Laparoscopic liver resection or enucleation for giant hepatic hemangioma: how to choose?

BACKGROUND: Laparoscopic treatment has been increasingly adopted for giant hepatic hemangioma (HH), but the role of liver resection or enucleation remains uncertain. The aim of this study is to compare the laparoscopic resection (LR) with laparoscopic enucleation (LE) for HH, and to provide evidence on how to choose the most suitable approach for HH. METHODS: A retrospective analysis of HH patients underwent laparoscopic treatment between March 2015 and August 2022 was performed. Perioperative outcomes were compared based on the surgical approaches, and risk factors for increased blood loss was calculated by logistic regression analysis. RESULTS: A total of 127 patients in LR group and 287 patients in LE group were enrolled in this study. The median blood loss (300 vs. 200 mL, P < 0.001) was higher in LE group than that in LR group. Independent risk factors for blood loss higher than 400 mL were tumor size ≥ 10 cm, tumor adjacent to major vessels, tumor occupying right liver or caudate lobe, and the portal phase enhancement ratio (PER) ≥ 38.9%, respectively. Subgroup analysis showed that LR was associated with less blood loss (155 vs. 400 mL, P < 0.001) than LE procedure in patients with high PER value. Both LR and LE approaches exhibited similar perioperative outcomes in patients with low PER value. CONCLUSIONS: Laparoscopic treatment for HH could be feasibly and safely performed by both LE and LR. For patients with PER higher than 38.9%, the LR approach is recommended.

Berberine-based self-assembly agents with enhanced synergistic antitumor efficacy.

Tumors are still a major threat to people worldwide. Nanodrug delivery and targeting systems can significantly improve the therapeutic efficacy of chemotherapeutic drugs for antitumor purposes. However, many nanocarriers are likely to exhibit drawbacks such as a complex preparation process, limited drug-loading capacity, untargeted drug release, and toxicity associated with nanocarriers. Therefore, new therapeutic alternatives are urgently needed to develop antitumor drugs. Natural products with abundant scaffold diversity and structural complexity, which are derived from medicinal plants, are important sources of new antitumor drugs. Here, two carrier-free berberine (BBR)-based nanoparticles (NPs) were established to increase the synergistic efficacy of tumor treatment. BBR can interact with glycyrrhetinic acid (GA) and artesunate (ART) to self-assemble BBR-GA and BBR-ART NPs without any nanocarriers, respectively, the formation of which is dominated by electrostatic and hydrophobic interactions. Moreover, BBR-GA NPs could lead to mitochondria-mediated cell apoptosis by regulating mitochondrial fission and dysfunction, while BBR-ART NPs induced ferroptosis in tumor cells. BBR-based NPs have been demonstrated to possess significant tumor targeting and enhanced antitumor properties compared with those of simple monomer mixes both in vitro and in vivo. These carrier-free self-assemblies based on natural products provide a strategy for synergistic drug delivery and thus offer broad prospects for developing enhanced antitumor drugs.

Accumulation of TOX high mobility group box family member 3 promotes the oncogenesis and development of hepatocellular carcinoma through the MAPK signaling pathway.

Microvascular invasion (MVI) has been widely valued in the field of liver surgery because MVI positivity indicates poor prognosis in hepatocellular carcinoma (HCC) patients. However, the potential molecular mechanism underlying the poor prognosis of MVI-positive HCC patients is unclear. Therefore, this study focused on identifying the key genes leading to poor prognosis in patients with a high degree of malignancy of HCC by examining the molecular signaling pathways in MVI-positive HCC patients. Through RNA sequencing, TOX high mobility group box family member 3 (TOX3) was demonstrated to be significantly highly expressed in MVI-positive HCC tissues, which was associated with poor prognosis. The results of in vivo and in vitro showed that TOX3 can promote the oncogenesis and development of HCC by targeting key molecules of the MAPK and EMT signaling pathways. The IP-MS results indicated that proteasome degradation of TOX3 in HCC cells is potentially mediated by a tripartite motif containing 56 (TRIM56, an E3 ligase) in HCC cells. Inhibiting TRIM56 enhances TOX3 protein levels. Overall, our study identified TOX3 as a key gene in the MAPK and EMT signaling pathways in HCC, and its overexpression confers significant proliferation and invasiveness to tumor cells.

