Triple Surgical Technique for the Repair of Auricular Keloids: Achieving Perfect Restoration of the Ear Contour.

BACKGROUND: Ear keloids, often resulting from ear piercing or other traumas, significantly alter appearance, adversely impacting patients' quality of life and psychological well-being. Thus, developing an effective and esthetically pleasing surgical repair technique is crucial for enhancing patient quality of life. METHODS: This study introduces a novel tripartite surgical approach, which includes arcuate incision design, blind dissection for scar flap, and centrifugal keloid core serial shave excision (ABC for short). This technique is particularly suited for keloids induced by ear piercing that are inoperable for direct suturing or where direct suturing significantly alters the ear contour. RESULTS: In this study, 17 patients underwent the surgical treatment without observing special complications such as infection or necrosis. Long-term postoperative follow-up demonstrated good restoration of the ear contour, with only one case of recurrence. Patients expressed satisfaction with both the surgical process and outcomes. CONCLUSIONS: The triple surgical technique (ABC surgery method) for treating auricular keloids has demonstrated excellent repair results, significantly improving auricle shape. Despite relying on the surgeon's experience, keloid characteristics, and patient comorbidities, it provides an effective treatment option. When combined with local radiotherapy, the recurrence rate is also significantly controlled. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Case Report: Perianal infection in children caused by ingested jujube pits: a report of two cases.

Background: The ingestion of jujube pits by children is a rare cause of perianal infection.This article aimed to report two cases of perianal infection in children resulting from the ingestion of jujube pits. Methods: We reviewed the clinical records of perianal infection caused by jujube pits at our hospital. Details of the patients' presentation, imaging studies, complications and treatment were recorded. Results: Both pediatric patients presented with perianal swelling and pain. The caregivers of both patients denied a history of jujube consumption. Magnetic resonance imaging (MRI) indicated the presence of jujube pits, which were subsequently removed during surgery. Postoperatively, both patients recovered well, and follow-up showed no recurrence or the formation of anal fistulas. Conclusion: The ingestion of jujube pits leading to perianal infection is rare and inconspicuous. Early diagnosis and treatment are beneficial in preventing the occurrence of serious complications.

Dynamic changes in cardiac biomarkers in radiotherapy for oesophageal cancer and their correlations with cardiac radiation dosimetry.

Background and purpose: To investigate the dynamic changes in cardiac enzymes, high-sensitivity troponin T (hs-TnT), pro-brain natriuretic peptide (pro-BNP) and left ventricular ejection fraction (LVEF) during radiotherapy (RT) and 6 months after RT for oesophageal squamous cell carcinoma (ESCC) in the middle and lower locations and to analyse the correlations between these indicators and cardiac radiation dosimetry parameters. Methods: For 35 patients with ESCC in the middle and lower locations receiving radical concurrent chemoradiotherapy (cCRT), intensity-modulated RT was performed at 1.8 Gy or 2.0 Gy per day, and the totle dose was 50.4 Gy or 60 Gy. Serum creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (α-HBDH), hs-TnT, pro-BNP and LVEF were measured before, during, and at the end of RT and 1, 3 and 6 months after RT, and correlations of these indicators with mean heart dose (MHD) and heart V5-V50 were analysed. Results: hs-TnT during, at the end and 6 months after RT for oesophageal cancer showed increasing trends, however, LVEF showed a downward trend. pro-BNP showed an increasing trend during RT and gradually returned to normal after RT. CK and CK-MB showed decreasing trends during RT and continued until one month after RT and then gradually returned to normal. Compared with the low-dose group (MHD < 2000 cGy), the high-dose group (MHD ≥ 2000 cGy) had larger increases in hs-TnT and pro-BNP, a more significant decrease in LVEF, and a longer recovery time for these indicators. MHD and V35 were positively correlated with dynamic changes in hs-TnT. Conclusions: Cardiac injury caused by cCRT for ESCC in the middle and lower locations led to increased hs-TnT and pro-BNP levels and a decrease in LVEF in the early stage of treatment, effects that were more pronounced in the high-dose group. MHD and V35 may be potential indicators to predict the degree of cardiac damage. hs-TnT and pro-BNP are sensitive indicators reflecting cardiac injury in RT for oesophageal cancer. Continuous dynamic monitoring of these markers can provide a reference for cardiac protection in clinical RT.

