Comparison of the variability and diagnostic efficacy of respiratory-gated PET/CT based radiomics features with ungated PET/CT in lung lesions.

OBJECTIVES: To investigate the variability and diagnostic efficacy of respiratory-gated (RG) PET/CT based radiomics features compared to ungated (UG) PET/CT in the differentiation of non-small cell lung cancer (NSCLC) and benign lesions. METHODS: 117 patients with suspected lung lesions from March 2020 to May 2021 and consent to undergo UG PET/CT and chest RG PET/CT (including phase-based quiescent period gating, pQPG and phase-matched 4D PET/CT, 4DRG) were prospectively included. 377 radiomics features were extracted from PET images of each scan. Paired t test was used to compare UG and RG features for inter-scan variability analysis. We developed three radiomics models with UG and RG features (i.e. UGModel, pQPGModel and 4DRGModel). ROC curves were used to compare diagnostic efficiencies, and the model-level comparison of diagnostic value was performed by five-fold cross-validation. A P value < 0.05 was considered as statistically significant. RESULTS: A total of 111 patients (average age ± standard deviation was 59.1 ± 11.6 y, range, 29 - 88 y, and 63 were males) with 209 lung lesions were analyzed for features variability and the subgroup of 126 non-metastasis lesions in 91 patients without treatment before PET/CT were included for diagnosis analysis. 101/377 (26.8 %) 4DRG features and 82/377 (21.8 %) pQPG features showed significant difference compared to UG features (both P<0.05). 61/377 (16.2 %) and 59/377 (15.6 %) of them showed significantly better discriminant ability (ΔAUC% (i.e. (AUCRG - AUCUG) / AUCUG×100 %) > 0 and P<0.05) in malignant recognition, respectively. For the model-level comparison, 4DRGModel achieved the highest diagnostic efficacy (sen 73.2 %, spe 87.3 %) compared with UGModel (sen 57.7 %, spe 76.4 %) and pQPGModel (sen 63.4 %, spe 81.8 %). CONCLUSION: RG PET/CT performs better in the quantitative assessment of metabolic heterogeneity for lung lesions and the subsequent diagnosis in patients with NSCLC compared with UG PET/CT.

Construction of Magnesium Phosphate Chemical Conversion Coatings with Different Microstructures on Titanium to Enhance Osteogenesis and Angiogenesis.

Titanium (Ti) and its alloys are widely used as hard tissue substitutes in dentistry and orthopedics, but their low bioactivity leads to undesirable osseointegration defects in the early osteogenic phase. Surface modification is an important approach to overcome these problems. In the present study, novel magnesium phosphate (MgP) coatings with controllable structures were fabricated on the surface of Ti using the phosphate chemical conversion (PCC) method. The effects of the microstructure on the physicochemical and biological properties of the coatings on Ti were researched. The results indicated that accelerators in PCC solution were important factors affecting the microstructure and properties of the MgP coatings. In addition, the coated Ti exhibited excellent hydrophilicity, high bonding strength, and good corrosion resistance. Moreover, the biological results showed that the MgP coatings could improve the spread, proliferation, and osteogenic differentiation of mouse osteoblast cells (MC3T3-E1) and vascular differentiation of human umbilical vein endothelial cells (HUVECs), indicating that the coated Ti samples had a great effect on promoting osteogenesis and angiogenesis. Overall, this study provided a new research idea for the surface modification of conventional Ti to enhance osteogenesis and angiogenesis in different bone types for potential biomedical applications.

Fabrication and properties of hydroxyapatite/chitosan composite scaffolds loaded with periostin for bone regeneration.

This paper reports a facile fabrication method of hydroxyapatite/chitosan (HAp/CS) composite scaffold with 3D porous structure without using any chemical cross-linkers. The HAp particles had an urchin-like hollow microstructure and high surface area, which was uniformly dispersed into the pore walls of the HAp/CS scaffold. The addition of HAp can efficiently enhance the mechanical properties and bioactivity of the HAp/CS scaffold. Moreover, periostin was successfully loaded onto the HAp/CS scaffold. When applied to the repair of bone defect in a rat mandibular model, the HAp/CS scaffold loaded with periostin can enhance osteointegration and accelerate bone regeneration. Our research combines periostin with the HAp/CS composite material, which provides a novel strategy to improve bone regeneration and has great application prospect in bone repair fields.

