous photoplethysmography (PPG) and PPG-based algorithms for AF burden estimation was evaluated in a prospective study enrolling AF patients admitted to Beijing Anzhen Hospital for catheter ablation from September to November 2022. A continuous Electrocardiograph patch (ECG) was used as the reference device to validate algorithm performance for AF detection in 30-s intervals. RESULTS: A total of 578669 non-overlapping 30-s intervals for PPG and ECG each from 245 eligible patients were generated. An interval-level sensitivity of PPG was 96.3% (95% CI 96.2%-96.4%), and specificity was 99.5% (95% CI 99.5%-99.6%) for the estimation of AF burden. AF burden estimation by PPG was highly correlated with AF burden calculated by ECG via Pearson correlation coefficient (R2 = 0.996) with a mean difference of -0.59 (95% limits of agreement, -7.9% to 6.7%). The subgroup study showed the robust performance of the algorithm in different subgroups, including heart rate and different hours of the day. CONCLUSION: Our results showed the smartwatch with an algorithm-based PPG monitor has good accuracy and stability in continuously monitoring AF burden compared with ECG patch monitors, indicating its potential for diagnosing and managing AF.

Transcranial direct-current stimulation confers neuroprotection by regulating isoleucine-dependent signalling after rat cerebral ischemia-reperfusion injury.

Isoleucine is a branched chain amino acid. The role of isoleucine in cerebral ischemia-reperfusion injury remains unclear. Here, we show that the concentration of isoleucine is decreased in cerebrospinal fluid in a rat model of cerebral ischemia-reperfusion injury, the rat middle cerebral artery occlusion (MCAO). To our surprise, the level of intraneuronal isoleucine is increased in an in vitro model of cerebral ischemia injury, the oxygen-glucose deprivation (OGD). We found that the increased activity of LAT1, an L-type amino acid transporter 1, leads to the elevation of intraneuronal isoleucine after OGD insult. Reducing the level of intraneuronal isoleucine promotes cell survival after cerebral ischemia-reperfusion injury, but supplementing isoleucine aggravates the neuronal damage. To understand how isoleucine promotes ischemia-induced neuronal death, we reveal that isoleucine acts upstream to reduce the expression of CBFB (core binding factor ß, a transcript factor involved in cell development and growth) and that the phosphatase PTEN acts downstream of CBFB to mediate isoleucine-induced neuronal damage after OGD insult. Interestingly, we demonstrate that direct-current stimulation reduces the level of intraneuronal isoleucine in cortical cultures subjected to OGD and that transcranial direct-current stimulation (tDCS) decreases the cerebral infarct volume of MCAO rat through reducing LAT1-depencent increase of intraneuronal isoleucine. Together, these results lead us to conclude that LAT1 over activation-dependent isoleucine-CBFB-PTEN signal transduction pathway may mediate ischemic neuronal injury and that tDCS exerts its neuroprotective effect by suppressing LAT1 over activation-dependent signalling after cerebral ischemia-reperfusion injury.

A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway.

BACKGROUND: The NOD-, LRR- and pyrin domain­containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1ß, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan-Meier survival curves, and Cox regression analysis. RESULTS: In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan-Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis. CONCLUSIONS: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target. TRIAL REGISTRATION: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910).

Fascicular ventricular tachycardia arising from the left side His and its adjacent region: a subset of upper septal idiopathic left ventricular tachycardia.

