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BACKGROUND: Blood loss is an important consideration in metastatic spine tumour surgery (MSTS). Allogeneic blood transfusion (ABT) is the current standard of blood replenishment for MSTS despite known complications. Salvaged blood transfusion (SBT) through intraoperative cell salvage addresses the majority of complications related to ABT. However, the use of SBT in MSTS still remains controversial. We aim to conduct a prospective propensity-score (PS) matched analysis to evaluate the long-term clinical outcomes of intraoperative cell salvage (IOCS) in MSTS. METHODS: Our study included 98 patients who underwent MSTS from 2014-2017. A PS matched cohort was created using the relevant and available predictors of treatment assignment and outcomes of interest. Clinical outcomes consisting of overall survival (OS), as well tumour progression (TP) that was evaluated using RECIST (v1.1) were compared in the matched cohort. RESULTS: Our study had a total of 98 patients with a mean age of 60 years old. A total of 33 patients received SBT. Overall median blood loss was 600 mL [interquartile range (IQR): 300-1,000 mL] and overall median blood transfusion (BT) was 620 mL (IQR: 110-1,600 mL). Group PS matching included 30 patients who received ABT and 28 patients who received SBT. There was also no significant difference between the OS of patients who underwent ABT or SBT (P=0.19). SBT did not show any significant increase in 4-year tumour progression [PS matched hazard ratio (HR) 3.659; 95% confidence interval (CI): 0.346-38.7; P=0.28]. CONCLUSIONS: SBT has been shown to have similar clinical outcomes to that of ABT in patients undergoing MSTS, with potential benefits of avoiding complications and costs of ABT. This will be the first long-term PS matched analysis to report on the clinical outcomes of SBT and affirms the clinical role of SBT in MSTS today.

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BACKGROUND: Metastatic spine tumour surgery (MSTS) is an important treatment modality of metastatic spinal disease (MSD). Open spine surgery (OSS) was previously the gold standard of treatment. However, advancements in MSTS in recent years has resulted in a current paradigm shift towards today's gold standard of minimally invasive spinal surgery (MISS) and early adjuvant RT in treating MSD patients. Nonetheless, there are still certain situations whereby MISS is not desirable or even suitable. There has also yet to be any literature describing the considerations for not using MISS in MSD in today's clinical context. We aim to bridge the gap where OSS should be considered with caution and highlight situations where MISS is preferable using the available literature and personal experience. METHODS: This narrative review was conducted using PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), The Cochrane Library and Scopus databases through August 31, 2023. Inclusion criteria for the review were studies with discussion on the type of surgery in MSTS. RESULTS: A total of 52 studies were included in this review. We discussed various advantages and situations appropriate for MISS for MSD in today's clinical context. Nonetheless, there are still various unique circumstances in which MISS may be less suitable. MISS is less feasible in patients of paediatric profile, having short stature or having had previous surgery at the level of operation. Occipitocervical and cervicothoracic location of vertebrae metastasis also makes MISS less feasible due to access and imaging difficulty. MISS for tumours which are hypersclerotic and hypervascular can also result in more difficulty for cannulation of MISS probes as well as control of bleeding respectively, and hence will be less encouraged in the above settings. CONCLUSIONS: Our review will be the first to discuss circumstances in which MISS is less applicable, despite the advantages it may confer over traditional OSS. MSTS should be individualized to the patient, depending on the experience of the surgeon. OSS is still a time-tested approach that holds weight in MSTS and should be readily utilized depending on the clinical situation.