Enhanced photocatalysis of metal/covalent organic frameworks by plasmonic nanoparticles and homo/hetero-junctions.

Metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) have garnered attention in photocatalysis due to their unique features including extensive surface area, adjustable pores, and the ability to incorporate various functional groups. However, challenges such as limited visible light absorption and rapid electron-hole recombination often hinder their photocatalytic efficiency. Recent developments have introduced plasmonic nanoparticles (NPs) and junctions to enhance the photocatalytic performance of MOFs/COFs. This paper provides a comprehensive review of recent advancements in MOF/COF-based photocatalysts improved by integration of plasmonic NPs and junctions. We begin by examining the utilization of plasmonic NPs, known for absorbing longer-wavelength light compared to typical MOFs/COFs. These NPs exhibit localized surface plasmon resonance (LSPR) when excited, effectively enhancing the photocatalytic performance of MOFs/COFs. Moreover, we discuss the role of homo/hetero-junctions in facilitating charge separation, further boosting the photocatalytic performance of MOFs/COFs. The mechanisms behind the improved photocatalytic performance of these composites are discussed, along with an assessment of challenges and opportunities in the field, guiding future research directions.

An Iterative Scale Purification Procedure on lz for the Detection of Aberrant Responses.

Many person-fit statistics have been proposed to detect aberrant response behaviors (e.g., cheating, guessing). Among them, lz is one of the most widely used indices. The computation of lz assumes the item and person parameters are known. In reality, they often have to be estimated from data. The better the estimation, the better lz will perform. When aberrant behaviors occur, the person and item parameter estimations are inaccurate, which in turn degrade the performance of lz. In this study, an iterative procedure was developed to attain more accurate person parameter estimates for improved performance of lz. A series of simulations were conducted to evaluate the iterative procedure under two conditions of item parameters, known and unknown, and three aberrant response styles of difficulty-sharing cheating, random-sharing cheating, and random guessing. The results demonstrated the superiority of the iterative procedure over the non-iterative one in maintaining control of Type-I error rates and improving the power of detecting aberrant responses. The proposed procedure was applied to a high-stake intelligence test.

Buccal plate preservation with immediate post-extraction implant placement and provisionalization in anterior maxillary tooth: Preliminary results of a new technique using Teruplug collagen.

BACKGROUND: Bone resorption and remodelling are inevitable results of dental extraction and begin immediately after the extraction procedure. The buccal plate is especially predisposed to these phenomena, and if affected, may result in an increased risk of facial soft-tissue recession and other adverse clinical effects that may decrease the predictability of implant placement or impair the final aesthetic result. PERPOSE: The application of Teruplug collagen to prevent buccal plate resorption technique is a new technique aimed at maintaining or improving the appearance of the soft and hard tissues after dental extraction procedures. METHODS: All patients underwent teeth extraction and buccal plate preservation followed by immediate implant placement and provisionalisation using Teruplug collagen. The distance from the external surface of the labial bone to the buccal surface of the implant was measured immediately after placement 6 months and 12 months using computed tomography(CT) images. The aesthetic outcome of 35 implant supported dentures was evaluated by the pink aesthetic score (PAS). Patient aesthetic satisfaction was investigated by a visual analogue scale (VAS). RESULTS: In a four-wall intact socket, this approach is aimed at optimising the ability of the Teruplug collagen to improve regeneration and maintain or improve labial/buccal contours without interfering with the natural healing capability of the alveolus after extraction and implant placement. During the different observation period, there were no major biologic or prosthodontic complications as determined by a clinical examination at each follow-up visit. CONCLUSIONS: Buccal plate preservation as described may help to maintain or improve the appearance and contours of the ridge after tooth extraction, laying the groundwork for optimal functional and aesthetic replacement of the missing tooth with an implant-supported prosthesis.

An analysis of Chinese nursing electronic medical records to predict violence in psychiatric inpatients using text mining and machine learning techniques.