AIMS: Fascicular ventricle tachycardia (FVT) arising from the proximal aspect of left His-Purkinje system (HPS) has not been specially addressed. Current study was to investigate its clinical, electrocardiographic, and electrophysiological characteristics. METHODS AND RESULTS: Eighteen patients who were identified as this rare FVT were consecutively enrolled, and their scalar electrocardiogram and electrophysiological data were collected and analysed. The ventricular tachycardia (VT) morphology was similar to sinus rhythm (SR) in eight patients, left bundle branch block type in one patient, right bundle branch block type in seven patients, and both narrow and wide QRS type in two patients. During VT, right-sided His potential preceded the QRS with His-ventricle (H-V) interval of 36.3 ± 12.4 ms, which was shorter than that during SR (-51.4 ± 8.6 ms) (P = 0.002). The earliest Purkinje potentials (PPs) were recorded within 7 ± 3 mm of left-side His and preceded the QRS by 49.1 ± 14.0 ms. Mapping along the left anterior fascicle and left posterior fascicle revealed an antegrade activation sequence in all with no P1 potentials recorded. In the two patients with two VT morphologies, the earliest PP was documented at the same site, and the activation sequence of HPS remained antegrade. Ablation at the earliest PP successfully eliminated the tachycardia, except one patient who developed complete atrial-ventricular block and two patients who abandoned ablations. After at least 12 months follow-up, 15 patients were free from any recurrences. CONCLUSIONS: Fascicular ventricle tachycardia arising from the proximal aspect of left HPS was featured by recording slightly shorter H-V interval and absence of P1 potentials. Termination of VT requires ablation at the left-sided His or its adjacent region.

Predictors for quality of life in older adults: network analysis on cognitive and neuropsychiatric symptoms.

BACKGROUND: Quality of life (QoL) of older adults has become a pivotal concern of the public and health system. Previous studies found that both cognitive decline and neuropsychiatric symptoms (NPS) can affect QoL in older adults. However, it remains unclear how these symptoms are related to each other and impact on QoL. Our aim is to investigate the complex network relationship between cognitive and NPS symptoms in older adults, and to further explore their association with QoL. METHODS: A cross-sectional study was conducted in a sample of 389 older individuals with complaints of memory decline. The instruments included the Neuropsychiatric Inventory, the Mini Mental State Examination, and the 36-item Short Form Health Survey. Data was analyzed using network analysis and mediation analysis. RESULTS: We found that attention and agitation were the variables with the highest centrality in cognitive and NPS symptoms, respectively. In an exploratory mediation analysis, agitation was significantly associated with poor attention (ß = -0.214, P < 0.001) and reduced QoL (ß = -0.137, P = 0.005). The indirect effect of agitation on the QoL through attention was significant (95% confidence interval (CI) [-0.119, -0.035]). Furthermore, attention served as a mediator between agitation and QoL, accounting for 35.09% of the total effect. CONCLUSIONS: By elucidating the NPS-cognition-QoL relationship, the current study provides insights for developing rehabilitation programs among older adults to ensure their QoL.

Postoperative recurarization after sugammadex administration in two patients who received neoadjuvant chemotherapy: case reports and literature review.

BACKGROUND: Preoperative neoadjuvant chemotherapy plays a critical role in multidisciplinary therapy for a variety of malignant tumours. Although oncologists consider myocardial injury to be the most concerning side effect of chemotherapy, unique chemotherapy-mediated skeletal muscular damage has received attention recently. CLINICAL FEATURES: We report two unusual cases of postoperative delayed respiratory failure following administration of the recommended sugammadex dosage for patients undergoing lengthy operations with deep neuromuscular blockade (NMB) after neoadjuvant chemotherapy. Based on clinical outcomes, especially the comparison of muscle imaging results in patients at different treatment time points, we concluded that NMB recurrence had a possible correlation with neoadjuvant chemotherapy-induced muscular damage. CONCLUSION: The early identification of neoadjuvant chemotherapeutic side effects on NMB could be instrumental for clinical safety, especially in cases of major surgery requiring deep NMB. Thus, the timing of NMB antagonism and the recommended dosage of sugammadex warrant special consideration in these patients. In addition to neuromuscular monitoring during the operation, a more extended and closer observation period in the postanesthesia care unit is warranted.

