3D SHINKEI MR neurography in evaluation of traumatic brachial plexus.

3D SHINKEI neurography is a new sequence for imaging the peripheral nerves. The study aims at assessing traumatic brachial plexus injury using this sequence. Fifty-eight patients with suspected trauma induced brachial plexus injury underwent MR neurography (MRN) imaging in 3D SHINKEI sequence at 3 T. Surgery and intraoperative somatosensory evoked potentials or clinical follow-up results were used as the reference standard. MRN, surgery and electromyography (EMG) findings were recorded at four levels of the brachial plexus-roots, trunks, cords and branches. Fifty-eight patients had pre- or postganglionic injury. The C5-C6 nerve postganglionic segment was the most common (average 42%) among the postganglionic injuries detected by 3D SHINKEI MRN. The diagnostic accuracy (83.75%) and the specificity (90.30%) of MRN higher than that of EMG (p < 0.001). There was no significant difference in the diagnostic sensitivity of MRN compared with EMG (p > 0.05). Eighteen patients with brachial plexus injury underwent surgical exploration after MRN examination and the correlation between MRN and surgery was 66.7%. Due to the high diagnostic accuracy and specificity, 3D SHINKEI MRN can comprehensively display the traumatic brachial plexus injury. This sequence has great potential in the accurate diagnosis of traumatic brachial plexus injury.

Contact-Inhibited ERK Signaling is Determined by Cellular-Resolution Western Blotting.

Extracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire both phenotypic (cell-contact state) and proteomic profile (ERK phosphorylation) on the same HeLa cells, we prepend high-content, whole-cell imaging prior to endpoint cellular-resolution western blot analyses for hundreds of cancer cells cultured on chip. By indexing the phosphorylation level of ERK in each cell or cell-contact cluster to the imaged cell-contact state, we compare ERK signaling between isolated and in-contact cells. We observe attenuated (∼2×) ERK signaling in HeLa cells which are in contact versus isolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. The contact-dependent differential ERK-phosphorylation corresponds to the differential EGFR distribution on cell surfaces, suggesting the involvement of EGFRs in contact-inhibited ERK signaling. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells, hence providing a new tool into control and scrutiny of cell-cell interactions.

Flexible Fusion Network for Multi-Modal Brain Tumor Segmentation.

Automated brain tumor segmentation is crucial for aiding brain disease diagnosis and evaluating disease progress. Currently, magnetic resonance imaging (MRI) is a routinely adopted approach in the field of brain tumor segmentation that can provide different modality images. It is critical to leverage multi-modal images to boost brain tumor segmentation performance. Existing works commonly concentrate on generating a shared representation by fusing multi-modal data, while few methods take into account modality-specific characteristics. Besides, how to efficiently fuse arbitrary numbers of modalities is still a difficult task. In this study, we present a flexible fusion network (termed F 2Net) for multi-modal brain tumor segmentation, which can flexibly fuse arbitrary numbers of multi-modal information to explore complementary information while maintaining the specific characteristics of each modality. Our F 2Net is based on the encoder-decoder structure, which utilizes two Transformer-based feature learning streams and a cross-modal shared learning network to extract individual and shared feature representations. To effectively integrate the knowledge from the multi-modality data, we propose a cross-modal feature-enhanced module (CFM) and a multi-modal collaboration module (MCM), which aims at fusing the multi-modal features into the shared learning network and incorporating the features from encoders into the shared decoder, respectively. Extensive experimental results on multiple benchmark datasets demonstrate the effectiveness of our F 2Net over other state-of-the-art segmentation methods.

Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors.

Histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1) are attractive targets for epigenetic cancer therapy. There is an intimate interplay between the two enzymes. HDACs inhibitors have shown synergistic anticancer effects in combination with LSD1 inhibitors in several types of cancer. Herein, we describe the discovery of compound 5e, a highly potent HDACs inhibitor (HDAC1/2/6/8; IC50 = 2.07/4.71/2.40/107 nM) with anti-LSD1 potency (IC50 = 1.34 µM). Compound 5e exhibited marked antiproliferative activity in several cancer cell lines. 5e effectively induced mitochondrial apoptosis with G2/M phase arrest, inhibiting cell migration and invasion in MGC-803 and HCT-116 cancer cells. It also showed good liver microsomal stability and acceptable pharmacokinetic parameters in SD rats. More importantly, orally administered compound 5e demonstrated higher in vivo antitumor efficacy than SAHA in the MGC-803 (TGI = 71.5%) and HCT-116 (TGI = 57.6%) xenograft tumor models accompanied by good tolerability. This study provides a novel lead compound with dual inhibitory activity against HDACs and LSD1 to further develop epigenetic drugs for solid tumor therapy. Further optimization is needed to improve the LSD1 activity to achieve dual inhibitors with balanced potency on LSD1 and HDACs.

Morphology and phylogeny identify two new species and one new subspecies of Podoscypha from Yunnan Province, Southwest China.

In this study, Podoscypha was taxonomically and phylogenetically evaluated. In total, five specimens collected from the tropical areas of Yunnan Province in Southwest China were studied. In combination with morphological observations and phylogenetic analyses based on ITS and LSU loci, two new species and one new subspecies, Podoscypha subinvoluta, P. tropica, and P. petalodes subsp. cystidiata, respectively, were discovered. The illustrated descriptions of the new species and subspecies are provided. Moreover, the main morphological differences between related species are discussed.

Efficiency of probiotics in elderly patients undergoing orthopedic surgery for postoperative cognitive dysfunction: a study protocol for a multicenter, randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) refers to a neurological dysfunction after a major surgery and anesthesia. It is common in elderly patients and is characterized by impairment in consciousness, orientation, thinking, memory, and executive function after surgical anesthesia. However, at present, there is no definite preventive or treatable strategy for it. Previous animal experiments showed that giving probiotics to mice before operation can prevent POCD, but there is a lack of clinical evidence. This study aims to intervene with the intestinal flora imbalance using probiotics during the perioperative period to reduce the incidence of POCD in elderly patients after orthopedic surgery and to provide new ideas and methods for the clinical prevention and treatment of POCD. METHODS: A multicenter, double-blind, placebo-controlled clinical trial will be performed to evaluate the efficacy of probiotics in elderly patients undergoing orthopedic surgery. Participants (n = 220) will receive probiotics (Peifeikang, Live Combined Bifidobacterium, 210 mg per capsule, twice a day, four capsules each time, which contains Bifidobacterium longum, Lactobacillus acidophilus and Streptococcus faecalis no less than 1.0 × 107 CFU viable bacteria respectively) or placebo from 1 day before surgery to 6 days after surgery. Neuropsychological tests will be performed 1 day before surgery and 1 week and 1 month after surgery. The main outcome of this study is the incidence of POCD 7 days after surgery. Our secondary objective is to assess the incidence of POCD 1 month after surgery; the cognitive status will be determined based on a telephone interview and will be evaluated via TICS-m; postoperative delirium will be assessed 7 days after surgery using the Confusion Assessment Method (CAM). DISCUSSION: Discovering the correlation between the intestinal microbiota and POCD is an important breakthrough. Based on the key role of the intestinal microbiota in other cognitive disorders, we hope that probiotics can reduce its incidence in elderly orthopedic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017403. Registered on August 15, 2019.

A new label-free optical imaging method for the lymphatic system enhanced by deep learning.