BACKGROUND: The prevalence of violence in acute psychiatric wards is a critical concern. According to a meta-analysis investigating violence in psychiatric inpatient units, researchers estimated that approximately 17% of inpatients commit one or more acts of violence during their stay. Inpatient violence negatively affects health-care providers and patients and may contribute to high staff turnover. Therefore, predicting which psychiatric inpatients will commit violence is of considerable clinical significance. OBJECTIVE: The present study aimed to estimate the violence rate for psychiatric inpatients and establish a predictive model for violence in psychiatric inpatients. METHODS: We collected the structured and unstructured data from Chinese nursing electronic medical records (EMRs) for the violence prediction. The data was obtained from the psychiatry department of a regional hospital in southern Taiwan, covering the period between January 2008 and December 2018. Several text mining and machine learning techniques were employed to analyze the data. RESULTS: The results demonstrated that the rate of violence in psychiatric inpatients is 19.7%. The patients with violence in psychiatric wards were generally younger, had a more violent history, and were more likely to be unmarried. Furthermore, our study supported the feasibility of predicting aggressive incidents in psychiatric wards by using nursing EMRs and the proposed method can be incorporated into routine clinical practice to enable early prediction of inpatient violence. CONCLUSIONS: Our findings may provide clinicians with a new basis for judgment of the risk of violence in psychiatric wards.

Redox-Bipolar Polyimide Two-Dimensional Covalent Organic Framework Cathodes for Durable Aluminium Batteries.

Emerging rechargeable aluminium batteries (RABs) offer a sustainable option for next-generation energy storage technologies with low cost and exemplary safety. However, the development of RABs is restricted by the limited availability of high-performance cathode materials. Herein, we report two polyimide two-dimensional covalent organic frameworks (2D-COFs) cathodes with redox-bipolar capability in RAB. The optimal 2D-COF electrode achieves a high specific capacity of 132 mAh g-1 . Notably, the electrode presents long-term cycling stability (with a negligible ≈0.0007 % capacity decay per cycle), outperforming early reported organic RAB cathodes. 2D-COFs integrate n-type imide and p-type triazine active centres into the periodic porous polymer skeleton. With multiple characterizations, we elucidate the unique Faradaic reaction of the 2D-COF electrode, which involves AlCl2+ and AlCl4 - dual-ions as charge carriers. This work paves the avenue toward novel organic cathodes in RABs.

OTUB1 Catalytic-Independently Deubiquitinates TGFBI and Mediates the Angiogenesis in Infantile Hemangioma by Regulating Glycolysis.

BACKGROUND: Infantile hemangioma (IH) arises as a result of dysregulation of both angiogenesis and vasculogenesis. The deubiquitylase OTUB1 (OTU domain, ubiquitin aldehyde binding 1) has been reported to play an essential role in multiple cancers; however, its function in the progression of IH and the underlying mechanisms regulating angiogenesis remain unclear. METHODS: Transwell assays, EdU assays, and tube formation assays were performed to investigate the biological behavior of IH in vitro. IH animal models were established to estimate the progression of IH in vivo. Mass spectrometric analysis were conducted to detect the downstream of OTUB1 and ubiquitination sites of transforming growth factor beta induced (TGFBI). Half-life assays and ubiquitination test were performed to investigate the interaction between TGFBI and OTUB1. Extracellular acidification rate assays were employed to estimate the glycolysis level in IH. RESULTS: The expression of OTUB1 was obviously increased in proliferating IH as compared to the involuting and involuted IH tissues. Through in vitro experiments, the knockdown of OTUB1 inhibited the proliferation, migration and tube formation of human hemangioma endothelial cells, while the overexpression of OTUB1 promoted the proliferation, migration and angiogenic abilities of human hemangioma endothelial cells. The knockdown of OTUB1 significantly suppressed IH progression in vivo. Furthermore, TGFBI was predicted as a functional downstream target of OTUB1 in IH by mass spectrometry. Mechanistically, OTUB1 interacted with and deubiquitylated TGFBI on the K22 and K25 residues, which was demonstrated to be independent of the catalytic activity of OTUB1. The inhibitory effects of OTUB1 knockdown on cell proliferation, migration and tube formation ability of human hemangioma endothelial cells were reversed by TGFBI overexpression. Further, we found that OTUB1 mediated glycolysis by regulating TGFBI in infantile hemangioma. CONCLUSIONS: OTUB1 deubiquitinates TGFBI in a catalytic-independent manner and promotes angiogenesis in infantile hemangioma by regulating glycolysis. Targeting OTUB1 might be an effective therapeutic strategy for inhibiting IH progression and tumor angiogenesis.