RéSUMé: CONTEXTE: La chimiothérapie néoadjuvante préopératoire joue un rôle crucial dans le traitement multidisciplinaire de diverses tumeurs malignes. Bien que les oncologues considèrent les lésions myocardiques comme l'effet secondaire le plus inquiétant de la chimiothérapie, des lésions musculosquelettiques spécifiques induites par la chimiothérapie ont récemment fait l'objet d'une attention plus précise. CARACTéRISTIQUES CLINIQUES: Nous signalons deux cas inhabituels d'insuffisance respiratoire postopératoire retardée suite à l'administration de la posologie recommandée de sugammadex chez des patient·es bénéficiant d'opérations prolongées avec blocage neuromusculaire (BNM) profond après une chimiothérapie néoadjuvante. Sur la base des résultats cliniques, en particulier de la comparaison des résultats d'imagerie musculaire chez les patient·es à différents moments du traitement, nous avons conclu que la récurrence du BNM avait une corrélation intéressante avec les lésions musculaires induites par la chimiothérapie néoadjuvante. CONCLUSION: L'identification précoce des effets secondaires de la chimiothérapie néoadjuvante sur le BNM pourrait jouer un rôle déterminant dans l'innocuité clinique, en particulier en cas de chirurgie majeure nécessitant un BNM profond. Ainsi, le moment de l'antagonisme du BNM et la posologie recommandée de sugammadex nécessitent une attention particulière chez ces patient·es. En plus du monitorage neuromusculaire pendant l'opération, une période d'observation plus longue et plus étroite en salle de réveil est justifiée.

Sustainable Dielectric Films with Ultralow Permittivity from Soluble Fluorinated Polyimide.

In the rapidly growing area of high-frequency communications, polyimide films with ultralow dielectric constant and dielectric loss, adequate insulating strength, and recyclability are in high demand. Using a synthesized soluble fluorinated polyimide, a series of recyclable porous dielectric films with varying porosities were fabricated in this study through nonsolvent-induced phase separation. By manipulating the mass ratio of the binary solvent used to dissolve the polyimide, the shape, size, and size distribution of the pores generated throughout the polyimide matrix can be accurately regulated. The porosity and average pore size of the as-prepared porous films were adjustable between 71% and 33% and between 9.31 and 1.00 µm, respectively, which resulted in a variable dielectric constant of 1.51-2.42 (100 kHz) and electrical breakdown strength of 30.3-119.7 kV/mm. The porous sPI film with a porosity rate of 48% displayed a low dielectric constant of 2.48 at 10 GHz. Coupled with their superior thermal stability, mechanical characteristics, and recyclability, these porous polyimide films are highly promising for constructing high-frequency microelectronic devices.

Recent advances of transcriptomics and proteomics in triple-negative breast cancer prognosis assessment.

Triple-negative breast cancer (TNBC), a heterogeneous tumour that lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), is often characterized by aggressiveness and tends to recur or metastasize. TNBC lacks therapeutic targets compared with other subtypes and is not sensitive to endocrine therapy or targeted therapy except chemotherapy. Therefore, identifying the prognostic characteristics and valid therapeutic targets of TNBC could facilitate early personalized treatment. Due to the rapid development of various technologies, researchers are increasingly focusing on integrating 'big data' and biological systems, which is referred to as 'omics', as a means of resolving it. Transcriptomics and proteomics analyses play an essential role in exploring prospective biomarkers and potential therapeutic targets for triple-negative breast cancers, which provides a powerful engine for TNBC's therapeutic discovery when combined with complementary information. Here, we review the recent progress of TNBC research in transcriptomics and proteomics to identify possible therapeutic goals and improve the survival of patients with triple-negative breast cancer. Also, researchers may benefit from this article to catalyse further analysis and investigation to decipher the global picture of TNBC cancer.

Flexible Disk Ultramicroelectrode for High-Resolution and Substrate-Tolerable Scanning Electrochemical Microscopy Imaging.