Our understanding of the lymphatic vascular system lags far behind that of the blood vascular system, limited by available imaging technologies. We present a label-free optical imaging method that visualizes the lymphatic system with high contrast. We developed an orthogonal polarization imaging (OPI) in the shortwave infrared range (SWIR) and imaged both lymph nodes and lymphatic vessels of mice and rats in vivo through intact skin, as well as human mesenteric lymph nodes in colectomy specimens. By integrating SWIR-OPI with U-Net, a deep learning image segmentation algorithm, we automated the lymph node size measurement process. Changes in lymph nodes in response to cancer progression were monitored in two separate mouse cancer models, through which we obtained insights into pre-metastatic niches and correlation between lymph node masses and many important biomarkers. In a human pilot study, we demonstrated the effectiveness of SWIR-OPI to detect human lymph nodes in real time with clinical colectomy specimens. One Sentence Summary: We develop a real-time high contrast optical technique for imaging the lymphatic system, and apply it to anatomical pathology gross examination in a clinical setting, as well as real-time monitoring of tumor microenvironment in animal studies.

A comprehensive review of BET-targeting PROTACs for cancer therapy.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as an effective strategy for drug discovery, given their unique advantages over target protein inhibition. The bromodomain and extra-terminal (BET) family proteins play a key role in regulating oncogene expression and are considered attractive therapeutic targets for cancer therapy. Considering the therapeutic potential of BET proteins in cancer and the marked attractiveness of PROTACs, BET-targeting PROTACs have been extensively pursued. Recently, BET-targeting PROTACs based on new E3 ligases and novel strategies, such as light-activated, macrocyclic, folate-caged, aptamer-PROTAC conjugation, antibody-coupling, and autophagy-targeting strategies, have emerged. In the present review, we provide a comprehensive summary of advances in BET-targeting PROTACs.

Peripheral Neutrophils-Derived Matrix Metallopeptidase-9 Induces Postoperative Cognitive Dysfunction in Aged Mice.

Background: Aging is one of the most important risk factors of postoperative cognitive dysfunction (POCD); however, the mechanisms are still not completely understood. In this study, we explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD. Methods: Appendectomy was performed in 18-month-old C57BL/6 and MMP-9-/- mice under anesthesia to establish the POCD model. Learning and memory were assessed using the Morris water maze (MWM) or Barnes maze. Protein expression of MMP-9 was measured by Western blotting or enzyme-linked immunosorbent assay (ELISA). To explore the role of neutrophils-derived MMP-9 in POCD, we treated mice with anti-Gr-1 monoclonal antibody to deplete peripheral neutrophils. And the percentage of neutrophils and other leukocytes were detected by flow cytometry. We further used sodium fluorescein (NaFlu) to evaluate the blood-brain barrier (BBB) permeability. Results: The spatial learning and memory ability was injured, and expression of MMP-9 increased in both plasma and the hippocampus after anesthesia/surgery. However, cognitive dysfunction was alleviated in both MMP-9-/- and peripheral neutrophils-depleted mice. The permeability of BBB was increased after anesthesia/surgery while recused by anti-Gr-1 antibody administration. Conclusion: These findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.

Isolation, Identification, and Immunomodulatory Mechanism of Peptides from Lepidium meyenii (Maca) Protein Hydrolysate.

Maca is a protein-enriched edible plant with immunomodulatory activity. However, the role of proteins in the immunomodulatory activity of maca is unclear. In this study, peptide products of maca proteins obtained through in vitro gastrointestinal digestion were isolated and purified, and the immunomodulatory activities of these peptides were assessed in macrophages (RAW 264.7 cells). The results show that the maca protein hydrolysate enhanced the phagocytic capacity and NO, TNF-α, and IL-6 secretion of RAW 264.7 cells. Forty-five peptides from known proteins of maca or the cruciferous family were identified by ultraperformance liquid chromatography-tandem mass spectrometry in the hydrolysate, and the peptide RNPFLP exhibited the strongest immunomodulatory activity. Antibody blocking, siRNA, pathway inhibitors, and western blot assays showed that RNPFLP-activated RAW 264.7 cells through the NF-κB and MAPK signaling pathways mediated by TLR2 and TLR4 receptors. An analysis of the structure-activity relationship showed that the N9-H60 active site in arginine plays an important role in the immunomodulatory activity of RNPFLP. This study provides a new understanding of the immunomodulatory activity of maca.

Electroacupuncture relieves neuropathic pain by inhibiting degradation of the ecto-nucleotidase PAP in the dorsal root ganglions of CCI mice.