Silver nanoparticle enhanced metal-organic matrix with interface-engineering for efficient photocatalytic hydrogen evolution.

Integrating plasmonic nanoparticles into the photoactive metal-organic matrix is highly desirable due to the plasmonic near field enhancement, complementary light absorption, and accelerated separation of photogenerated charge carriers at the junction interface. The construction of a well-defined, intimate interface is vital for efficient charge carrier separation, however, it remains a challenge in synthesis. Here we synthesize a junction bearing intimate interface, composed of plasmonic Ag nanoparticles and matrix with silver node via a facile one-step approach. The plasmonic effect of Ag nanoparticles on the matrix is visualized through electron energy loss mapping. Moreover, charge carrier transfer from the plasmonic nanoparticles to the matrix is verified through ultrafast transient absorption spectroscopy and in-situ photoelectron spectroscopy. The system delivers highly efficient visible-light photocatalytic H2 generation, surpassing most reported metal-organic framework-based photocatalytic systems. This work sheds light on effective electronic and energy bridging between plasmonic nanoparticles and organic semiconductors.

An end-to-end multi-task system of automatic lesion detection and anatomical localization in whole-body bone scintigraphy by deep learning.

SUMMARY: Limited by spatial resolution and visual contrast, bone scintigraphy interpretation is susceptible to subjective factors, which considerably affects the accuracy and repeatability of lesion detection and anatomical localization. In this work, we design and implement an end-to-end multi-task deep learning model to perform automatic lesion detection and anatomical localization in whole-body bone scintigraphy. A total of 617 whole-body bone scintigraphy cases including anterior and posterior views were retrospectively analyzed. The proposed semi-supervised model consists of two task flows. The first one, the lesion segmentation flow, received image patches and was trained in a supervised way. The other one, skeleton segmentation flow, was trained on as few as five labeled images in conjunction with the multi-atlas approach, in a semi-supervised way. The two flows joint in their encoder layers so each flow can capture more generalized distribution of the sample space and extract more abstract deep features. The experimental results show that the architecture achieved the highest precision in the finest bone segmentation task in both anterior and posterior images of whole-body scintigraphy. Such an end-to-end approach with very few manual annotation requirement would be suitable for algorithm deployment. Moreover, the proposed approach reliably balances unsupervised labels construction and supervised learning, providing useful insight for weakly labeled image analysis. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Prognosis of adenoid cystic carcinoma in head and neck region treated with different regimens-A single-centre study.

BACKGROUND: No study has evaluated the impact of regimen on recurrence, metastasis and survival in patients with adenoid cystic carcinoma (ACC). The present study aimed to compare the efficacy of radioactive seed implantation and other regimens in treating ACC, so as to investigate the clinical applicability of radioactive seed implantation and determine the indications for this regimen. METHODS: A total of 188 patients with ACC in oromaxillofacial region were allocated to four groups according to the treatment regimen: group 1 was treated with a combination of surgery and 125 I seed therapy, group 2 with a combination of surgery and external radiotherapy, group 3 with surgery, whereas group 4 was untreated. The Kaplan-Meier method was used to assess the survival rates, and the Cox regression analyses were used to identify the associated prognostic factors. RESULTS: The overall survival rates of 188 patients and groups 1, 2, 3 and 4 were 85.7%, 75%, 68.2% and 37.5%, respectively. Cox regression analysis revealed that age, T stage, N stage and regimen were independent prognostic factors of survival. Amongst patients with primary ACC, the efficacy of radioactive seed implantation was higher in those with perineural invasion than in those without. CONCLUSION: Patient age, T stage, N stage and regimen are independent prognostic factors of survival in patients with ACC. Patients treated with surgery combined with postoperative 125 I seed radiotherapy have a higher overall survival rate, and those with perineural invasion are more suitable for radioactive seed implantation therapy.

Shikonin reverses pyruvate kinase isoform M2-mediated propranolol resistance in infantile hemangioma through reactive oxygen species-induced autophagic dysfunction.