A simple and universal strategy for fabricating flexible 25 µm platinum (Pt) disk ultramicroelectrodes (UMEs) was proposed, where a pulled borosilicate glass micropipette acted as a mold for shaping the flexible tip with flexible epoxy resin. The whole preparation procedure was highly efficient, enabling 10 or more probes to be manually fabricated within 10 h. Intriguingly, this technique permits an adjustable RG ratio, tip length, and stiffness, which could be tuned according to varying experimental demands. Besides, the electroactive area of the probe could be exposed and made renewable with a thin blade, allowing its reuse in multiple experiments. The flexibility characterization was then employed to optimize the resin/hardener mass ratio of epoxy resin and the tip position during HF etching in the fabrication process, suggesting that more hardener, a larger RG value, or a longer tip length obtained stronger deformation resistance. Subsequently, the as-prepared probe was examined by optical microscopy, cyclic voltammetry, and SECM approach curves. The results demonstrated the probe possessed good geometry with a small RG ratio of less than 3 and exceptional electrochemical properties, and its insulating sheath remained undeformed after blade cutting. Owing to the tip's flexibility, it could be operated in contactless mode with an extremely low working distance and even in contact mode scanning to achieve high spatial resolution and high sensitivity while guaranteeing that the tip and samples would suffer minimal damage if the tip crashed. Finally, the flexible probe was successfully employed in three scanning scenarios where tilted and 3D structured PDMS microchips, a latent fingerprint deposited on the stiff copper sheet, and soft egg white were included. In all, the flexible probe encompasses the advantages of traditional disk UMEs and circumvents their principal drawbacks of tip crash and causing sample scratches, which is thus more compatible with large specimens of 3D structured, stiff, or even soft topography.

Metastasis to Breast from Extramammary Solid Tumors and Lymphomas: A 20-Year Population-Based Study.

To discuss the clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors and lymphomas, we reviewed Cancer Hospital of Chinese Academy of Medical Sciences database from 01/01/2000 to 12/31/2020. Fifty-nine patients were identified. The most common primary sites for breast metastases were lymph node and pulmonary, followed by nasal cavity, ovary, skin, etc. All the patients were treated with chemotherapy, 18 were operated, 14 accepted radiotherapy. Metastasis to breast should be considered in any patient with tumor history presenting a breast lump. Pathological with immunohistochemical examination should be performed to identify the original site.

Midazolam exhibits antitumour and enhances the efficiency of Anti-PD-1 immunotherapy in hepatocellular carcinoma.

BACKGROUND: Midazolam (MDZ) is an anaesthetic that is widely used for anxiolysis and sedation. More recently, MDZ has also been described to be related to the outcome of various types of carcinomas. However, how MDZ influences the progression of hepatocellular carcinoma (HCC) and its effects on the biological function and tumour immune microenvironment of this type of tumour remain unknown. METHODS: The effects of MDZ on the proliferation, invasion, and migration of HCC cell lines were examined in vitro using the Cell Counting Kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and wound healing assays. Additionally, western blotting was employed to confirm that PD-L1 was expressed. Chromatin immunoprecipitation-seq (ChIP-seq) analysis was used to pinpoint the transcriptional regulation regions of NF-κB and programmed death-ligand 1 (PD-L1). A C57BL/6 mouse model was used to produce subcutaneous HCC tumors in order to evaluate the in vivo performance of MDZ. Mass spectrometry was also used to assess changes in the tumour immunological microenvironment following MDZ injection. RESULTS: The HCC-LM3 and Hep-3B cell lines' proliferation, invasion, and migration were controlled by MDZ, according to the results of the CCK8, EdU, Transwell, and wound healing assays. PD-L1 expression was shown by ChIP-seq analysis to be boosted by NF-κB, and by Western blotting analysis, it was shown that MDZ downregulated the expression of NF-κB. Additionally, in vivo tests revealed that intraperitoneal MDZ injections reduced HCC tumor development and enhanced the effectiveness of anti-PD-1 therapy. The CD45+ immune cell proportions were higher in the MDZ group than in the PBS group, according to the mass spectrometry results. Injection of MDZ resulted in a decrease in the proportions of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, monocytes, Tregs, and M2 macrophages and a rise in the proportion of dendritic cells. Additionally, the concentrations of the cytokines IFN-g and TNF-a were noticeably raised whereas the concentrations of the CD8+ T-cell fatigue markers ICOS, TIGIT, and TIM3 were noticeably lowered. CONCLUSION: According to this study, MDZ inhibited the progression of HCC by inhibiting the NF-κB pathway and reducing the exhaustion of CD8+ T cells. In clinical practice, MDZ combined with anti-PD-1 therapy might contribute to synergistically improving the antitumor efficacy of HCC treatment.

Origin of Capillary-Force-Induced Welding in Ag Nanowires and Ag Nanowire/Carbon Nanotube Conductive Networks.