BACKGROUND: Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs). METHODS: We applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5'-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase-polymerase chain reaction, Western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation. RESULTS: EA treatment alleviated CCI surgery-induced mechanical pain hypersensitivity. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4-L5 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP. CONCLUSIONS: EA treatment alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs. SIGNIFICANCE: In a mouse model of chronic pain, electroacupuncture treatment increased levels of prostatic acid phosphatase (PAP: an ecto-nucleotidase known to relieve pain hypersensitivity) by inhibiting PAP degradation in dorsal root ganglions. This promoted extracellular ATP dephosphorylation, inhibited glia activation and eventually alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice. Our findings represent an important step forward in clarifying the mechanisms of pain relief afforded by acupuncture treatment.

Paeoniflorin mitigates PBC-induced liver fibrosis by repressing NLRP3 formation.

PURPOSE: To delve into the influence of paeoniflorin (PA) on abating primary biliary cholangitis (PBC)-induced liver fibrosis and its causative role. METHODS: Our team allocated the mice to control group, PA group, PBC group and PBC+PA group. We recorded the weight change of mice in each group. We used Masson staining for determining liver fibrosis, immunofluorescence staining for measuring tumor necrosis factor-α (TNF-α) expression, quantitative real-time polymerase chain reaction (qRT-PCR) for assaying related gene expression, as well as Western blot for testing related protein expression. RESULTS: The weight of PBC model mice declined. Twenty-four weeks after modeling, the positive rate of anti-mitochondrial antibody-M2 (AMA-M2) in PBC mice reached 100%. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline (HYP), laminin (LN), procollagen type III (PC III), and malondialdehyde (MDA) contents saliently waxed (p<0.01). Meanwhile, superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity patently waned (p<0.01). Liver fibrosis levels were flagrantly higher (p<0.01), and TNF-α, NOD-like receptor protein 3 (NLRP3), caspase-1, interleukin-18 (IL-18), and interleukin-1ß (IL-1ß) protein or gene expression were manifestly up-regulated (p<0.01). PA could restore the weight of PBC mice, strikingly restrain the positive expression of AMA-M2, and down-regulate serum ALP, ALT, AST, HYP, LN, PC III, MDA in PBC mice (p<0.01). PA could also significantly up-regulate SOD and GSH-px levels (p<0.01), down-regulate IL-1ß, IL-18, caspase-1, NLRP3, and TNF-α protein or gene expression in PBC mice (p<0.01) and inhibit liver fibrosis levels (p<0.01). CONCLUSIONS: PA can reduce PBC-induced liver fibrosis in mice and may function by curbing the formation of NLRP3.

Genome Editing with AAV-BR1-CRISPR in Postnatal Mouse Brain Endothelial Cells.

Brain endothelial cells (ECs) are an important component of the blood-brain barrier (BBB) and play key roles in restricting entrance of possible toxic components and pathogens into the brain. However, identifying endothelial genes that regulate BBB homeostasis remains a time-consuming process. Although somatic genome editing has emerged as a powerful tool for discovery of essential genes regulating tissue homeostasis, its application in brain ECs is yet to be demonstrated in vivo. Here, we used an adeno-associated virus targeting brain endothelium (AAV-BR1) combined with the CRISPR/Cas9 system (AAV-BR1-CRISPR) to specifically knock out genes of interest in brain ECs of adult mice. We first generated a mouse model expressing Cas9 in ECs (Tie2Cas9). We selected endothelial ß-catenin (Ctnnb1) gene, which is essential for maintaining adult BBB integrity, as the target gene. After intravenous injection of AAV-BR1-sgCtnnb1-tdTomato in 4-week-old Tie2Cas9 transgenic mice resulted in mutation of 36.1% of the Ctnnb1 alleles, thereby leading to a dramatic decrease in the level of CTNNB1 in brain ECs. Consequently, Ctnnb1 gene editing in brain ECs resulted in BBB breakdown. Taken together, these results demonstrate that the AAV-BR1-CRISPR system is a useful tool for rapid identification of endothelial genes that regulate BBB integrity in vivo.