A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs.

Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.

Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa.

The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.

Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK-Sirt3 pathway in stress-induced hypertension.

BACKGROUND: Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. METHODS: The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor-α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. RESULTS: The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF-α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α-treated N2a cells. AMPK activator A769662 upregulated AMPK-Sirt3 signaling pathway and consequently reversed TNF-α-induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p-AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. CONCLUSIONS: This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK-Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.

PDZD8-mediated endoplasmic reticulum-mitochondria associations regulate sympathetic drive and blood pressure through the intervention of neuronal mitochondrial homeostasis in stress-induced hypertension.

Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) drives heightened sympathetic nerve activity and contributes to the etiology of stress-induced hypertension (SIH). Maintenance of mitochondrial functions is central to neuronal homeostasis. PDZD8, an endoplasmic reticulum (ER) transmembrane protein, tethers ER to mitochondria. However, the mechanisms of PDZD8-mediated ER-mitochondria associations regulating neuronal mitochondrial functions and thereby mediating blood pressure (BP) in the RVLM of SIH were largely unknown. SIH rats were subjected to intermittent electric foot shocks plus noise for 2 h twice daily for 15 consecutive days. The underlying mechanisms of PDZD8 were investigated through in vitro experiments by using small interfering RNA and through in vivo experiments, such as intra-RVLM microinjection and Western blot analysis. The function of PDZD8 on BP regulation in the RVLM was determined in vivo via the intra-RVLM microinjection of adeno-associated virus (AAV)2-r-Pdzd8. We found that the c-Fos-positive RVLM tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) level, BP, and heart rate (HR) were elevated in SIH rats. ER-mitochondria associations in RVLM neurons were significantly reduced in SIH rats. PDZD8 was mainly expressed in RVLM neurons, and mRNA and protein levels were markedly decreased in SIH rats. In N2a cells, PDZD8 knockdown disrupted ER-mitochondria associations and mitochondrial structure, decreased mitochondrial membrane potential (MMP) and respiratory metabolism, enhanced ROS levels, and reduced catalase (CAT) activity. These effects suggested that PDZD8 dysregulation induced mitochondrial malfunction. By contrast, PDZD8 upregulation in the RVLM of SIH rats could rescue neuronal mitochondrial function, thereby suppressing c-Fos expression in TH neurons and decreasing RSNA, plasma NE, BP, and HR. Our results indicated that the dysregulation of PDZD8-mediated ER-mitochondria associations led to the loss of the activity homeostasis of RVLM neurons by disrupting mitochondrial functions, thereby participating in the regulation of SIH pathology.

[Research progress on the questionnaire related to persistent postural-perceptual dizziness].

Persistent postural-perceptual dizziness（PPPD） is the most common chronic vestibular disease, the clinical manifestation is dizziness, unstable and non-rotational dizziness for three months or more. And the symptom is exacerbated by upright posture, active or passive movement, and complex visual stimuli. In addition, PPPD is a functional disease, so routine vestibular function tests and imaging tests are often negative. According to the diagnostic criteria established by the Barany Association, the diagnosis of PPPD often relies on history. This article provides a review of PPPD-related questionnaires.

Bif-1c Attenuates Viral Proliferation by Regulating Autophagic Flux Blockade Induced by the Rabies Virus CVS-11 Strain in N2a Cells.