Human umbilical cord derived mesenchymal stem cells overexpressing HO-1 attenuate neural injury and enhance functional recovery by inhibiting inflammation in stroke mice.

AIMS: The current evidence demonstrates that mesenchymal stem cells (MSCs) hold therapeutic potential for ischemic stroke. However, it remains unclear how changes in the secretion of MSC cytokines following the overexpression of heme oxygenase-1 (HO-1) impact excessive inflammatory activation in a mouse ischemic stroke model. This study investigated this aspect and provided further insights. METHODS: The middle cerebral artery occlusion (MCAO) mouse model was established, and subsequent injections of MSC, MSCHO-1 , or PBS solutions of equal volume were administered via the mice's tail vein. Histopathological analysis was conducted on Days 3 and 28 post-MCAO to observe morphological changes in brain slices. mRNA expression levels of various factors, including IL-1ß, IL-6, IL-17, TNF-α, IL-1Ra, IL-4, IL-10, TGF-ß, were quantified. The effects of MSCHO-1 treatment on neurons, microglia, and astrocytes were observed using immunofluorescence after transplantation. The polarization direction of macrophages/microglia was also detected using flow cytometry. RESULTS: The results showed that the expression of anti-inflammatory factors in the MSCHO-1 group increased while that of pro-inflammatory factors decreased. Small animal fluorescence studies and immunofluorescence assays showed that the homing function of MSCsHO-1 was unaffected, leading to a substantial accumulation of MSCsHO-1 in the cerebral ischemic region within 24 h. Neurons were less damaged, activation and proliferation of microglia were reduced, and polarization of microglia to the M2 type increased after MSCHO-1 transplantation. Furthermore, after transplantation of MSCsHO-1 , the mortality of mice decreased, and motor function improved significantly. CONCLUSION: The findings indicate that MSCs overexpressing HO-1 exhibited significant therapeutic effects against hyper-inflammatory injury after stroke in mice, ultimately promoting recovery after ischemic stroke.

Case Report: CD19 and CD20 monoclonal antibodies with sequential chemotherapy for refractory acute B-lymphocytic leukemia in children.

Objective: This paper observes the efficacy of chemotherapy combined with CD19 and CD20 monoclonal antibodies in clearing minimal residual disease (MRD) and bridging transplantation for refractory acute B-lymphoblastic leukemia (B-ALL) in children and reviews the literature. Methods: A 4-year-old boy diagnosed with B-ALL in our hospital was treated with the SCCLG-ALL-2016 protocol. MRD and gene quantification decreased after induction but remained persistently positive, with poor efficacy. After this patient received three cycles of consolidation chemotherapy combined with blinatumomab and rituximab, MRD and fusion gene quantification became negative, and he received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: During the use of monoclonal antibodies, neurotoxicity, CRS, or other side effects did not occur. Before transplantation, MRD became negative, and the bone marrow had been in complete remission since transplantation (13 months). Conclusion: Chemotherapy combined with blinatumomab for refractory B-ALL in children can bring a better remission rate for patients and is a means of bridging transplantation. Nevertheless, sequential CD20 monoclonal antibody therapy is the first report , and no adverse effects were observed in our case. It is well tolerated and can be used as one of the treatments for refractory B-ALL.

Covalent 14-3-3 Molecular Glues and Heterobifunctional Molecules Against Nuclear Transcription Factors and Regulators.