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BACKGROUND: Delayed treatment in symptomatic metastatic epidural spinal cord compression (MESCC) is significantly associated with poorer functional outcomes. In this study, we aim to identify the patterns of treatment delay in patients and factors predictive of postoperative ambulatory function. METHODS: Retrospective review of patients with symptomatic MESCC treated surgically between January 2015 and January 2022. MESCC symptoms were categorized into symptoms suggesting cord compression requiring immediate referral and symptoms suggestive of spinal metastases. Multivariate analysis was performed to identify factors predictive of postoperative ambulatory function. Delays in treatment were identified and categorized into patient delay (onset of symptoms till initial medical consultation), diagnostic delay (medical consultation till radiological diagnosis of MESCC), referral delay (from diagnosis till spine surgeon review) and surgical delay (from spine surgeon review till surgery) and compared between patients. RESULTS: One hundred and seventy-eight patients were identified. In this cohort 92 (52.0%) patients were able to ambulate independently, and 86 (48.3%) patients were non independent. One hundred and thirty-nine (78.1%) of patients had symptoms of cord compression and 93 (52.3%) had neurological deficits on presentation. On multivariate analysis, pre-operative neurological deficits (P=0.01) and symptoms of cord compression (P=0.01) were significantly associated with post-operative ambulatory function. Mean total delay was 66 days, patient delay was 41 days, diagnostic delay was 16 days, referral delay was 3 days and surgical delay was 6 days. In patients with neurological deficits, there was a significant decrease in all forms of treatment delay (P<0.05). There was no significant decrease in patient delay, diagnostic delay and referral delay in patients with symptoms of cord compression. CONCLUSIONS: Both patients and physicians understand the need for urgent surgical treatment of MESCC with neurological deficits, however there is still a need for increased education and recognition of the symptoms of MESCC.

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BACKGROUND: Survival prognostication plays a key role in the decision-making process for the surgical treatment of patients with spinal metastases. In the past traditional scoring systems such as the modified Tokuhashi and Tomita scoring systems have been used extensively, however in recent years their accuracy has been called into question. This has led to the development of machine learning algorithms to predict survival. In this study, we aim to compare the accuracy of prognostic scoring systems in a surgically treated cohort of patients. METHODS: This is a retrospective review of 318 surgically treated spinal metastases patients between 2009 and 2021. The primary outcome measured was survival from the time of diagnosis. Predicted survival at 3 months, 6 months and 1 year based on the prognostic scoring system was compared to actual survival. Predictive values of each scoring system were measured via area under receiver operating characteristic curves (AUROC). The following scoring systems were compared, Modified Tokuhashi (MT), Tomita (T), Modified Bauer (MB), Van Den Linden (VDL), Oswestry (O), New England Spinal Metastases score (NESMS), Global Spine Study Tumor Group (GSTSG) and Skeletal Oncology Research Group (SORG) scoring systems. RESULTS: For predicting 3 months survival, the GSTSG 0.980 (0.949-1.0) and NESM 0.980 (0.949-1.0) had outstanding predictive value, while the SORG 0.837 (0.751-0.923) and O 0.837 (0.775-0.900) had excellent predictive value. While for 6 months survival, only the O 0.819 (0.758-0.880) had excellent predictive value and the GSTSG 0.791(0.725-0.857) had acceptable predictive value. For 1 year survival, the NESM 0.871 (0.822-0.919) had excellent predictive value and the O 0.722 (0.657-0.786) had acceptable predictive value. The MT, T and MB scores had an area under the curve (AUC) of <0.5 for 3-month, 6-month and 1-year survival. CONCLUSIONS: Increasingly, traditional scoring systems such as the MT, T and MB scoring systems have become less predictive. While newer scoring systems such as the GSTSG, NESM and SORG have outstanding to excellent predictive value, there is no one survival scoring system that is able to accurately prognosticate survival at all 3 time points. A multidisciplinary, personalised approach to survival prognostication is needed.

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Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-ß1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-ß1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

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Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their association and function in gene regulation. More recently, IDRs have been shown to promote multivalent protein-protein interactions between coregulators and TFs to drive their association into condensates. By contrast, here we demonstrate how the IDR of the corepressor LSD1 excludes TF association, acting as a dynamic conformational switch that tunes repression of active cis-regulatory elements. Hydrogen-deuterium exchange shows that the LSD1 IDR interconverts between transient open and closed conformational states, the latter of which inhibits partitioning of the protein's structured domains with TF condensates. This autoinhibitory switch controls leukemic differentiation by modulating repression of active cis-regulatory elements bound by LSD1 and master hematopoietic TFs. Together, these studies unveil alternative mechanisms by which disordered regions and their dynamic crosstalk with structured regions can shape coregulator-TF interactions to control cis-regulatory landscapes and cell fate.