Bax-interacting factor-1 (Bif-1) is a multifunctional protein involved in apoptosis, autophagy, and mitochondrial morphology. However, the associations between Bif-1 and viruses are poorly understood. As discrete Bif-1 isoforms are selectively expressed and exert corresponding effects, we evaluated the effects of neuron-specific/ubiquitous Bif-1 isoforms on rabies virus (RABV) proliferation. First, infection with the RABV CVS-11 strain significantly altered Bif-1 expression in mouse neuroblastoma (N2a) cells, and Bif-1 knockdown in turn promoted RABV replication. Overexpression of neuron-specific Bif-1 isoforms (Bif-1b/c/e) suppressed RABV replication. Moreover, our study showed that Bif-1c colocalized with LC3 and partially alleviated the incomplete autophagic flux induced by RABV. Taken together, our data reveal that neuron-specific Bif-1 isoforms impair the RABV replication process by abolishing autophagosome accumulation and blocking autophagic flux induced by the RABV CVS-11 strain in N2a cells. IMPORTANCE Autophagy can be triggered by viral infection and replication. Autophagosomes are generated and affect RABV replication, which differs by viral strain and infected cell type. Bax-interacting factor-1 (Bif-1) mainly has a proapoptotic function but is also involved in autophagosome formation. However, the association between Bif-1-involved autophagy and RABV infection remains unclear. In this study, our data reveal that a neuron-specific Bif-1 isoform, Bif-1c, impaired viral replication by unchoking autophagosome accumulation induced by RABV in N2a cells to a certain extent. Our study reveals for the first time that Bif-1 is involved in modulating autophagic flux and plays a crucial role in RABV replication, establishing Bif-1 as a potential therapeutic target for rabies.

PROTAC Nanoplatform with Targeted Degradation of NAD(P)H:Quinone Oxidoreductase 1 to Enhance Reactive Oxygen Species-Mediated Apoptosis.

Apoptosis mediated by reactive oxygen species (ROS) has emerged as a promising therapeutic strategy for tumors. However, the overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) protein restricted ROS production through a negative feedback pathway in tumor cells, promoting tumor progression, and weakening the effect of drug therapy. Here, a PROTACs nanodrug delivery system (PN) was constructed to increase ROS generation by degrading the NQO1 protein. Specifically, a PROTAC (proteolytic targeting chimera) molecule DQ was designed and synthesized. Then DQ and withaferin A (WA, an inducer of ROS) were loaded into PNs. DQ degraded the overexpressed NQO1 protein in tumor cells through a protein ubiquitination degradation pathway, thereby weakening the antioxidant capacity of tumor cells. Meanwhile, the reduction of NQO1 could inhibit the negative feedback effect of ROS production, thus increasing ROS generation. It has been demonstrated that PNs can significantly increase ROS production and possess potent antitumor properties in vitro and in vivo. This nanoplatform may offer an alternative approach to treating tumors with NQO1 overexpression.

A density functional theory study of a water gas shift reaction on Ag(111): potassium effect.

Density functional theory (DFT) calculations are executed to investigate the effect of a potassium (K) promoter on the activity of the water gas shift reaction (WGSR) over an Ag(111) surface. It is found that the WGSR proceeds mainly through the OH(O)-assisted carboxy pathway in which H2O dehydrogenation is the rate-controlling step on both Ag(111) and K/Ag(111) surfaces. Energetic span model analysis shows that K addition can enhance the activity of the WGSR by reducing the apparent activation energy of the whole reaction since it can promote H2O dissociation and stabilize the adsorption of the reactants (CO and H2O). Importantly, the K adatom can stabilize the binding of all oxygenates by direct K-O bonding and the stabilizing effect of K on OH adsorption of the transition state (TS) plays a leading role in promoting H2O dissociation. Moreover, the K-O distance and K coverage are two key factors affecting H2O activation, that is, the shorter the K-O distance (2-3 Å) the more the K coverage (25%) contributes to the stronger promotion effect. For various metals catalyzing the WGSR, K promotes H2O dissociation on inert metals like Ag, Au and Cu better than those on reactive metals (Pd and Ni) since the more inert metal surfaces would weaken the K and O binding and accordingly strengthen the interaction between them, resulting in a higher promotion effect.

Risk factors associated with postoperative complications and prolonged postoperative length of stay after laparoscopic liver resection.

