Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

Temporal resolution of ultrafast compressive imaging using a single-chirped optical probe.

Ultrafast compressive imaging captures three-dimensional spatiotemporal information of transient events in a single shot. When a single-chirped optical probe is applied, the temporal information is obtained from the probe modulated in amplitude or phase using a direct frequency-time mapping method. Here, we extend the analysis of the temporal resolution of conventional one-dimensional ultrafast measurement techniques such as spectral interferometry to that in three-dimensional ultrafast compressive imaging. In this way, both the amplitude and phase of the probe are necessary for a full Fourier transform method, which obtains temporal information with an improved resolution determined by probe spectral bandwidth. The improved temporal resolution potentially enables ultrafast compressive imaging with an effective imaging speed at the quadrillion-frames-per-second level.

Effect of ion migration on lead halide perovskite on visible light communication system.

Benefiting from the high modulation bandwidth (BW), low energy consumption and excellent optical performance, lead halide perovskite has attracted wide attention in visible light communication (VLC). However, the ion migration which results in mobile point defects in perovskite structures is recognized as a crucial key factor inducing the performance degradation. Here, the influence of ion migration in perovskite devices on the performance of VLC was systematically studied. The ion migration process is realized by mixing CsPbBr3 and CsPbI3 quantum dots, during which, the performance of the VLC system is reduced, but it can return to its initial state after stabilization. The on-off keying (OOK) modulation scheme of the perovskite light-emitting diode (LED) device was carried out, achieving a data rate of 90 Mbps.

KAMPNet: multi-source medical knowledge augmented medication prediction network with multi-level graph contrastive learning.

BACKGROUNDS: Predicting medications is a crucial task in intelligent healthcare systems, aiding doctors in making informed decisions based on electronic medical records (EMR). However, medication prediction faces challenges due to complex relations within heterogeneous medical data. Existing studies primarily focus on the supervised mining of hierarchical relations between homogeneous codes in medical ontology graphs, such as diagnosis codes. Few studies consider the valuable relations, including synergistic relations between medications, concurrent relations between diseases, and therapeutic relations between medications and diseases from historical EMR. This limitation restricts prediction performance and application scenarios. METHODS: To address these limitations, we propose KAMPNet, a multi-sourced medical knowledge augmented medication prediction network. KAMPNet captures diverse relations between medical codes using a multi-level graph contrastive learning framework. Firstly, unsupervised graph contrastive learning with a graph attention network encoder captures implicit relations within homogeneous medical codes from the medical ontology graph, generating knowledge augmented medical code embedding vectors. Then, unsupervised graph contrastive learning with a weighted graph convolutional network encoder captures correlative relations between homogeneous or heterogeneous medical codes from the constructed medical codes relation graph, producing relation augmented medical code embedding vectors. Finally, the augmented medical code embedding vectors, along with supervised medical code embedding vectors, are fed into a sequential learning network to capture temporal relations of medical codes and predict medications for patients. RESULTS: Experimental results on the public MIMIC-III dataset demonstrate the superior performance of our KAMPNet model over several baseline models, as measured by Jaccard, F1 score, and PR-AUC for medication prediction. CONCLUSIONS: Our KAMPNet model can effectively capture the valuable relations between medical codes inherent in multi-sourced medical knowledge using the proposed multi-level graph contrastive learning framework. Moreover, The multi-channel sequence learning network facilitates capturing temporal relations between medical codes, enabling comprehensive patient representations for downstream tasks such as medication prediction.

Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data.

BACKGROUND: Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists. METHODS: All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS. RESULTS: LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965-0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications. CONCLUSIONS: LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

Generalized central slice theorem perspective on Fourier-transform spectral imaging at a sub-Nyquist sampling rate.

Fourier-transform spectral imaging captures frequency-resolved images with high spectral resolution, broad spectral range, high photon flux, and low stray light. In this technique, spectral information is resolved by taking Fourier transformation of the interference signals of two copies of the incident light at different time delays. The time delay should be scanned at a high sampling rate beyond the Nyquist limit to avoid aliasing, at the price of low measurement efficiency and stringent requirements on motion control for time delay scan. Here we propose, what we believe to be, a new perspective on Fourier-transform spectral imaging based on a generalized central slice theorem analogous to computerized tomography, using an angularly dispersive optics decouples measurements of the spectral envelope and the central frequency. Thus, as the central frequency is directly determined by the angular dispersion, the smooth spectral-spatial intensity envelope is reconstructed from interferograms measured at a sub-Nyquist time delay sampling rate. This perspective enables high-efficiency hyperspectral imaging and even spatiotemporal optical field characterization of femtosecond laser pulses without a loss of spectral and spatial resolutions.

Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy.

PURPOSE: Fibroblast activation protein (FAP) is a pan-cancer target and now the state-of-the-art to develop radiopharmaceuticals. FAP inhibitors have been of great success in developing imaging tracers. Yet, the overly rapid clearance cannot match with the long half-lives of regular therapeutic radionuclides. Though strategies that aim to elongate the circulation of FAPIs are being developed, here we describe an innovation that uses α-emitters of short half-lives (e.g., 213Bi) to pair the rapid pharmacokinetics of FAPIs. METHODS: An organotrifluoroborate linker is engineered to FAPIs to give two advantages: (1) selectively increases tumor uptake and retention; (2) facile 18F-radiolabeling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general. RESULTS: The organotrifluoroborate linker helps to improve the internalization in cancer cells, resulting in notably higher tumor uptake while the background is clean. In FAP-expressed tumor-bearing mice, this FAPI labeled with 213Bi, a short half-life α-emitter, exhibits almost complete suppression to tumor growth while the side effect is negligible. Additional data shows that this strategy is generally applicable to guide other α-emitters, such as 212Bi, 212Pb, and 149Tb. CONCLUSION: The organotrifluoroborate linker may be of importance to optimize FAP-targeted radiopharmaceuticals, and the short half-lived α-emitters may be of choice for the rapid-cleared small molecule-based radiopharmaceuticals.

Establishment of a patient-derived organoid model and living biobank for nasopharyngeal carcinoma.

Background: Recurrent nasopharyngeal carcinoma (NPC) remains a major challenge for clinicians and scientists. Tumor organoid is a revelational disease model that highly resembled the heterogeneity and histopathological characteristics of original tumors. This study aimed to optimize the modeling process of patient-derived NPC organoids (NPCOs), and establish a living-biobank of NPCs to study the mechanism and explore the more effective treatment of the disease. Methods: Sixty-two fresh NPC tissue samples and 15 normal mucosa samples were collected for 3-dimensional (3D) organoid culture. The organoids were confirmed using hematoxylin and eosin assays. The expression levels of CD133, CD44, BMI-1, and Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected by immunohistochemistry (IHC) and in situ hybridization (ISH). Recurrent NPCOs were frozen in liquid nitrogen for 6 months and then resuscitated and passaged. Results: We identified a novel two-step enzymatic strategy for the treatment of NPC and nasal mucosa specimens and an optimal medium for culturing NPCOs and nasal mucosa organoids (NMOs). Organoid cultures were generated from 34 primary NPC samples, 28 recurrent NPC samples, and 15 normal mucosa samples. The success rates for primary NPCO, recurrent NPCO, and NMO formation were 47.06%, 81.25%, and 86.5%, respectively. All the NPCOs were EBER positive and CK7 negative. Recurrent NPCOs had higher expressions of stem cell markers, including BMI-1, CD44, and CD133. Additionally, recurrent NPCOs could be cultured to passage 4 and frozen and revived repeatedly, while primary NPCOs were challenging to culture. Conclusions: In summary, we successfully established a living biobank using the NPCO model, which has enormous potential in basic and clinical research on NPC.

Single-shot compressed optical field topography.

Femtosecond lasers are powerful in studying matter's ultrafast dynamics within femtosecond to attosecond time scales. Drawing a three-dimensional (3D) topological map of the optical field of a femtosecond laser pulse including its spatiotemporal amplitude and phase distributions, allows one to predict and understand the underlying physics of light interaction with matter, whose spatially resolved transient dielectric function experiences ultrafast evolution. However, such a task is technically challenging for two reasons: first, one has to capture in single-shot and squeeze the 3D information of an optical field profile into a two-dimensional (2D) detector; second, typical detectors are only sensitive to intensity or amplitude information rather than phase. Here we have demonstrated compressed optical field topography (COFT) drawing a 3D map for an ultrafast optical field in single-shot, by combining the coded aperture snapshot spectral imaging (CASSI) technique with a global 3D phase retrieval procedure. COFT can, in single-shot, fully characterize the spatiotemporal coupling of a femtosecond laser pulse, and live stream the light-speed propagation of an air plasma ionization front, unveiling its potential applications in ultrafast sciences.