Capillary-force-induced welding can effectively reduce the contact resistance between two silver nanowires (AgNWs) by merging the NW-NW junctions. Herein, we report a model for quantifying the capillary force between two nano-objects. The model can be used to calculate the capillary force generated between AgNWs and carbon nanotubes (CNTs) during water evaporation. The results indicate that the radius of one-dimensional nano-objects is crucial for capillary-force-induced welding. AgNWs with larger radii can generate a greater capillary force (FAgNW-AgNW) at NW-NW junctions. In addition, for AgNW/CNT hybrid films, the use of CNTs with a radius close to that of AgNWs can result in a larger capillary force (FAgNW-CNT) at NW-CNT junctions. The reliability of the model is verified by measuring the change in sheet resistance before and after capillary-force-induced welding of a series of AgNW and AgNW/CNT conductive films with varying radii.

A Meta-analysis of 37 Studies on the Effectiveness of Microsurgical Techniques for Lymphedema.

BACKGROUND: Microsurgery is a new technique for lymphedema treatment. Its advantages and disadvantages remain controversial. This study is sought to collect clinical data from patients who underwent lymphovenous bypass and vascularized lymph node transplantation to explore whether surgical procedures can effectively treat lymphedema. METHODS: We performed a meta-analysis of the effectiveness of lymphatic microsurgery. We searched the databases of literature for articles in Chinese and English. These articles were graded for quality. Report details and outcomes were recorded. Data extraction, systematic review, and meta-analysis were performed. RESULTS: Thirty-seven studies were included. Patients who underwent microsurgery had a significantly better chance of achieving an excellent result than patients who received conservative treatment (odds ratio = 7.07). The affected limb circumference was reduced by approximately, 44.68% after the microsurgery. After the microsurgery, 63% of the patients did not need physiotherapy, and 96% were free from painful skin infections. Lymphography showed that lymphatic transport capacity was enhanced. Moreover, 12% of the patients reported that edema reappeared in the long-term, 26% required reoperation for unsatisfactory results, and 32% experienced lymphatic leakage. CONCLUSIONS: A vast majority of patients derive more benefit from lymphatic microsurgery than from conventional treatment. The advantages of lymphatic microsurgery outweigh the disadvantages for patients in the early and middle stages of chronic secondary lymphedema and patients in whom conventional treatment failed.

The role of ER stress and ATP/AMPK in oxidative stress meditated hepatotoxicity induced by citrinin.

Citrinin, a secondary metabolite, can pose serious risks to the environment and organisms, but its hepatotoxic mechanisms are still unclear. Histopathological and ultrastructural results showed that citrinin-induced liver injury in Kunming mice, and the mechanism of citrinin-induced hepatotoxicity was studied in L02 cells. Firstly, citrinin mades L02 cell cycle arrest in G2/M phase by inhibition of cyclin B1, cyclin D1, cyclin-dependent kinases 2 (CDK2), and CDK4 expression. Secondly, citrinin inhibits proliferation and promotes apoptosis of L02 cells via disruption of mitochondria membrane potential, increase Bax/Bcl-2 ration, activation of caspase-3, 9, and enhance lactate dehydrogenase (LDH) release. Then, citrinin inhibits superoxide dismutase (SOD) activity and increases the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), resulting oxidative damage in L02 cells; upregulates the protein expression of binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), PKR-like ER kinase (PERK) and activating transcription factor6 (ATF6), inducing ER stress in L02 cells; increases the phosphorylation of AMP-activated protein kinase (AMPK) and decreases the content of adenosine-triphosphate (ATP), activating AMPK pathway in L02 cells. Eventually, pretreatment with NAC, an ROS inhibitor, alleviates citrinin-induced cell cycle G2/M arrest and apoptosis by inhibiting ROS-mediated ER stress; pretreatment with 4-PBA, an ER stress inhibitor, reversed ER stress and p-AMPK; pretreatment with dorsomorphin, an AMPK inhibitor, decreases citrinin-induced cell cycle G2/M arrest and apoptosis. In summary, citrinin induces cell cycle arrest and apoptosis to aggravate liver injury by activating ROS-ER stress-AMPK signaling pathway.