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Metropolitan integration development refers to the interconnection between cities and the coordinated development of various aspects such as economy, society, culture, and nature, which is the goal of metropolitan area development. With the Zhengzhou metropolitan area as the research area and based on nighttime light data from 2012 to 2021, we comprehensively used landscape index and landscape morphology spatial pattern analysis methods, systematically evaluated the integration process of the metropolitan area from the perspective of spatial expansion and spatial connection, analyzed the spatiotemporal variations of the landscape pattern of the metropolitan area, and revealed the spatiotemporal expansion and connection patterns of the metropolitan area. The results showed that the area of the Zhengzhou metropolitan area expanded year by year from 2012 to 2021, with the number of landscape patches continuously increasing, showing an agglomeration phenomenon. In the metropolitan area, there was a trend towards stability and multi-directional coordinated growth. The contribution of non-central cities to expansion increased annually, while the expansion patterns of various constituent cities gradually shifted from internal filling to external expansion. The connection scale within the metropolitan area had been expanding annually, with enhanced intercity connections. Intercity connection belts and channels for material and information exchange were emerging, and the integrated network of urban agglomeration connections was gradually forming. Metropolitan integration planning provided positive guidance for the development of metropolitan areas. We should fully leverage the driving effects of metropolitan areas, pay attention to the integration of Zhengzhou-Kaifeng and Zhengzhou-Xuchang, promote the formation of emerging growth poles in Xinxiang and Jiaozuo, as well as regional coordinated development, strengthen the network of policies, economy, transportation, information, etc., and form a diversified and integrated development situation.

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Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1 . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) 2 , the most common embryonal brain tumor in children, and pineoblastoma 3 . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST 4 . However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.

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UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1 to promote the degradation of select HDAC1/2 corepressor complexes. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy (cryo-EM) analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an unexpected asymmetric assembly, in which a single UM171 molecule enables a pair of KBTBD4 KELCH-repeat propeller domains to recruit HDAC1 by clamping on its catalytic domain. One of the KBTBD4 propellers partially masks the rim of the HDAC1 active site pocket, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a separate and distinct interface. The overall neomorphic interaction is further buttressed by an endogenous cofactor of HDAC1-CoREST, inositol hexakisphosphate, which makes direct contacts with KBTBD4 and acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces defined by cryo-EM is demonstrated by in situ base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, our results reveal how the cooperativity offered by a large dimeric CRL E3 family can be leveraged by a small molecule degrader and establish for the first time a dual molecular glue paradigm.

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Purpose: A variety of instabilities are grouped under multidirectional instability (MDI) of the shoulder. This makes understanding its diagnostic process, presentation and treatment difficult due to lack of evidence-based consensus. This review aims to propose a novel classification for subtypes of MDI. Methods: A systematic search was performed on PubMed Medline and Embase. A combination of the following 'MeSH' and 'non-MesH' search terms were used: (1) Glenohumeral joint[tiab] OR Glenohumeral[tiab] OR Shoulder[tiab] OR Shoulder joint[tiab] OR Shoulder[MeSH] OR Shoulder joint[MeSH], (2) Multidirectional[tiab], (3) Instability[tiab] OR Joint instability[MeSH]. Sixty-eight publications which met our criteria were included. Results: There was a high degree of heterogeneity in the definition of MDI. Thirty-one studies (46%) included a trauma etiology in the definition, while 23 studies (34%) did not. Twenty-five studies (37%) excluded patients with labral or bony injuries. Only 15 (22%) studies defined MDI as a global instability (instability in all directions), while 28 (41%) studies considered MDI to be instability in two directions, of which one had to include the inferior direction. Six (9%) studies included the presence of global ligamentous laxity as part of the definition. To improve scientific accuracy, the authors propose a novel AB classification which considers traumatic etiology and the presence of hyperlaxity when subdividing MDI. Conclusion: MDI is defined as symptomatic instability of the shoulder joint in two or more directions. A comprehensive classification system that considers predisposing trauma and the presence of hyperlaxity can provide a more precise assessment of the various existing subtypes of MDI. Level of Evidence: III.