Data-Driven Deep Supervision for Medical Image Segmentation.

Medical image segmentation plays a vital role in disease diagnosis and analysis. However, data-dependent difficulties such as low image contrast, noisy background, and complicated objects of interest render the segmentation problem challenging. These difficulties diminish dense prediction and make it tough for known approaches to explore data-specific attributes for robust feature extraction. In this paper, we study medical image segmentation by focusing on robust data-specific feature extraction to achieve improved dense prediction. We propose a new deep convolutional neural network (CNN), which exploits specific attributes of input datasets to utilize deep supervision for enhanced feature extraction. In particular, we strategically locate and deploy auxiliary supervision, by matching the object perceptive field (OPF) (which we define and compute) with the layer-wise effective receptive fields (LERF) of the network. This helps the model pay close attention to some distinct input data dependent features, which the network might otherwise 'ignore' during training. Further, to achieve better target localization and refined dense prediction, we propose the densely decoded networks (DDN), by selectively introducing additional network connections (the 'crutch' connections). Using five public datasets (two retinal vessel, melanoma, optic disc/cup, and spleen segmentation) and two in-house datasets (lymph node and fungus segmentation), we verify the effectiveness of our proposed approach in 2D and 3D segmentation.

Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs.

The polycomb repressive complex 2 (PRC2), which comprised of the core subunits: Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), and Embryonic Ectoderm Development (EED), is an essential epigenetic gene silencer responsible for depositing repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on chromatin. The aberrant activity of PRC2 is closely involved in tumorigenesis and progression, making its inhibition a viable strategy for epigenetic cancer therapy. Although the clinical development of small PRC2 inhibitors has made impressive progress, with one EZH2 inhibitor approved for cancer therapy and several other candidates in clinical trials, current EZH2 inhibitors are limited to treating certain hematological malignancies and have acquired drug resistance. EED is essential for PRC2 stabilization and allosterically stimulating PRC2 activity because it functions as a scaffold protein and an H3K27me3-recognizing protein. Thus, due to its novel mechanism of action, targeting EED provides a promising new strategy for inhibiting PRC2 function and exhibits the potential to overcome the issues encountered by EZH2 inhibitors. This review provides a comprehensive overview of available cancer therapy strategies that target EED, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and proteolysis-targeting chimeras (PROTACs).

Pre-operative administration of butorphanol mitigates emergence agitation in patients undergoing functional endoscopic sinus surgery: A randomized controlled clinical trial.

Background: This study explored the effectiveness of pre-operative intravenous injection of butorphanol in the alleviation of emergence agitation (EA) in patients undergoing functional endoscopic sinus surgery (FESS). Methods: Patients (n = 708) were randomized into two groups. The butorphanol group (Group B, n = 358) received butorphanol infusion (20 ug/kg) before anesthesia induction, while the control group (Group C, n = 350) received an equal volume of normal saline infusion. General anesthesia was induced with sufentanil, propofol, and rocuronium, and was maintained with sevoflurane and remifentanil. Vasoactive drugs maintained the hemodynamic indices within 20% of the baseline. Results: The incidence of EA was significantly lower in Group B than that in Group C (Group B vs. C: 24.3% vs. 31.4%, respectively; P = 0.034). The times to spontaneous breathing (26.5 min vs. 23.7 min, P = 0.011), verbal response (36.0 min vs. 33.4 min, P = 0.012), and extubation (31.0 min vs. 28.7 min, P = 0.025) were longer in Group B, and the grade of cough (0.33 vs. 0.43, P = 0.024) at extubation in Group B was lower than that in Group C (P = 0.024). The mean arterial pressure at the end of the operation (P = 0.004) and at 5 min after extubation (P = 0.008) was higher and hypotension was less prominent (0.6% vs. 2.6%, P = 0.030) in Group B. Conclusion: Pre-operative intravenous injection of butorphanol decreased the incidence of EA after FESS and provided smooth and hemodynamically stable emergence without extending the stay in post-anesthesia care unit. Clinical trial registration: https://www.clinicaltrials.gov/, identifier NCT03398759.