14-3-3 proteins have the unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that 14-3-3 interactions with specific phosphorylated substrate proteins can be enhanced through small-molecule natural product or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates as well as potential neo-substrates to sequester and inhibit their function has remained elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has a cysteine C38 at the substrate binding interface near sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screened a fully synthetic cysteine-reactive covalent ligand library to identify molecular glues that enhance interaction of 14-3-3σ with not only druggable transcription factors such as estrogen receptor (ERα), but also challenging oncogenic transcription factors such as YAP and TAZ that are part of the Hippo transducer pathway. We identified a hit EN171 that covalently targets 14-3-3 to enhance 14-3-3 interactions with ERα, YAP, and TAZ leading to impaired estrogen receptor and Hippo pathway transcriptional activity. We further demonstrate that EN171 could not only be used as a molecular glue to enhance native protein interactions, but also could be used as a covalent 14-3-3 recruiter in heterobifunctional molecules to sequester nuclear neo-substrates such as BRD4 into the cytosol. Overall, our study reveals a covalent ligand that acts as a novel 14-3-3 molecular glue for challenging transcription factors such as YAP and TAZ and also demonstrates that these glues can be potentially utilized in heterobifunctional molecules to sequester nuclear neo-substrates out of the nucleus and into the cytosol to enable targeted protein localization.

Prevention of STAT3-related pathway in SK-N-SH cells by natural product astaxanthin.

PURPOSE: Neuroblastoma (NB) is the most common solid malignancy in children. Despite current intensive treatment, the long-term event-free survival rate is less than 50% in these patients. Thus, patients with NB urgently need more valid treatment strategies. Previous research has shown that STAT3 may be an effective target in high-risk NB patients. However, there are no effective inhibitors in clinical evaluation with low toxicity and few side effects. Astaxanthin is a safe and natural anticancer product. In this study, we investigated whether astaxanthin could exert antitumor effects in the SK-N-SH neuroblastoma cancer cell line. METHOD: MTT and colony formation assays were used to determine the effect of astaxanthin on the proliferation and colony formation of SK-N-SH cells. Flow cytometry assays were used to detect the apoptosis of SK-N-SH cells. The migration and invasion ability of SK-N-SH cells were detected by migration and invasion assays. Western blot and RT-PCR were used to detect the protein and mRNA levels. Animal experiments were carried out and cell apoptosis in tissues were assessed using a TUNEL assay. RESULT: We confirmed that astaxanthin repressed proliferation, clone formation ability, migration and invasion and induced apoptosis in SK-N-SH cells through the STAT3 pathway. Furthermore, the highest inhibitory effect was observed when astaxanthin was combined with si-STAT3. The reason for this may be that the combination of astaxanthin and si-STAT3 can lower STAT3 expression further than astaxanthin or si-STAT3 alone. CONCLUSION: Astaxanthin can exert anti-tumor effect on SK-N-SH cells. The inhibitory effect was the higher when astaxanthin was combined with si-STAT3.

Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis.

Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.

[Clinical Features and Prognosis of Multiple Myeloma Patients with Secondary Primary Malignancies].

OBJECTIVE: To explore the clinical characteristics and prognosis of multiple myeloma(MM) patients with secondary primary malignancies. METHODS: The clinical data of newly diagnosed MM patients admitted to the First Affiliated Hospital of Zhengzhou University from January 2011 to December 2019 were retrospectively analyzed. The patients with secondary primary malignancies were retrieved, and their clinical features and prognosis were evaluated. RESULTS: A total of 1 935 patients with newly diagnosed MM were admitted in this period, with a median age of 62 (18-94) years old, of which 1 049 cases were hospitalized twice or more. There were eleven cases with secondary primary malignancies (the incidence rate was 1.05%), including three cases of hematological malignancies (2 cases of acute myelomonocytic leukemia and 1 case of acute promyelocytic leukemia) and eight cases of solid tumors (2 cases of lung adenocarcinoma, and 1 case each of endometrial cancer, esophageal squamous cell carcinoma, primary liver cancer, bladder cancer, cervical squamous cell carcinoma, and meningioma). The median age of onset was 57 years old. The median time between diagnosis of secondary primary malignancies and diagnosis of MM was 39.4 months. There were seven cases with primary or secondary plasma cell leukemia, the incidence rate was 0.67%, and the median age of onset was 52 years old. Compared with the randomized control group, the ß2-microglobulin level in the secondary primary malignancies group was lower (P=0.028), and more patients were in stage I/II of ISS (P=0.029). Among the 11 patients with secondary primary malignancies, one survived, ten died, and the median survival time was 40 months. The median survival time of MM patients after the secondary primary malignancies was only seven months. All seven patients with primary or secondary plasma cell leukemia died, with a median survival time of 14 months. The median overall survival time of MM patients with secondary primary malignancies was longer than that of the patients with plasma cell leukemia (P=0.027). CONCLUSION: The incidence rate of MM with secondary primary malignancies is 1.05%. MM patients with secondary primary malignancies have poor prognosis and short median survival time, but the median survival time is longer than that of patients with plasma cell leukemia.

Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors.

While vaccines and antivirals are now being deployed for the current SARS-CoV-2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS-CoV-2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly "druggable" or relatively easy-to-drug target is the coronavirus Main Protease (3CLpro or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors.

Research progress on microRNAs as molecular markers in pancreatic cancer: a narrative review.

Background and Objective: The incidence and mortality of pancreatic cancer (PC) have increased in recent years. The current status of PC diagnosis and treatment remains grim in clinical practice because the commonly used early screening tools are not sufficient. Improving the early detection of PC and strengthening standardized comprehensive treatment remain the focus of PC research. Many studies have shown that micro RNAs (miRNAs) play an important role in the occurrence, development, and treatment of PC. It is expected that miRNAs will become new molecular markers of PC. Methods: We extracted and compiled useful information from the PubMed database that met our criteria for analyzing PC diagnosis, treatment, and prognosis. Key Content and Findings: In this narrative review, we summarize the mechanism of some miRNAs in the occurrence and development of PC and review them as potential markers for the diagnosis, treatment, and prognosis of PC. The function of miRNAs in PC has great potential in studying the pathogenesis of PC. The discovery of many important oncogenic miRNAs and their downstream targets will bring new ideas and research paths for the diagnosis and targeted therapy of PC. Conclusions: MiRNAs are expected to provide novel ideas and research directions for the diagnosis and targeted treatment of PC. However, more patient data and clinical trials are needed before miRNAs can become novel molecular markers for PC.

A comprehensive mouse brain acetylome-the cellular-specific distribution of acetylated brain proteins.

Nε-lysine acetylation is a reversible posttranslational modification (PTM) involved in multiple physiological functions. Genetic and animal studies have documented the critical roles of protein acetylation in brain development, functions, and various neurological disorders. However, the underlying cellular and molecular mechanism are still partially understood. Here, we profiled and characterized the mouse brain acetylome and investigated the cellular distribution of acetylated brain proteins. We identified 1,818 acetylated proteins, including 5,196 acetylation modification sites, using a modified workflow comprising filter-aided sample preparation (FSAP), acetylated peptides enrichment, and MS analysis without pre- or post-fraction. Bioinformatics analysis indicated these acetylated mouse brain proteins were mainly located in the myelin sheath, mitochondrial inner membrane, and synapse, as well as their involvement in multiple neurological disorders. Manual annotation revealed that a set of brain-specific proteins were acetylation-modified. The acetylation of three brain-specific proteins was verified, including neurofilament light polypeptide (NEFL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), and neuromodulin (GAP43). Further immunofluorescence staining illustrated that acetylated proteins were mainly distributed in the nuclei of cortex neurons and axons of hippocampal neurons, sparsely distributed in the nuclei of microglia and astrocytes, and the lack of distribution in both cytoplasm and nuclei of cerebrovascular endothelial cells. Together, this study provided a comprehensive mouse brain acetylome and illustrated the cellular-specific distribution of acetylated proteins in the mouse brain. These data will contribute to understanding and deciphering the molecular and cellular mechanisms of protein acetylation in brain development and neurological disorders. Besides, we proposed some problems that need to be solved in future brain acetylome research.

Effect of thoracic radiotherapy dose on the prognosis of advanced lung adenocarcinoma harboring EGFR mutations.