Infantile hemangioma (IH) is the most common benign tumor in infancy. Propranolol, a nonselective ß-adrenergic receptor blocker, is now the first-line therapy for IH. Recently, low sensitivity to propranolol therapy has become one major reason for the failure of IH treatment. However, the exact underlying mechanisms are yet to be fully elucidated. Here, we reported that pyruvate kinase isoform M2 (PKM2), an essential glycolytic enzyme, played a critical role in regulating the progression of IH and the therapeutic resistance of propranolol treatment. Shikonin reversed the propranolol resistance in hemangioma-derived endothelial cells and in hemangioma animal models. Moreover, shikonin combined with propranolol could induce excessive reactive oxygen species (ROS) accumulation and lead to autophagic dysfunction, which is essential for the enhanced therapeutic sensitivity of propranolol treatment. Taken together, our results indicated that PKM2 has a significant role in hemangiomas progression and therapeutic resistance; it could be a safe and effective therapeutic strategy for those hemangiomas with poor propranolol sensitivity combined with shikonin.

Dynamic FDG-PET imaging for differentiating metastatic from non-metastatic lymph nodes of lung cancer.

Objectives: 18F-fluorodeoxyglucose (FDG) PET/CT has been widely used in tumor diagnosis, staging, and response evaluation. To determine an optimal therapeutic strategy for lung cancer patients, accurate staging is essential. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may fail to differentiate between benign and malignant lesions. Lymph nodes (LNs) in the mediastinal and pulmonary hilar regions with high FDG uptake due to granulomatous lesions such as tuberculosis, which has a high prevalence in China, pose a diagnostic challenge. This study aims to evaluate the diagnostic value of the quantitative metabolic parameters derived from dynamic 18F-FDG PET/CT in differentiating metastatic and non-metastatic LNs in lung cancer. Methods: One hundred and eight patients with pulmonary nodules were enrolled to perform 18F-FDG PET/CT dynamic + static imaging with informed consent. One hundred and thirty-five LNs in 29 lung cancer patients were confirmed by pathology. Static image analysis parameters including LN-SUVmax, LN-SUVmax/primary tumor SUVmax (LN-SUVmax/PT-SUVmax), mediastinal blood pool SUVmax (MBP-SUVmax), LN-SUVmax/MBP-SUVmax, and LN-SUVmax/short diameter. Quantitative parameters including K1, k2, k3 and Ki and of each LN were obtained by applying the irreversible two-tissue compartment model using in-house Matlab software. Ki/K1 was computed subsequently as a separate marker. We further divided the LNs into mediastinal LNs (N=82) and pulmonary hilar LNs (N=53). Wilcoxon rank-sum test or Independent-samples T-test and receiver-operating characteristic (ROC) analysis was performed on each parameter to compare the diagnostic efficacy in differentiating lymph node metastases from inflammatory uptake. P<0.05 were considered statistically significant. Results: Among the 135 FDG-avid LNs confirmed by pathology, 49 LNs were non-metastatic, and 86 LNs were metastatic. LN-SUVmax, MBP-SUVmax, LN-SUVmax/MBP-SUVmax, and LN-SUVmax/short diameter couldn't well differentiate metastatic from non-metastatic LNs (P>0.05). However, LN-SUVmax/PT-SUVmax have good performance in the differential diagnosis of non-metastatic and metastatic LNs (P=0.039). Dynamic metabolic parameters in addition to k3, the parameters including K1, k2, Ki, and Ki/K1, on the other hand, have good performance in the differential diagnosis of metastatic and non-metastatic LNs (P=0.045, P=0.001, P=0.001, P=0.001, respectively). For ROC analysis, the metabolic parameters Ki (AUC of 0.672 [0.579-0.765], sensitivity 0.395, specificity 0.918) and Ki/K1 (AUC of 0.673 [0.580-0.767], sensitivity 0.570, specificity 0.776) have good performance in the differential diagnosis of metastatic from non-metastatic LNs than SUVmax (AUC of 0.596 [0.498-0.696], sensitivity 0.826, specificity 0.388), included the mediastinal region and pulmonary hilar region. Conclusion: Compared with SUVmax, quantitative parameters such as K1, k2, Ki and Ki/K1 showed promising results for differentiation of metastatic and non-metastatic LNs with high uptake. The Ki and Ki/K1 had a high differential diagnostic value both in the mediastinal region and pulmonary hilar region.