Electroacupuncture for Gastrointestinal Function Recovery after Gynecological Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Evidence for the efficacy and safety of electroacupuncture (EA) on gastrointestinal function recovery after gynecological surgery is unclear. OBJECTIVE: This meta-analysis aimed to evaluate the effects of EA on recovery of postoperative gastrointestinal function for patients receiving gynecological surgery. Data sources: PubMed, Cochrane Central Register of Controlled Trials (CINAHL), Embase, China National Knowledge Infrastructure (CNKI), Weipu (CQVIP), and Wanfang databases were systematically searched from the inception dates to May 30, 2020, for relevant randomized controlled trials (RCTs). Study selection: RCTs that evaluated EA for postoperative gastrointestinal function directly related to gynecological surgery in adults aged 18 years or over. Data extraction and synthesis: paired reviewer independently extracted the data and assessed study quality. Standardized mean differences (SMD) were calculated as the effect measure from a random effects model. Main outcomes and measures: time to first flatus (TFF), time to bowel sounds recovery (TBS), and time to first defecation (TFD) were recorded as primary outcomes; postoperative nausea and vomiting (PONV), motilin (MTL), gastrin (GAS), pH value of gastric mucosa (pHi), gastric mucosal partial pressure of carbon dioxide (PgCO2), vasoactive intestinal peptide (VIP), and adverse event were reported as secondary outcomes. RESULTS: We included eighteen RCTs (1117 participants). Our findings suggested that compared to the control group (CG), electroacupuncture group (EG) showed significant effects on TFF (SMD = -0.98, 95% CI: [-1.28, -0.68], P < 0.00001, I 2 = 69%), TBS (SMD = -0.98, 95% CI: [-1.84, -0.12], P=0.03, I 2 = 92%), and TFD (SMD = -1.23, 95% CI: [-1.59, -0.88], P < 0.0001, I 2 = 0%). Moreover, the incidence of PONV at postoperative 6 h (OR = 0.42, 95% CI: [0.27, 0.64], P < 0.0001, I 2 = 0%) and 24 h (OR = 0.46, 95% CI: [0.32, 0.68], P < 0.0001, I 2 = 0%) was lower in the EG than that in the CG, whereas no significant difference in ratio of PONV at postoperative 48 h (OR = 0.55, 95% CI: [0.20, 1.51], P=0.25, I 2 = 0%) was detected between the two groups. Meanwhile, there was a significant effect in favor of EA on the level of MTL at postoperative 6 h (SMD = -0.93, 95% CI: [-1.36, -0.61], P < 0.0001, I 2 = 21%), while no significant effect was observed at postoperative 24 h (SMD = -0.43, 95% CI: [-0.89, 0.02], P=0.06, I 2 = 69%) in the EG when compared to the CG. Additionally, a large significant effect on decreasing PgCO2 was found in the EG in comparison to the CG, but no significant effect in favor of EA on GAS, VIP, or pHi was observed. It was reported that there was one participant with pain at the needling sites and bruising, and three participants withdrew because they were not intolerant to EA. CONCLUSIONS: EA could be a promising strategy for the prevention and treatment of gastrointestinal dysfunction after gynecological surgery, including shortening TFF and TFD, TBS, regulating MTL, and decreasing the ratio of PONV within postoperative 24h. The effects on MTL and PONV varied with different intervention points, and EA used at 30 min prior to surgery might be recommended. However, the evidence quality ranged from low to very low, and large-scale and high-quality RCTs were warranted.

Buzhong Tiaogan Formula for delaying colorectal liver metastasis (liver depression spleen deficient type): A multicenter randomized controlled trial: A study protocol.