BACKGROUND: The aim of this study was to investigate the effects of different thoracic radiotherapy doses on OS and incidence of radiation pneumonia which may provide some basis for optimizing the comprehensive treatment scheme of these patients with advanced EGFR mutant lung adenocarcinoma. METHODS: Data from 111 patients with EGFR-mutant lung adenocarcinoma who received thoracic radiotherapy were included in this retrospective study. Overall survival (OS) was the primary endpoints of the study. Kaplan-Meier method was used for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate analyses to determine the prognostic factors related to the disease. RESULTS: The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50-60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). Although trend suggested a higher levels of pneumonia cases with increasing radiation doses, these lack statistical significance (χ2 = 1.331; P = 0.514). The multivariate analysis showed that the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033). CONCLUSIONS: For the patients with advanced EGFR-mutant lung adenocarcinoma, the radical thoracic radiotherapy dose scheme (≥ 60 Gy) could significantly prolong the OS of patients during the whole course management.

Application of artificial intelligence to pancreatic adenocarcinoma.

Background and Objectives: Pancreatic cancer (PC) is one of the deadliest cancers worldwide although substantial advancement has been made in its comprehensive treatment. The development of artificial intelligence (AI) technology has allowed its clinical applications to expand remarkably in recent years. Diverse methods and algorithms are employed by AI to extrapolate new data from clinical records to aid in the treatment of PC. In this review, we will summarize AI's use in several aspects of PC diagnosis and therapy, as well as its limits and potential future research avenues. Methods: We examine the most recent research on the use of AI in PC. The articles are categorized and examined according to the medical task of their algorithm. Two search engines, PubMed and Google Scholar, were used to screen the articles. Results: Overall, 66 papers published in 2001 and after were selected. Of the four medical tasks (risk assessment, diagnosis, treatment, and prognosis prediction), diagnosis was the most frequently researched, and retrospective single-center studies were the most prevalent. We found that the different medical tasks and algorithms included in the reviewed studies caused the performance of their models to vary greatly. Deep learning algorithms, on the other hand, produced excellent results in all of the subdivisions studied. Conclusions: AI is a promising tool for helping PC patients and may contribute to improved patient outcomes. The integration of humans and AI in clinical medicine is still in its infancy and requires the in-depth cooperation of multidisciplinary personnel.

MiR-520a-5p/PPP5C regulation pattern is identified as the key to gemcitabine resistance in pancreatic cancer.

Objective: To explore the effects of the expression level of miR-520-5p/PPP5C in pancreatic cancer cells and exosomes on cell viability, angiogenesis, autophagy, which involved in the mechanism of gemcitabine resistance in pancreatic cancer. Methods: APSC-1 cell line was treated with gemcitabine, after which its exosomes were extracted for NTA assay. Subsequently, the drug resistance of APSC-1 cells was assayed using CCK8, as well as the activity of HUVEC cells treated with exosomes from each group of APSC-1 cells after drug resistance treatment as well as overexpression treatment. Five groups of HUVEC cells treated with exosomes were subjected to in vitro tubule formation assay. levels of PPP5C in each group of ASPC-1 cells and their exosomes, levels of overexpressed PPP5C, and related exosomal proteins were examined by WB. mRNA expression levels of PPP5C and levels of miR-520a were examined by qPCR The relationship between miR-520a-5p and PPP5C was investigated. After that, the autophagy of PPP5C was detected. Finally, it was analyzed by TCGA database for survival prognosis analysis. Results: APSC-1 cells had an IC50 value of 227.1 µM for gemcitabine, elevated PPP5C expression, drug resistance, and enhanced HUVEC cell activity; exosomes CD9, CD63, and CD81 were significantly expressed in all groups; meanwhile, enhanced PPP5C expression not only promoted in vitro tubule formation but also increased autophagy levels; meanwhile, its relationship with miR-520-5p and There was a targeted inhibitory relationship between its level and miR-520-5p and PPP5C, and its elevated level also led to a decrease in the survival level of patients over 3-5 years. Conclusion: PPP5C has a prognostic role in pancreatic cancer by promoting the value-added and invasion of pancreatic cancer cells, and a targeted inhibitory relationship between miR-520-5p and PPP5C was found.

Dosimetric Evaluation of Incidental Irradiation to the Internal Mammary Chain After Surgery in Breast Cancer Patients.