Structural insights into DNA binding domain of vancomycin-resistance-associated response regulator in complex with its promoter DNA from Staphylococcus aureus.

In Staphylococcus aureus, vancomycin-resistance-associated response regulator (VraR) is a part of the VraSR two-component system, which is responsible for activating a cell wall-stress stimulon in response to an antibiotic that inhibits cell wall formation. Two VraR-binding sites have been identified: R1 and R2 in the vraSR operon control region. However, the binding of VraR to a promoter DNA enhancing downstream gene expression remains unclear. VraR contains a conserved N-terminal receiver domain (VraRN ) connected to a C-terminal DNA binding domain (VraRC ) with a flexible linker. Here, we present the crystal structure of VraRC alone and in complex with R1-DNA in 1.87- and 2.0-Å resolution, respectively. VraRC consisting of four α-helices forms a dimer when interacting with R1-DNA. In the VraRC -DNA complex structure, Mg2+ ion is bound to Asp194. Biolayer interferometry experiments revealed that the addition of Mg2+ to VraRC enhanced its DNA binding affinity by eightfold. In addition, interpretation of NMR titrations between VraRC with R1- and R2-DNA revealed the essential residues that might play a crucial role in interacting with DNA of the vraSR operon. The structural information could help in designing and screening potential therapeutics/inhibitors to deal with antibiotic-resistant S. aureus via targeting VraR.

Positive lymph node ratio predicts adverse prognosis for patients with lymph nodes metastatic hypopharyngeal squamous cell carcinoma after primary surgery.

Background: Positive lymph node ratio (LNR) is associated with the prognosis of many cancers. However, its prognostic value in patients with hypopharyngeal squamous cell carcinoma (HSCC) is unclear due to the rarity of HSCC. This study aimed to investigate the prognostic value of LNR in HSCC using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Data spanning 2004 to 2015 of eligible HSCC patients were retrospectively retrieved from the SEER database. Clinicopathological data, including age at diagnosis, race, gender, marital status, primary tumor site, tumor size, tumor grade, Tumor-Lymph Node-Metastasis (TNM) stage, surgical type, postoperative adjuvant therapy (POAT) record, the number of lymph nodes (LNs) examined, the number of positive LNs, survival time, and death classification were collected and dichotomized through the receiver operating characteristic (ROC) curve. The LNR was defined as the ratio of positive LNs to the total number of LNs examined. The Kaplan-Meier method and Cox regression models were used to assess the association between LNR vs. cancer-specific survival (CSS) and overall survival (OS). Results: The 5-year CSS and OS rates of the 391 patients were 44% and 33.7%, respectively. The median LNR was 0.083 [interquartile range (IQR), 0.043-0.179], and the optimal cut-off value of LNR was 0.23. Kaplan-Meier curves showed that patients with LNR ≥0.23 had significantly shorter CSS and OS than LNR <0.23. In multivariable analysis, large tumor size [hazard ratio (HR): 1.012, P=0.016], N3 stage (HR: 2.113, P=0.040), M1 stage (HR: 2.458, P=0.041), with POAT (HR: 0.559, P=0.001), and LNR ≥0.23 (HR: 1.795, P=0.001) independently predicted CSS, while old age (HR: 1.019, P=0.009), large tumor size (HR: 1.012, P=0.006), M1 stage (HR: 3.422, P=0.001), with POAT (HR: 0.610, P=0.001), and LNR ≥0.23 (HR: 1.667, P=0.001) independently predicted OS. The subgroup analysis showed that patients with LNR ≥0.23 shared worse CSS and OS in either N2 or N3 subgroups than those with LNR <0.23. Furthermore, POAT provided an independent protective factor in the LNR ≥0.23 group, while it had no significant effect in the LNR <0.23 group. Conclusions: This study demonstrates a strong association between LNR and prognosis in patients with LNs metastatic HSCC. Further, it provides an alternative tool for providing supplemental information regarding prognosis.

Fragment-Directed Random Mutagenesis by the Reverse Kunkel Method.