Downregulation of NF-κB by Shp-1 Alleviates Cerebral Venous Sinus Thrombosis-Induced Brain Edema Via Suppression of AQP4.

Aquaporin 4 (AQP4), a water channel protein, has been well studied in arterial stroke-induced brain edema. However, the role of AQP4 in cerebral venous sinus thrombosis (CVST) has not been reported. Here, we showed that AQP4 expression was increased in the brain of a rat CVST model, whereas inhibition of AQP4 decreased cerebral edema. Subsequent experiments showed that Shp-1 (Src homology 2-containing phosphatase-1) expression and NF-κB phosphorylation were upregulated after CVST. We found that Shp-1 inhibition resulted in enhancement of NF-κB activation and increased AQP4 expression accompanied by aggravated brain edema. We further showed that NF-κB inhibition led to decreased AQP4 expression and subsequent attenuation of brain edema but had no significant effect on Shp-1 expression. These results provide the first evidence suggesting that downregulation of NF-κB by Shp-1 alleviates CVST-induced brain edema through suppression of AQP4.

CCL14 exacerbates intraplaque vulnerability by promoting neovascularization in the human carotid plaque.

OBJECTIVE: To examine the role of CCL14 in the neovascularization process and vulnerability progression within carotid plaques by investigating the mechanism of CCL14 regulation of VEGF-A. METHODS: We first performed histological analysis and immunohistochemical staining of human carotid plaque tissue to detect the expression of CCL14, JAK2, STAT3 and VEGF-A. We next examined the protein expression of CCL14, VEGF-A, JAK2, STAT3, and phosphorylation of JAK2 and STAT3 in human carotid atherosclerotic plaques by Western blotting. Finally, we performed in vitro culture of human umbilical vein endothelial cells (HUVEC). In the tube formation assay of HUVEC, we added CCL14 siRNA or VEGF-A siRNA to the culture medium using lentiviral transfection to knock down CCL14 or VEGF-A and grouped them for control assays, and detected the changes in the expression of the above proteins using Western blotting. RESULTS: Histological and Western blotting analysis of human carotid plaque samples showed that the expression of CCL14 and VEGF-A was higher in the vulnerable plaques than in stable plaques. In the in vitro cultures of HUVEC, CCL14 was found to increase the number and length of intercellularly generated tubular structures. CCL14 increases VEGF-A expression via activating JAK2/STAT3 signaling. CONCLUSION: In the human carotid plaques, CCL14 promotes angiogenesis by upregulation of VEGF-A via JAK2/STAT3 pathway and thus drives the progression of carotid plaques vulnerability.

Arrangement of Indocyanine Green in a 1.5-Nanometer Channel to Achieve High-Efficiency Imaging of the Intestinal Lymphatic System.

The complications of inflammatory bowel diseases (IBDs) seriously endanger people's health, such as bleeding, polyp hyperplasia, and even cancer. Although the precise pathophysiology of IBD is unknown, alterations in the intestinal lymphatic network, such as lymphangiogenesis and lymphatic vessel dysfunction, are well-established features. Therefore, the development of a reliable technology is urgently required, with a stereoscopic, deep, and high-resolution technology for IBD lymphatic targeting imaging in clinical practice. However, indocyanine green, the only clinically approved imaging agent by the Food and Drug Administration, can easily cause self-aggregation or be interfered with by microenvironments, causing fluorescence quenching, which seriously affects the imaging and detective capabilities. Herein, indocyanine green molecules are arranged in a 1.5-nanometer one-dimensional channel (TpPa-1@ICG). Based on this specified structure, the fluorescence enhancement effect is observed in the TpPa-1@ICG resultant, and the fluorescence intensity is enhanced by 27%. In addition, the ICG-incorporated porous solid reveals outstanding solvent (dichloromethane, tetrahydrofuran, etc.) and thermal (>300 °C) stability. After modifying the target molecules, TpPa-1@ICG showed excellent imaging ability for intestinal lymphatic vessels, providing a new imaging tool for IBDs research.