Background and Purpose: The low rate of internal mammary node (IMN) recurrence was attributed to systemic therapy and internal mammary chain (IMC) coverage by the tangential fields of irradiation. This study aimed to evaluate the incidental irradiation dose to the IMC in breast cancer patients after surgery and to estimate the clinical predictive parameters affecting the magnitude of the IMC. Materials and Methods: A total of 138 patients treated with postmastectomy radiotherapy and 210 patients undergoing radiotherapy after breast-conserving surgery (BCS) in our hospital were retrospectively analyzed. The mean dose (Dmean) to the IMC and the first to third intercostal spaces of IMC levels (ICS1-3) were evaluated. We evaluated the IMC coverage according to the type of surgery and whether the ipsilateral supraclavicular fossa (SCF) was included in the irradiation field. Results: The incidental radiation dose to the IMC was 29.69 Gy, and the dose delivered to the IMC, ICS1, and ICS2 showed a greater coverage in the modified radical mastectomy (MRM) group when compared with the BCS group (32.85 vs. 27.1 Gy, 26.6 vs. 12.5 Gy, 34.63 vs. 30.42 Gy). The dose delivered to ICS3 showed no difference between the MRM and BCS groups (37.41 vs. 36.24 Gy). Furthermore, 131 patients (37.64%) received radiotherapy to the chest wall and ipsilateral SCF. In the univariate analysis, both surgery type and SCF irradiation were parameters affecting the Dmean of incidental radiation to the IMC (r = -0.179, P = 0.001; r = -0.175, P = 0.001). In the multivariate analysis, surgery type was the only correlative factor that affected incidental radiation dose to the IMC (r = -3.534, P = 0.000). Conclusion: The real influencing factor of incidental dose to the IMC was the surgery form rather than the accession of SCF irradiation.

CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways.

Neuroinflammation is closely related to the pathogenesis of neurodegenerative diseases. Activation of microglia, the resident immune cells in CNS, induces inflammatory responses, resulting in the release of neurotoxic molecules, which favors neuronal death and neurodegeneration. Nuclear receptor-related 1 (Nurr1) protein, one of the orphan nuclear receptor superfamilies, is an emerging target for neuroprotective therapy. In addition, the anti-inflammatory function of cannabinoid (CB) receptors has attracted increasing interest. As both CB receptors (especially CB2 receptor) and Nurr1 exist in microglia, and regulate a number of same molecular points such as NF-κB, we herein explored the interplay between the CB2 receptor and Nurr1 as well as the regulatory mechanisms in microglial cells. We showed that the application of CB2 receptor agonists JWH015 (1, 10 µM) significantly increased the nuclear Nurr1 protein in BV-2 cells and primary midbrain microglia. Overexpression of Nurr1 or application of Nurr1 agonist C-DIM12 (10 µM) significantly increased the mRNA level of CB2 receptor in BV-2 cells, suggesting that positive expression feedback existing between the CB2 receptor and Nurr1. After 2-AG and JWH015 activated the CB2 receptors, the levels of p-ERK, p-AKT, p-GSK-3ß in BV-2 cells were significantly increased. Using ERK1/2 inhibitor U0126 and PI3K/AKT inhibitor LY294002, we revealed that the amount of Nurr1 in the nucleus was upregulated through ß-arrestin2/ERK1/2 and PI3K/AKT/GSK-3ß signaling pathways. With these inhibitors, we found a cross-talk interaction between the two pathways, and the ERK1/2 signaling pathway played a more dominant regulatory role. Furthermore, we demonstrated that when the CB2 receptor was activated, the phagocytic function of BV-2 cells was significantly weakened; the activation of Nurr1 also inhibited the phagocytic function of BV-2 cells. Pretreatment with the signaling pathway inhibitors, especially U0126, reversed the inhibitory effect of 2-AG on phagocytosis, suggesting that CB2 receptor may regulate the phagocytic function of microglia by activating Nurr1. In conclusion, CB2 receptor or/and Nurr1-mediated signal pathways play instrumental roles in the progress of phagocytosis, which are expected to open up new treatment strategies for neurodegenerative diseases.

[Gene Mutation and Overexpression of Newly Diagnosed Multiple Myeloma Patients].