Introduction: Laparoscopic liver resection (LLR) has expanded rapidly. Previously published studies are limited to small samples and selected patients. Comprehensive data that may significantly influence the incidence of perioperative complications and postoperative length of stay (PLOS) are lacking. Aim: To characterize complications after LLR and to identify risk factors associated with postoperative complications and prolonged PLOS. Material and methods: This study was carried out at a high-volume HPB centre and included all patients who underwent LLRs between 2015 and 2018. Postoperative complications were analysed in detail. Logistic regression was used to identify independent risk factors. The primary outcome was postoperative complications with a comprehensive complication index (CCI) ≥ 26.2. The second outcome was prolonged length of stay. Results: We identified 938 patients who underwent LLR. In the full cohort, 79 (8.4%) patients experienced major complications with a CCI ≥ 26.2, with postoperative mortality in 4 (0.4%) patients. On multivariate analysis, the diagnosis of primary (OR = 8.97, 95% CI: 2.54-43.74, p = 0.001) and metastatic liver tumours (OR = 5.74, 95% CI: 1.20-30.90, p = 0.028), infectious liver disease (OR = 24.04, 95% CI: 5.30-129.53, p < 0.001), difficult liver resection (OR = 2.77, 95% CI: 1.29-6.69, p = 0.014), and intraoperative bleeding > 1000 ml (OR = 9.29, 95% CI: 3.40-26.43, p < 0.001) were independent factors that increased the odds of major complications. The median PLOS after the operation was 5 days (range: 2-35 days). Factors that independently influenced prolonged PLOS on multivariate analysis were age over 70 years, metastatic liver tumour, difficult liver resection, liver cirrhosis, and right hepatectomy. Conclusions: LLR remains safe for most liver space-occupying lesions. Several preoperative and intraoperative factors associated with the risk of complications and prolonged PLOS were identified. These factors should be considered during patient selection and perioperative management.

[Serum 25-hydroxyvitamin D expression and its correlation in patients with vestibular neuritis].

Objective:To investigate the expression level of serum 25-（OH） D and its correlation in patients with vestibular neuritis（VN）. Methods:30 acute VN patients and 50 age-and sex-matched healthy controls who attended the Otolaryngology, Head and Neck Surgery Department of the First Hospital of Shanxi Medical University from October 2020 to October 2021 were selected. The demographic and clinical data of all subjects were recorded, the levels of serum 25-（OH） D and inflammatory markers were measured and compared, and the changes of serum 25-（OH） D levels in convalescent patients with VN were followed up. Results:The serum level of 25-（OH） D in the acute phase VN group was significantly lower than that in healthy controls[（10.14±2.92） ng/mL vs （20.61±4.70） ng/mL, P<0.01], and the deficiency rate of 100.0%（30/30） was significantly higher than 54.0%（27/50）. Moreover, the serum level of 25-（OH） D in the recovery period（3 months later） was significantly higher[（10.14±2.92） ng/mL vs （15.94±4.88） ng/mL, P<0.01], and the deficiency rate was significantly decreased by 76.7%（23/30）. However, the serum 25-（OH） D level was significantly lower in both the VN group than that in both the acute period and the recovery group, and the deficiency rate was significantly higher than that in the control group. Multivariate binary Logistic regression model analysis showed that low-level serum 25-（OH） D was associated with the onset of VN, with an OR value of 0.193（95%CI=0.043-0.861, P=0.031）. In addition, the results of this study showed that peripheral blood leukocyte（WBC） and neutrophil / lymphocyte ratio（NLR） levels in the acute VN group were significantly higher than in healthy controls[（7.65±3.02） ×108/L vs （5.50±2.50） ×108/L, P<0.01; （2.46±2.95） ×100% vs（1.67±0.92） ×100%, P<0.01 ], and there was no significant difference in Platelet / lymphocyte ratio（PLR） and and average platelet volume（MPV） levels in the two groups（P>0.05）. There were no significant differences in age distribution, sex ratio, body mass index, persistent health problems, or lifestyle groups（P>0.05）. Conclusion:This study is the first to detect serum 25-（OH） D level and inflammation index level, and dynamically assess the serum 25-（OH） D level in different stages, found that low serum 25-（OH） D is associated with the onset of VN, physiological concentration of serum 25-（OH） D is a protective factor of VN, vitamin D supplementation therapy may be a new target of VN treatment.