INTRODUCTION: Colorectal cancer has been ranked third among the most common cancers worldwide and raised to the second leading cause of cancer death with nearly one-tenth of cancer-related deaths globally, and nearly half of colorectal cancer patients present with or develop colorectal cancer liver metastasis (CRLM). Buzhong Tiaogan Formula (BTF) has been proven to treat CRLM in our team, but there are lacking of evidence on its effective in delaying colorectal liver metastasis (liver depression spleen deficiency type), so we will evaluate the efficacy and safety of BTF in preventing the occurrence of CRLM. METHODS: This randomized controlled trial (RCT) will be carried out in 3 different hospitals in Shanxi Province planning to recruit 150 CRLM patients with the type of liver depression spleen deficiency. The control group will be treated by basic antitumor therapy and the treatment group will use BTF plus basic antitumor therapy. The primary outcomes will be quality of life of included patients, the time of occurrence of liver metastasis, the score of traditional Chinese medicine symptom for the type of liver depression spleen deficiency; and the secondary outcomes will include overall survival, progression-free survival, DFS, tumor microenvironment and immune state of the included patient. Safety evaluation will be recorded during the whole study. All data in this RCT will be analyzed by SPSS 23.0 software. This study has been approved by the Clinical Research Ethics Committee of Shanxi Province Hospital of Traditional Chinese medicine (2021Y-06016). DISCUSSION: The results of this RCT will contribute to BTF for delaying colorectal liver metastasis (liver depression spleen deficient type). And the results from this RCT will be published in a relevant journal after finished. TRIAL REGISTRATION: ChiMCTR2100005268 (September 4, 2021).

Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons.

The awareness of the long-term toxicities of cancer survivors after chemotherapy treatment has been gradually strengthened as the population of cancer survivors grows. Generally, chemotherapy-induced peripheral neurotoxicity (CIPN) is studied by animal models which are not only expensive and time-consuming, but also species-specific differences. The generation of human induced pluripotent stem cells (hiPSCs) and differentiation of peripheral neurons have provided an in vitro model to elucidate the risk of CIPN. Here, we developed a drug-induced peripheral neurotoxicity model using hiPSC-derived peripheral neurons (hiPSC-PNs) to study the mechanisms of different chemotherapeutic agents on neuronal viability using LDH assay, a cell apoptosis assay determined by caspase 3/7 activation, neurite outgrowth, ion channel expression and neurotransmitter release following treatment of cisplatin, bortezomib, ixabepilone, or pomalidomide. Our data showed that the multiple endpoints of the hiPSC-PNs model had different sensitivity to various chemotherapeutic agents. Furthermore, the chemotherapeutics separated cell viability from the decrease in neurite lengthand changed levels of ion channels and neurotransmitters to a certain extent. Thus, we study the mechanisms of peripheral neurotoxicity induced by chemotherapeutic agents through changes in these indicators.

Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability.

The low level of transcytosis is a unique feature of cerebrovascular endothelial cells (ECs), ensuring restrictive blood-brain barrier (BBB) permeability. Major facilitator superfamily domain-containing 2a (MFSD2A) is a key regulator of the BBB function by suppressing caveolae-mediated transcytosis. However, the mechanisms regulating MFSD2A at the BBB have been barely explored. Here, we show that cerebrovascular EC-specific deletion of Pten (phosphatase and tensin homolog) results in a dramatic increase in vesicular transcytosis by the reduction of MFSD2A, leading to increased transcellular permeability of the BBB. Mechanistically, AKT signaling inhibits E3 ubiquitin ligase NEDD4-2-mediated MFSD2A degradation. Consistently, cerebrovascular Nedd4-2 overexpression decreases MFSD2A levels, increases transcytosis, and impairs BBB permeability, recapitulating the phenotypes of Pten-deficient mice. Furthermore, Akt deletion decreases phosphorylated NEDD4-2 levels, restores MFSD2A levels, and normalizes BBB permeability in Pten-mutant mice. Altogether, our work reveals the essential physiological function of the PTEN/AKT/NEDD4-2/MFSD2A axis in the regulation of BBB permeability.