Two fundamentally different approaches are routinely used for protein engineering: user-defined mutagenesis and random mutagenesis, each with its own strengths and weaknesses. Here, we invent a unique mutagenesis protocol, which combines the advantages of user-defined mutagenesis and random mutagenesis. The new method, termed the reverse Kunkel method, allows the user to create random mutations at multiple specified regions in a one-pot reaction. We demonstrated the reverse Kunkel method by mimicking the somatic hypermutation in antibodies that introduces random mutations concentrated in complementarity-determining regions. Coupling with the phage display and yeast display selections, we successfully generated dramatically improved antibodies against a model protein and a neurotransmitter peptide in terms of affinity and immunostaining performance. The reverse Kunkel method is especially suitable for engineering proteins whose activities are determined by multiple variable regions, such as antibodies and adeno-associated virus capsids, or whose functional domains are composed of several discontinuous sequences, such as Cas9 and Cas12a.

Structural basis for promoter DNA recognition by the response regulator OmpR.

OmpR, a response regulator of the EnvZ/OmpR two-component system (TCS), controls the reciprocal regulation of two porin proteins, OmpF and OmpC, in bacteria. During signal transduction, OmpR (OmpR-FL) undergoes phosphorylation at its conserved Asp residue in the N-terminal receiver domain (OmpRn) and recognizes the promoter DNA from its C-terminal DNA-binding domain (OmpRc) to elicit an adaptive response. Apart from that, OmpR regulates many genes in Escherichia coli and is important for virulence in several pathogens. However, the molecular mechanism of the regulation and the structural basis of OmpR-DNA binding is still not fully clear. In this study, we presented the crystal structure of OmpRc in complex with the F1 region of the ompF promoter DNA from E. coli. Our structural analysis suggested that OmpRc binds to its cognate DNA as a homodimer, only in a head-to-tail orientation. Also, the OmpRc apo-form showed a unique domain-swapped crystal structure under different crystallization conditions. Biophysical experimental data, such as NMR, fluorescent polarization and thermal stability, showed that inactive OmpR-FL (unphosphorylated) could bind to promoter DNA with a weaker binding affinity as compared with active OmpR-FL (phosphorylated) or OmpRc, and also confirmed that phosphorylation may only enhance DNA binding. Furthermore, the dimerization interfaces in the OmpRc-DNA complex structure identified in this study provide an opportunity to understand the regulatory role of OmpR and explore the potential for this "druggable" target.

Direct Antibody Isolation on Cells Using Affinity-Tag-Guided Proximity Selection.

Traditional antibody generation, using either phage display or animal immunization, relies on purified antigens. Many membrane proteins, such as G protein-coupled receptors, solute carriers, or ion channels, are important drug targets but very challenging for the formation of antibodies due to the difficulty of protein purification. Whole-cell panning is an alternative approach for generating antibodies without the need for antigen purification. However, it often suffers from background interference and therefore requires extensive screening with low success rates. Here, we develop a new phage selection method, dubbed affinity-tag-guided proximity selection (A-GPS), to efficiently isolate specific antibodies directly from the antigen-presenting cells. By engineering a genetically fused affinity tag for the target antigen, A-GPS confines the proximity labeling reaction near the target antigen and preferentially enriches the phage bound to the target antigen. Using surface-presented GFP on human cells as a model antigen, we demonstrated that A-GPS successfully enriched the antigen-specific clones in two rounds of selection. Among the 46 randomly picked clones, >95% of clones showed great affinity and specificity for GFP over the background of HEK293T surface proteins. One of the best clones expressed as a Fab fragment showed subnanomolar binding affinity for GFP. This clone was successfully applied to common biological applications, such as immunofluorescence and flow cytometry, reflecting the usefulness of A-GPS for generating commercial-grade antibodies.

miR-223-3p Inhibits Antigen Endocytosis and Presentation and Promotes the Tolerogenic Potential of Dendritic Cells through Targeting Mannose Receptor Signaling and Rhob.