Real-time optical imaging of the hypoxic status in hemangioma endothelial cells during propranolol therapy.

Infantile hemangioma (IH) is the most common microvascular tumor of infancy involving the area of head and neck. One of the most important independent risk factors of IH is the hypoxia microenvironment. Fluorescent chemosensor provides a noninvasive intervention, high spatiotemporal resolution, ultrasensitive response, and real-time feedback approach to reveal the hypoxic status of cells. Our research group developed an ultrasensitive fluorescent chemosensor, HNT-NTR, and investigated the potential ability of imaging the hypoxic status of hemangioma-derived endothelial cells (HemECs). In this study, we successfully visualized the propranolol (PRN) treatment in HemECs using NHT-NTR with "Turn-off" sensing method. This chemosensor exhibited high sensitivity and selectivity for optical imaging of hypoxic status with fast responsiveness, real-time feedback and durable photostability of the fluorescent signal. It was also confirmed that HNT-NTR could monitor nitroreductase in vivo. Paramountly, we expected this chemosensor to offer an available optical method for imaging of the hypoxic status and visualizing the therapeutic status of PRN therapy in IH with the hypoxia-imaging capability.

An oxidative stress-related prognostic signature for indicating the immune status of oral squamous cell carcinoma and guiding clinical treatment.

Oral squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide and presents high mortality. Oxidative stress, caused by reactive oxygen species accumulation, plays a crucial role in tumorigenesis, cancer progression, and drug resistance. Nevertheless, the specific prognostic and clinical values of oxidative stress-related genes (OSGs) in OSCC remain unclear. Here, we developed an oxidative stress-related prognostic signature according to mRNA expression data from The Cancer Genome Atlas (TCGA) database and evaluated its connections with the prognosis, clinical features, immune status, immunotherapy, and drug sensitivity of OSCC through a series of bioinformatics analyses. Finally, we filtered out six prognostic OSGs to construct a prognostic signature. On the basis of both TCGA-OSCC and GSE41613 cohorts, the signature was proven to be an independent prognostic factor with high accuracy and was confirmed to be an impactful indicator for predicting the prognosis and immune status of patients with OSCC. Additionally, we found that patients with high-risk scores may obtain greater benefit from immune checkpoint therapy compared to those with low-risk scores, and the risk score presented a close interaction with the tumor microenvironment and chemotherapy sensitivity. The prognostic signature may provide a valid and robust predictive tool that could predict the prognosis and immune status and guide clinicians to develop personalized therapeutic strategies for patients with OSCC.

A disease-associated missense mutation in CYP4F3 affects the metabolism of leukotriene B4 via disruption of electron transfer.

BACKGROUND: Cytochrome P450 4F3 (CYP4F3) is an ω-hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26-year-old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation-related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. METHODS: Whole exome sequencing was performed and validated; flow cytometry and enzyme-linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co-immunoprecipitation, western blot, and enzyme-linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. RESULTS: We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P < 0.0001), leading to reduced metabolization of the pro-inflammatory LTB4. Systemic LTB4 levels (1034.0 ± 75.9 pg/mL) are significantly increased compared with healthy subjects (305.6 ± 57.0 pg/mL, P < 0.001), and immune phenotyping shows increased total CD19+ CD27- naive B cells (25%) and decreased total CD19+ CD27+ IgD- switched memory B cells (19%). The mutant CYP4F3 protein is stable and binding with its electron donors POR and Cytb5 is unaffected (P > 0.9 for both co-immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α-helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P < 0.0001), while montelukast and fluticasone do not (99% and 114% of control, respectively). CONCLUSIONS: A point mutation in the catalytic domain of CYP4F3 is associated with high leukotriene B4 plasma levels and features of a more naive adaptive immune response. Our data provide evidence for the pathogenicity of the CYP4F3 variant as a cause for the observed clinical features in the patient. Inhibitors of the LTB4 pathway such as zileuton show promising effects in blocking LTB4 production and might be used as a future treatment strategy.

The anti-tumor effect of proteasome inhibitor MG132 for human adenoid cystic carcinoma: correlate with the emerging role of Nrf2/Keap1 signaling pathway.