Four-year experience with more than 1000 cases of total laparoscopic liver resection in a single center.

BACKGROUND: Laparoscopic liver resection (LLR) has become a safe surgical procedure that needs additional summarization. AIM: To review 4 years of total LLR surgeries, exceeding 1000 cases, which were performed at a single center. METHODS: Patients who underwent LLR at West China Hospital of Sichuan University between January 2015 and December 2018 were identified. Surgical details, including the interventional year, category of liver disease, and malignant liver tumors prognosis, were evaluated. The learning curve for LLR was evaluated using the cumulative sum method. The Kaplan-Meier method was used to perform survival analysis. RESULTS: Ultimately, 1098 patients were identified. Hepatocellular carcinoma (HCC) was the most common disease that led to the need for LLR at the center (n = 462, 42.08%). The average operation time was 216.94 ± 98.51 min. The conversion rate was 1.82% (20/1098). The complication rate was 9.20% (from grade II to V). The 1-year and 3-year overall survival rates of HCC patients were 89.7% and 81.9%, respectively. The learning curve was grouped into two phases for local resection (cases 1-106 and 107-373), three phases for anatomical segmentectomy (cases 1-44, 45-74 and 75-120), and three phases for hemihepatectomy (cases 1-17, 18-48 and 49-88). CONCLUSION: LLR may be considered a first-line surgical intervention for liver resection that can be performed safely for a variety of primary, secondary, and recurrent liver tumors and for benign diseases once technical competence is proficiently attained.

Intermedin (adrenomedullin 2) promotes breast cancer metastasis via Src/c-Myc-mediated ribosome production and protein translation.

PURPOSE: Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD, also known as Adrenomedullin 2, ADM2) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. METHODS: Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting, immunoprecipitation, and animal tumor models were used. RESULTS: IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. CONCLUSION: These results suggest that IMD may be a novel target for the treatment of breast cancer.

A bacterium-like particle vaccine displaying Zika virus prM-E induces systemic immune responses in mice.

The emergence of Zika virus (ZIKV) infection, which is unexpectedly associated with congenital defects, has prompted the development of safe and effective vaccines. The Gram-positive enhancer matrix-protein anchor (GEM-PA) display system has emerged as a versatile and highly effective platform for delivering target proteins in vaccines. In this study, we developed a bacterium-like particle vaccine, ZI-△-PA-GEM, based on the GEM-PA system. The fusion protein ZI-△-PA, which contains the prM-E-△TM protein of ZIKV (with a stem-transmembrane region deletion) and the protein anchor PA3, was expressed. The fusion protein was successfully displayed on the GEM surface to form ZI-△-PA-GEM. Moreover, the intramuscular immunization of BALB/c mice with ZI-△-PA-GEM combined with ISA 201 VG and poly(I:C) adjuvants induced durable ZIKV-specific IgG and protective neutralizing antibody responses. Potent B-cell/DC activation was also stimulated early after immunization. Notable, splenocyte proliferation, the secretion of multiple cytokines, T/B-cell activation and central memory T-cell responses were elicited. These data indicate that ZI-△-PA-GEM is a promising bacterium-like particle vaccine candidate for ZIKV.

Dual-action nanoplatform with a synergetic strategy to promote oxygen accumulation for enhanced photodynamic therapy against hypoxic tumors.

With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO2, oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO2 reacted with excess H2O2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. STATEMENT OF SIGNIFICANCE: We constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O2 generation in hypoxic tumor microenvironment but also reduced O2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor.

Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.