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STUDY DESIGN: Narrative review. OBJECTIVE: The spine is the most common site of metastases, associated with decreased quality of life. Increase in metastatic spine tumour surgery (MSTS) has caused us to focus on the management of blood, as blood loss is a significant morbidity in these patients. However, blood transfusion is also not without its own risks, and hence this led to blood conservation strategies and implementation of a concept of patient blood management (PBM) in clinical practise focusing on these patients. METHODS: A narrative review was conducted and all studies that were related to blood management in metastatic spine disease as well as PBM surrounding this condition were included. RESULTS: A total of 64 studies were included in this review. We discussed a new concept of patient blood management in patients undergoing MSTS, with stratification to pre-operative and intra-operative factors, as well as anaesthesia and surgical considerations. The studies show that PBM and reduction in blood transfusion allows for reduced readmission rates, lower risks associated with blood transfusion, and lower morbidity for patients undergoing MSTS. CONCLUSION: Through this review, we highlight various pre-operative and intra-operative methods in the surgical and anaesthesia domains that can help with PBM. It is an important concept with the significant amount of blood loss expected from MSTS. LEVEL OF EVIDENCE: Not applicable.

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Lung adenocarcinoma (LUAD) remains one of the most aggressive tumors and the efficacy of conventional treatment has been bleak. Nowadays, gene-targeted therapy has become a new favorite in tumor therapy. Herein, we investigated the effect of platelet derived growth factor BB (PDGFBB) on LUAD. Firstly, PDGFBB was upregulated in LUAD patients and closely linked with poor survival. Furthermore, the expression of PDGFBB and PDGFRα/ß in LUAD cells was higher than that in normal lung cells. By loss-of-function with herpes simplex virus (HSV)-PDGFi-shRNA, we found that PDGFBB knockdown caused a significant decrease in proliferation and migration, but evoked apoptosis of LUAD cells in vitro. Conversely, exogenous PDGFBB held adverse effect. Additionally, A549 cells with PDGFBB knockdown had a low probability of tumorigenesis in vivo. Moreover, PDGFBB knockdown restrained the growth of xenografts derived from normal A549 cells. Mechanistically, PDGFBB knockdown suppressed PI3K/AKT and Ras/MAPK signaling, while PDGFBB was the opposite. Therefore, we concluded that PDGFBB might facilitate the tumorigenesis and malignancy of LUAD through its functional downstream nodes-PI3K/AKT and Ras/MAPK signaling, which supported that PDGFBB could serve as a rational therapeutic target for LUAD.

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STUDY DESIGN: Narrative Review. OBJECTIVE: Metastatic spine tumour surgery (MSTS) is an important treatment modality of metastatic spinal disease (MSD). Increase in MSTS has been due to improvements in our oncological treatment, as patients have increased longevity and even those with poorer comorbidities are now being considered for surgery. However, there is currently no guideline on how MSTS surgeons should select the appropriate levels to instrument, and which type of implants should be utilised. METHODS: The current literature on MSTS was reviewed to study implant and construct decision making factors, with a view to write this narrative review. All studies that were related to instrumentation in MSTS were included. RESULTS: A total of 58 studies were included in this review. We discuss novel decision-making models that should be taken into account when planning for surgery in patients undergoing MSTS. These factors include the quality of bone for instrumentation, the extent of the construct required for MSTS patients, the use of cement augmentation and the choice of implant. Various studies have advocated for the use of these modalities and demonstrated better outcomes in MSTS patients when used appropriately. CONCLUSION: We have established a new instrumentation algorithm that should be taken into consideration for patients undergoing MSTS. It serves as an important guide for surgeons treating MSTS, with the continuous evolvement of our treatment capacity in MSD.

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Background: Spinal infections are still showing increased incidence throughout the years as our surgical capabilities increase, coupled with an overall aging population with greater number of chronic comorbidities. The management of spinal infection is of utmost importance, due to high rates of morbidity and mortality, on top of the general difficulty in eradicating spinal infection due to the ease of hematogenous spread in the spine. We aim to summarize the utility of vacuum-assisted closure (VAC) and local drug delivery systems (LDDS) in the management of spinal infections. Methods: A narrative review was conducted. All studies that were related to the use of VAC and LDDS in Spinal Infections were included in the study. Results: A total of 62 studies were included in this review. We discussed the utility of VAC as a tool for the management of wounds requiring secondary closure, as well as how it is increasingly being used after primary closure as prophylaxis for surgical site infections in high-risk wounds of patients undergoing spinal surgery. The role of LDDS in spinal infections was also discussed, with preliminary studies showing good outcomes when patients were treated with various novel LDDS. Conclusions: We have summarized and given our recommendations for the use of VAC and LDDS for spinal infections. A treatment algorithm has also been established, to act as a guide for spine surgeons to follow when tackling various spinal infections in day-to-day clinical practice.