BACKGROUND: Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. Moreover, the unique biological characteristics and complex structures of ACC contribute to its poor survival rates. Recently, proteasome inhibitors have been shown to elicit satisfactory therapeutic effects in the treatment of certain solid tumors, but few studies have been implemented to investigate the effects of proteasome inhibitor therapy for ACC. METHODS: In this present study, cell counting kit-8 assay and flow cytometry assay were performed to examine the effects of proteasome inhibitor (MG132) on cell viability and apoptosis. We applied western blot and immunofluorescence staining to explore the expression of the Nrf2/Keap1 signaling pathway and P62, additionally Nrf2 inhibitor (ML385) was utilized to evaluate the role of Nrf2/Keap1 signaling pathway in MG132-induced cell apoptosis. RESULTS: Our data indicated that MG132 significantly suppressed the growth of ACC-83 cells(MG132 10µM P = 0.0046; 40µM P = 0.0033; 70µM P = 0.0007 versus control) and induced apoptosis (MG132 10µM P = 0.0458; 40µM P = 0.0018; 70µM P = 0.0087 versus control). The application of MG132 induced the up-regulation of Nrf2/Keap1 signaling pathway. Furthermore, inhibition of Nrf2 attenuated the therapeutic effects of MG132 for ACC (both ML385 + MG132 10µM P = 0.0013; 40µM P = 0.0057; 70µM P = 0.0003 versus MG132). P < 0.05 was considered statistically significant. CONCLUSIONS: Our results revealed that proteasome inhibitors MG132 could inhibit the cell viability and induce the apoptosis of ACC through Nrf2/Keap1 signaling pathway.

Ultra-sensitive responsive near-infrared fluorescent nitroreductase probe with strong specificity for imaging tumor and detecting the invasiveness of tumor cells.

Hypoxia plays an important role in cancer progression, which is a characteristic feature of the tumor micro-environment and reflects the invasiveness of tumor cells. Nitroreductase (NTR) is overexpressed in hypoxic tumors, which making it an efficient target for detecting the hypoxic state in tumor. In this work, a new type of nitro-based fluorescent probe, named HNT-NTR, has been proposed, HNT-NTR could detect specifically and rapidly the NTR degree, which reflects the level of hypoxia in bidimensional (2D) tumor cells, three-dimensional (3D) tumor spheres and even the real tumors in vivo without biological toxicity. Most importantly, according to the research, HNT-NTR even could distinguish tumor cells from other normal cells in vivo and reflect the invasiveness of tumor cells by the near-infrared fluorescence intensity, which provides a new way of clinical pathologic diagnosis. All in all, HNT-NTR not only is proven to be an ideal probe for detecting solid tumors in vivo, but also has great potential to distinguish if cells are benign or malignant and even guide therapeutic applications in the clinic.

A Ferroptosis-Related Gene Signature for Predicting the Prognosis and Drug Sensitivity of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and has a high mortality. Ferroptosis, an iron-dependent form of programmed cell death, plays a crucial role in tumor suppression and chemotherapy resistance in cancer. However, the prognostic and clinical values of ferroptosis-related genes (FRGs) in HNSCC remain to be further explored. In the current study, we constructed a ferroptosis-related prognostic model based on the Cancer Genome Atlas database and then explored its prognostic and clinical values in HNSCC via a series of bioinformatics analyses. As a result, we built a four-gene prognostic signature, including FTH1, BNIP3, TRIB3, and SLC2A3. Survival analysis showed that the high-risk group presented significantly poorer overall survival than the low-risk group. Moreover, the ferroptosis-related signature was found to be an independent prognostic predictor with high accuracy in survival prediction for HNSCC. According to immunity analyses, we found that the low-risk group had higher anti-tumor immune infiltration cells and higher expression of immune checkpoint molecules and meanwhile corelated more closely with some anti-tumor immune functions. Meanwhile, all the above results were validated in the independent HSNCC cohort GSE65858. Besides, the signature was found to be remarkably correlated with sensitivity of common chemotherapy drugs for HNSCC patients and the expression levels of signature genes were also significantly associated with drug sensitivity to cancer cells. Overall, we built an effective ferroptosis-related prognostic signature, which could predict the prognosis and help clinicians to perform individualized treatment strategy for HNSCC patients.