OBJECTIVE: To analyze the characteristics of gene mutation and overexpression in newly diagnosed multiple myeloma (NDMM) patients. METHODS: Bone marrow cells from 208 NDMM patients were collected and analyzed. The gene mutation of 28 genes and overexpression of 6 genes was detected by DNA sequencing. Chromosome structure abnormalities were detected by fluorescence in situ hybridization (FISH). RESULTS: Gene mutations were detected in 61 (29.33%) NDMM patients. Some mutations occurred in 5 or more cases, such as NRAS, PRDM1, FAM46C, MYC, CCND1, LTB, DIS3, KRAS, and CRBN. Overexpression of six genes (CCND1, CCND3, BCL-2, CCND2, FGFR3, and MYC) were detected in 83 (39.9%) patients, and cell cycle regulation gene was the most common. Single nucleotide polymorphisms (SNP) changes were detected in 169 (81.25%) patients, the TP53 P72R gene SNP (70.17%) was the most common. Abnormality in chromosome structure was correlated to gene overexpression. Compared to the patients with normal chromosome structure, patients with 14q32 deletion showed higher proportion of CCND1 overexpression. Similarly, patients with 13q14 deletion showed higher proportion of FGFR3 overexpression, whereas patients with 1q21 amplification showed higher proportion of CCND2, BCL-2 and FGFR3 overexpression. CONCLUSION: There are multiple gene mutations and overexpression in NDMM. However, there is no dominated single mutation or overexpression of genes. The most common gene mutations are those in the RAS/MAPK pathway and the genes of cyclin family CCND are overexpression.

Development of a nomograph integrating radiomics and deep features based on MRI to predict the prognosis of high grade Gliomas.

The purpose of this study was to assess the overall survival of patients with HGG using a nomogram which combines the optimized radiomics with deep signatures extracted from 3D Magnetic Resonance Images (MRI) as well as clinical predictors. One training cohort of 168 HGG patients and one validation cohort of 42 HGG patients were enrolled in this study. From each patient's 3D MRI, 1284 radiomics features were extracted, and 8192 deep features were extracted via transfer learning. By using Least Absolute Shrinkage and Selection Operator (LASSO) regression to select features, the radiomics signatures and deep signatures were generated. The radiomics and deep features were then analyzed synthetically to generate a combined signature. Finally, the nomogram was developed by integrating the combined signature and clinical predictors. The radiomics and deep signatures were significantly associated with HGG patients' survival time. The signature derived from the synthesized radiomics and deep features showed a better prognostic performance than those from radiomics or deep features alone. The nomogram we developed takes the advantages of both radiomics and deep signatures, and also integrates the predictive ability of clinical indicators. The calibration curve shows our predicted survival time by the nomogram was very close to the actual time.

Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer.

Pyroptosis is an inflammation-dependent and self-cascade amplifying type of programmed cell death, serving as an effective means for activating the local immune response and improving the anticancer efficacy. As the effector of pyroptosis, gasdermin-E (GSDME) is silenced in most tumor cells. The gene silencing can be reversed by DNA demethylation, but the systemic side effects and toxicity of chemotherapeutic agents are inevitable. In this work, inhaled poly(lactic-co-glycolic acid) (PLGA) porous microspheres loaded with Decitabine (DAC) and Doxorubicin (DOX) (denoted as CO-MPs) were prepared to induce cell pyroptosis for orthotopic lung cancer therapy with fewer systemic side effects. The CO-MPs showed a hollow and porous spherical morphology and exhibited an excellent aerodynamic property, lung distribution and a sustained release effect. The CO-MPs could reverse GSDME silencing and elevate the expression of cleaved-caspase 3 in tumor cells. The cleaved-caspase 3 protein cleaved the GSDEM protein to obtain GSDME-N protein, causing the rupture of cell plasma membranes, release of cell contents and activation of the immune system. The CO-MPs could lead to the suppression of lung tumors, the decrease of the lung metastatic nodules in tumor-bearing mice and the induction of immunological memory that provides continuous protection from the tumor rechallenge. The inhalable microspheres loaded with DAC and DOX could be an effective strategy for lung cancer treatment via the pyroptosis mechanism.