BACKGROUND: The role of miR-223-3p in dendritic cells (DCs) is unknown. This study is aimed at investigating the effect of miR-223-3p on the antigen uptake and presentation capacities of DCs and the underlying molecular mechanism. METHODS: FITC-OVA antigen uptake and cell surface markers in bone marrow-derived DCs (BMDCs) were analyzed by flow cytometry. BMDCs were transfected with the miR-223-3p mimic or inhibitor. Cytokine levels were determined by ELISA. CD4+ T cell differentiation was determined by mixed lymphocyte culture assay. RESULTS: OVA treatment significantly downregulated miR-223-3p in BMDCs. The miR-223-3p mimic significantly inhibited OVA-induced antigen uptake and surface expression of MHC-II on BMDCs (P < 0.01). The miR-223-3p mimic increased TGF-ß1 production in OVA-treated DCs (P < 0.01). Mixed lymphocyte reaction showed that the miR-223-3p mimic significantly promoted Treg cell differentiation. In addition, the miR-223-3p mimic significantly upregulated CD103 in DCs, indicating the promotion of tolerogenic DCs. The miR-223-3p mimic downregulated Rhob protein in OVA-induced DCs. Rhob knockdown significantly suppressed the ability of FITC-OVA endocytosis (P < 0.01) and surface MHC-II molecule expression (P < 0.01) in BMDCs, promoting promoted Treg cell differentiation. Mannose receptor (MR) knockdown significantly upregulated miR-223-3p, downregulated Rhob protein in OVA-treated DCs, inhibited the FITC-OVA endocytosis and surface MHC-II expression in BMDCs, and promoted Treg cell differentiation (all P < 0.01). CONCLUSION: These data suggest that miR-223-3p has an inhibitory effect on the antigen uptake and presentation capacities of BMDCs and promotes Treg cell differentiation, which is, at least partially, through targeting MR signaling and Rhob.

MicroRNA-200a Promotes Phagocytosis of Macrophages and Suppresses Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma by Targeting CD47.

Nasopharyngeal carcinoma (NPC) causes severe oncogenic lesions in the nasopharynx. CD47, a transmembrane integrin-associated protein, plays a key role in the ability of tumor cells to escape phagocytosis, working as an immune checkpoint in the immune response. Besides this role, CD47 has been reported to regulate cell proliferation and migration. The present study addresses the relationship between CD47 and microRNA-200a and examines their regulatory mechanisms in NPC. Bioinformatics analyses and dual-luciferase reporter assays were used to confirm the putative relationship between miR-200a and CD47, and their interaction was further detected using western blotting and RT-PCR. Further, results showed that miR-200a affect NPC cell proliferation, migration, and invasion by regulating CD47. A cell phagocytosis assay showed that miR-200a and a CD47 monoclonal antibody increased the sensitivity of NPC cells to macrophage phagocytosis by inhibiting the functions of CD47. Additionally, miR-200a expression was suppressed and CD47 expression increased in both clinical NPC tissues and cell lines. Taken together, these results show the miR-200a/CD47 combination as a potential therapeutic for treatment of NPC.

MiR-146a Promotes Tolerogenic Properties of Dendritic Cells and through Targeting Notch1 Signaling.

BACKGROUND: MiR-146a has been shown to negatively regulate innate immune, inflammatory response and antiviral pathway, however, its role in the tolerogenic responses remains largely unknown. This study aimed to investigate the role of miR-146a in the OVA-induced allergic inflammation of dendritic cells (DCs). METHODS: Bone marrow-derived DCs (BMDCs) were treated with OVA (100 µg/ml) for 24 h. MiR-146a expressions were assessed by quantitative RT-PCR. BMDCs were transfected with miR-146a mimics or inhibitor. Cell surface markers were analyzed by flow cytometry. Cytokine levels were determined by ELISA assay. Mixed lymphocyte culture assay was adopted to assess CD4 + T-cell differentiation. The 3' UTR luciferase reporter assay was utilized to determine the miRNA target sequence. RESULTS: OVA treatment significantly up-regulated miR-146a in BMDCs in a dose- and time-dependent manner. In the OVA-treated DCs, overexpression of miR-146a (mimics transfection) down-regulated the surface markers (CD80, CD86) and increased production of anti-inflammatory cytokines TGF-ß1 and IL-10 but decreased pro-inflammatory cytokine IL-12. MiR-146a overexpression promoted immature DC to induce regulatory T cells (Treg) differentiation. By contrast, transfection of miR-146a inhibitor into DC exhibited the opposite trends. Notch1 was a direct target of miR-146a, and Notch1 knock-down induced similar effects as miR-146a mimics transfection in BMDCs. Moreover, the effect of miR-146a inhibitor on OVA-induced DC was attenuated by Notch1 knock-down. CONCLUSION: miRNA-146a promoted tolerogenic properties of DCs, at least partially, through targeting Notch1 signaling.