With the development of precision medicine, visual and traceable treatments are highly desirable for cancer therapy. However, researchers and clinicians remain confused regarding where the drug distributes and location of the tumor, when the drug is released and when to irradiate the tumor, and how the drug presents antitumor activity, all of which hinders assessment of the cancer patient's condition and formulation of a follow-up treatment scheme for clinicians. Here, a supramolecular self-assembly theranostic nanosystem (MWNs) was designed for enhanced reactive oxygen species (ROS)-mediated cell apoptosis guided by dual-modality tumor imaging. Specifically, merocyanine was introduced in cyanine dye to extend its conjugated π-scaffolds, which could preferentially self-assemble into nanovesicles owing to its amphipathy. Furthermore, withaferin A (WA), used as a chemotherapeutic drug, was loaded to construct MWNs. The assembled or disassembled MWNs behaved differently in photoacoustic (PA) intensity and fluorescence signal intensity. The MWNs exhibited stronger PA signals and quenched fluorescence, which monitors their distribution and images the tumor location in vivo, while the disassembled MWNs showed weak PA signals and recovered fluorescence, indicating the release of drug and instructing the appropriate time to irradiate for photodynamic therapy (PDT). Thus, ROS generation introduced by PDT and released WA led to cell apoptosis. This intelligent nanosystem for precise cancer therapy that reveals where the tumor is, when to irradiate the tumor, and how the tumor is cured might establish the basis for biomedical applications of finely controlled platform.

Promising natural lysine specific demethylase 1 inhibitors for cancer treatment: advances and outlooks.

Lysine specific demethylase 1 (LSD1), a transcriptional corepressor or coactivator that serves as a demethylase of histone 3 lysine 4 and 9, has become a potential therapeutic target for cancer therapy. LSD1 mediates many cellular signaling pathways and regulates cancer cell proliferation, invasion, migration, and differentiation. Recent research has focused on the exploration of its pharmacological inhibitors. Natural products are a major source of compounds with abundant scaffold diversity and structural complexity, which have made a major contribution to drug discovery, particularly anticancer agents. In this review, we briefly highlight recent advances in natural LSD1 inhibitors over the past decade. We present a comprehensive review on their discovery and identification process, natural plant sources, chemical structures, anticancer effects, and structure-activity relationships, and finally provide our perspective on the development of novel natural LSD1 inhibitors for cancer therapy.

A Promising Preoperative Prediction Model for Microvascular Invasion in Hepatocellular Carcinoma Based on an Extreme Gradient Boosting Algorithm.

Background: The non-invasive preoperative diagnosis of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is vital for precise surgical decision-making and patient prognosis. Herein, we aimed to develop an MVI prediction model with valid performance and clinical interpretability. Methods: A total of 2160 patients with HCC without macroscopic invasion who underwent hepatectomy for the first time in West China Hospital from January 2015 to June 2019 were retrospectively included, and randomly divided into training and a validation cohort at a ratio of 8:2. Preoperative demographic features, imaging characteristics, and laboratory indexes of the patients were collected. Five machine learning algorithms were used: logistic regression, random forest, support vector machine, extreme gradient boosting (XGBoost), and multilayer perception. Performance was evaluated using the area under the receiver operating characteristic curve (AUC). We also determined the Shapley Additive exPlanation value to explain the influence of each feature on the MVI prediction model. Results: The top six important preoperative factors associated with MVI were the maximum image diameter, protein induced by vitamin K absence or antagonist-II, α-fetoprotein level, satellite nodules, alanine aminotransferase (AST)/aspartate aminotransferase (ALT) ratio, and AST level, according to the XGBoost model. The XGBoost model for preoperative prediction of MVI exhibited a better AUC (0.8, 95% confidence interval: 0.74-0.83) than the other prediction models. Furthermore, to facilitate use of the model in clinical settings, we developed a user-friendly online calculator for MVI risk prediction based on the XGBoost model. Conclusions: The XGBoost model achieved outstanding performance for non-invasive preoperative prediction of MVI based on big data. Moreover, the MVI risk calculator would assist clinicians in conveniently determining the optimal therapeutic remedy and ameliorating the prognosis of patients with HCC.