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PURPOSE: To develop a deep learning (DL) model for epidural spinal cord compression (ESCC) on CT, which will aid earlier ESCC diagnosis for less experienced clinicians. METHODS: We retrospectively collected CT and MRI data from adult patients with suspected ESCC at a tertiary referral institute from 2007 till 2020. A total of 183 patients were used for training/validation of the DL model. A separate test set of 40 patients was used for DL model evaluation and comprised 60 staging CT and matched MRI scans performed with an interval of up to 2 months. DL model performance was compared to eight readers: one musculoskeletal radiologist, two body radiologists, one spine surgeon, and four trainee spine surgeons. Diagnostic performance was evaluated using inter-rater agreement, sensitivity, specificity and AUC. RESULTS: Overall, 3115 axial CT slices were assessed. The DL model showed high kappa of 0.872 for normal, low and high-grade ESCC (trichotomous), which was superior compared to a body radiologist (R4, κ = 0.667) and all four trainee spine surgeons (κ range = 0.625-0.838)(all p < 0.001). In addition, for dichotomous normal versus any grade of ESCC detection, the DL model showed high kappa (κ = 0.879), sensitivity (91.82), specificity (92.01) and AUC (0.919), with the latter AUC superior to all readers (AUC range = 0.732-0.859, all p < 0.001). CONCLUSION: A deep learning model for the objective assessment of ESCC on CT had comparable or superior performance to radiologists and spine surgeons. Earlier diagnosis of ESCC on CT could reduce treatment delays, which are associated with poor outcomes, increased costs, and reduced survival.

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Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and cancer codependencies. Here we discover mutations that confer drug addiction to inhibitors of the transcriptional repressor polycomb repressive complex 2 (PRC2) in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Discontinuation of inhibitor treatment leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Exploiting this vulnerability, we show that inhibition of SETD2 similarly induces the spread of H3K27me3 and blocks lymphoma growth. Collectively, our findings demonstrate that constraints on chromatin landscapes can yield biphasic dependencies in epigenetic signaling in cancer cells. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

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Allostery enables dynamic control of protein function. A paradigmatic example is the tightly orchestrated process of DNA methylation maintenance. Despite the fundamental importance of allosteric sites, their identification remains highly challenging. Here, we perform CRISPR scanning on the essential maintenance methylation machinery-DNMT1 and its partner UHRF1-with the activity-based inhibitor decitabine to uncover allosteric mechanisms regulating DNMT1. In contrast to non-covalent DNMT1 inhibition, activity-based selection implicates numerous regions outside the catalytic domain in DNMT1 function. Through computational analyses, we identify putative mutational hotspots in DNMT1 distal from the active site that encompass mutations spanning a multi-domain autoinhibitory interface and the uncharacterized BAH2 domain. We biochemically characterize these mutations as gain-of-function, exhibiting increased DNMT1 activity. Extrapolating our analysis to UHRF1, we discern putative gain-of-function mutations in multiple domains, including key residues across the autoinhibitory TTD-PBR interface. Collectively, our study highlights the utility of activity-based CRISPR scanning for nominating candidate allosteric sites, and more broadly, introduces new analytical tools that further refine the CRISPR scanning framework.

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Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 µmol/L) and inhibitory activity (IC50 = 2.87 µmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.

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Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.

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There has been a growing interest in functional bakery products with enhanced health benefits, especially the prevention of some chronic diseases such as type 2 diabetes, cardiovascular diseases and neurodegenerative disorders. Fortification of wheat flour with phytochemicals, plant components with various bio-activities, is one of the promising approaches to improving public health with the ubiquitous consumption of baked goods. This chapter reviews the current knowledge of several representative phytochemicals, mainly plant polyphenols, including catechins, anthocyanins, fucoidan and quercetin extracted from various plant resources, and their application in bakery products, regarding their stability, impact on product quality and potential health benefits.

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