Comparing endoscopic surgeries with open surgeries in terms of effectiveness and safety in salvaging residual or recurrent nasopharyngeal cancer: Systematic review and meta-analysis.

Consensus has yet to be reached on the optimal operation for patients with residual or recurrent nasopharyngeal carcinoma (NPC). To compare effectiveness and safety of open surgery and endoscopic surgery for patients with residual or recurrent NPC. Pubmed, Embase, and Cochrane were searched for relevant publications from January 1, 2000 to May 1, 2017. Included studies reported specific residual or local recurrent nasopharyngeal cancer survival data. Proportional meta-analysis was performed on both outcomes with a random-effects model, and the 95% confidential intervals were calculated by Stata 12.0 software. For patients with different tumor classification, a downward trend of 2-year overall survival (OS) was observed for both surgical populations. Endoscopic surgeries achieved bigger rates than open surgeries in patients with recurrent tumor (rT) 1, rT2, and rT3 (93% vs 87%, 77% vs 63%, 67% vs 53%). As for patients with rT4, 2-year OS was similar (35% vs 35%).In addition, the former is less severe complications, lower local recurrence rates (27% vs 32%). Our study found that, compared to open surgery, endoscopic surgery was a safer and more effective treatment modality in managing patients with recurrent or residual NPC.

Third or fourth branchial pouch sinus lesions: a case series and management algorithm.

BACKGROUND: The purpose of this study was to develop an effective management algorithm for lesions of third or fourth branchial sinuses. STUDY DESIGN: Case series with chart review. METHODS: Data from patients who were identified as having third or fourth branchial pouch sinus lesions in a single institution between January 2014 and December 2018 were retrospectively collected. RESULTS: All 67 patients underwent fistulectomy. First, we classified the patients into five types based on their anatomic features. Then, we considered four optimized surgical methods and adopted the appropriate method with full consideration of the patient's clinical characteristics. The great majority of cases occurred on the left side of the neck (68.7%) and most commonly presented as either a recurrent low-neck abscess or cutaneous discharging fistula with neck infection. Effective preoperative examination included administering contrast agent prior to a computed tomography (CT) scan and in-office laryngoscopy during the quiescent period of inflammation. Ultrasound was also very helpful in determining the presence of thyroiditis. The mean follow-up duration after excision of the lesion was 25.8 months. To date, only 1 (1.5%) recurrence and no obvious complications have been observed. CONCLUSION: Refining fistula subtypes and adopting corresponding treatment measures can reduce the recurrence rate and improve curative effects. We propose and advocate this treatment algorithm for all third and fourth branchial pouch lesions.

microRNA­183 is involved in the differentiation and regeneration of Notch signaling­prohibited hair cells from mouse cochlea.

Auditory hair cell regeneration following injury is critical to hearing restoration. The Notch signaling pathway participates in the regulation of inner ear development and cell differentiation. Recent evidence suggests that microRNA (miR)­183 has a similar role in the inner ear. However, it is unclear how Notch signaling functions in hair cell regeneration in mammals and if there is cross­talk between Notch signaling and miR­183. The present study used a gentamicin­induced cochlear injury mouse model. Gentamicin­induced damage of the hair cells activated the Notch signaling pathway and downregulated miR­183 expression. Notch signaling inhibition by the γ­secretase inhibitor, 24­diamino­5­phenylthiazole (DAPT), attenuated gentamicin­induced hair cell loss and reversed the downregulation of miR­183 expression. Further investigation revealed that the novel hair cells produced, induced by DAPT, were derived from transdifferentiated supporting cells. Additionally, myosin VI­positive hair cell numbers were increased by Notch signaling inhibition in in vitro experiments with cultured neonatal mouse inner ear precursor cells. This effect was reversed by miR­183 inhibition. These findings indicate that the Notch signaling pathway served a repressing role during the regeneration of hair cells. Inhibiting this signal improved hair cell regeneration in the gentamicin­damaged cochlear model. miR­183 was demonstrated to be involved in hair cell differentiation and regeneration, and was required for the differentiation of the Notch­inhibited hair cells.