Exploring the multifaceted role of GCN1: Implications in cellular responses and disease pathogenesis.

GCN1 is a highly conserved protein present widely across eukaryotes. As an upstream activator of protein kinase GCN2, GCN1 plays a pivotal role in integrated stress responses, such as amino acid starvation and oxidative stress. Through interaction with GCN2, GCN1 facilitates the activation of GCN2, thus initiating downstream signaling cascades in response to cellular stressors. In these contexts, the activation of GCN2 necessitates the presence and action of GCN1. Notably, GCN1 also operates as a ribosome collision sensor, contributing significantly to the translation quality control pathway. These discoveries offer valuable insights into cellular responses to internal stresses, vital for maintaining cellular homeostasis. Additionally, GCN1 exhibits the ability to regulate the cell cycle and suppress inflammation, among other processes, independently of GCN2. Our review outlines the structural characteristics and biological functions of GCN1, shedding light on its significant involvement in the onset and progression of various cancer and non-cancer diseases. Our work underscores the role of GCN1 in the context of drug therapeutic effects, hinting at its potential as a promising drug target. Furthermore, our work delves deep into the functional mechanisms of GCN1, promising innovative avenues for the diagnosis and treatment of diseases in the future. The exploration of GCN1's multifaceted roles not only enhances our understanding of its mechanisms but also paves the way for novel therapeutic interventions. The ongoing quest to unveil additional functions of GCN1 holds the promise of further enriching our comprehension of its mode of action.

Continuous flow biocatalysis: synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus.

Purine nucleoside ester is one of the derivatives of purine nucleoside, which has antiviral and anticancer activities. In this work, a continuous flow synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus was successfully achieved. Various parameters including solvent, reaction temperature, reaction time/flow rate and substrate ratio were investigated. The best yields were obtained with a continuous flow microreactor for 35 min at 50 °C with the substrate ratio of 1 : 5 (nucleosides to vinyl esters) in the solvent of tert-amyl alcohol. 12 products were efficiently synthesized with yields of 78-93%. Here we reported for the first time the use of lipase TL IM from Thermomyces lanuginosus in the synthesis of purine nucleoside esters. The significant advantages of this methodology are a green solvent and mild conditions, a simple work-up procedure and the highly reusable biocatalyst. This research provides a new technique for rapid synthesis of anticancer and antiviral nucleoside drugs and is helpful for further screening of drug activity.

Cuproptosis-associated ncRNAs predict breast cancer subtypes.

BACKGROUND: Cuproptosis is a novel copper-dependent mode of cell death that has recently been discovered. The relationship between Cuproptosis-related ncRNAs and breast cancer subtypes, however, remains to be studied. METHODS: The aim of this study was to construct a breast cancer subtype prediction model associated with Cuproptosis. This model could be used to determine the subtype of breast cancer patients. To achieve this aim, 21 Cuproptosis-related genes were obtained from published articles and correlation analysis was performed with ncRNAs differentially expressed in breast cancer. Random forest algorithms were subsequently utilized to select important ncRNAs and build breast cancer subtype prediction models. RESULTS: A total of 94 ncRNAs significantly associated with Cuproptosis were obtained and the top five essential features were chosen to build a predictive model. These five biomarkers were differentially expressed in the five breast cancer subtypes and were closely associated with immune infiltration, RNA modification, and angiogenesis. CONCLUSION: The random forest model constructed based on Cuproptosis-related ncRNAs was able to accurately predict breast cancer subtypes, providing a new direction for the study of clinical therapeutic targets.

Development of a green, concise synthesis of nicotinamide derivatives catalysed by Novozym® 435 from Candida antarctica in sustainable continuous-flow microreactors.

An increasing number of studies have shown that many nicotinamide derivatives exhibited extensive biological activities, such as anti-inflammatory and antitumor activity. In this paper, a green, concise synthesis of nicotinamide derivatives in sustainable continuous-flow microreactors catalysed by Novozym® 435 from Candida antarctica has been developed. Application of an easily obtainable and reusable lipase in the synthesis of nicotinamide derivatives from methyl nicotinate and amines/benzylamines reacted for 35 min at 50 °C led to high product yields (81.6-88.5%). Environmentally friendly tert-amyl alcohol was applied as a reaction medium. Substantially shorter reaction times as well as a significant increase in the product yield were obtained as compared to the batch process. This innovative approach provides a promising green, efficient and rapid synthesis strategy for pharmaceutical synthesis and further activity research of novel nicotinamide derivatives.

Disulfidptosis-associated lncRNAs predict breast cancer subtypes.

Disulfidptosis is a newly discovered mode of cell death. However, its relationship with breast cancer subtypes remains unclear. In this study, we aimed to construct a disulfidptosis-associated breast cancer subtype prediction model. We obtained 19 disulfidptosis-related genes from published articles and performed correlation analysis with lncRNAs differentially expressed in breast cancer. We then used the random forest algorithm to select important lncRNAs and establish a breast cancer subtype prediction model. We identified 132 lncRNAs significantly associated with disulfidptosis (FDR < 0.01, |R|> 0.15) and selected the first four important lncRNAs to build a prediction model (training set AUC = 0.992). The model accurately predicted breast cancer subtypes (test set AUC = 0.842). Among the key lncRNAs, LINC02188 had the highest expression in the Basal subtype, while LINC01488 and GATA3-AS1 had the lowest expression in Basal. In the Her2 subtype, LINC00511 had the highest expression level compared to other key lncRNAs. GATA3-AS1 had the highest expression in LumA and LumB subtypes, while LINC00511 had the lowest expression in these subtypes. In the Normal subtype, GATA3-AS1 had the highest expression level compared to other key lncRNAs. Our study also found that key lncRNAs were closely related to RNA methylation modification and angiogenesis (FDR < 0.05, |R|> 0.1), as well as immune infiltrating cells (P.adj < 0.01, |R|> 0.1). Our random forest model based on disulfidptosis-related lncRNAs can accurately predict breast cancer subtypes and provide a new direction for research on clinical therapeutic targets for breast cancer.

Triple Tumor Microenvironment-Responsive Ferroptosis Pathways Induced by Manganese-Based Imageable Nanoenzymes for Enhanced Breast Cancer Theranostics.

Previous studies have found that activated CD8+ T cells secrete elevated levels of interferon-gamma (IFN-γ) to trigger ferroptosis in tumor cells. However, IFN-γ-mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN-γ secreted by CD8+ T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/stimulator of interferon genes (cGAS-STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor-infiltrating CD8+ T cells. Therefore, tumor microenvironment-responsive Mn-based nanoenzymes (Mn-based NEs) that activated the cGAS-STING pathway are designed to amplify immune-driven ferroptosis. The multifunctional all-in-one nanoplatform is simply and mildly synthesized by the coordination between Mn3+ ions and 3,3'-dithiodipropionic acid. After intracellular delivery, each component of Mn-based NEs exerts its function. That is, glutathione is depleted through disulfide-thiol exchange and redox pair of Mn3+ /Mn2+ , a hydroxyl radical (·OH) is generated via the Fenton-like reaction to cause ferroptosis, and Mn2+ augments cGAS-STING activity to boost immune-driven ferroptosis. In addition, ferroptosis amplifies Mn2+ -induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune-driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors.

Light plays a critical role in the accumulation of chlorogenic acid in Lonicera macranthoides Hand.-Mazz.

Light has important effects on plant metabolism. However, the relationship between the chlorogenic acid (CGA) content and light in plants remains unclear. Here, we investigated the effects of shading treatment on gene expression and CGA content in Lonicera macranthoides Hand.-Mazz. (LM), a widely used medicinal plant. A total of 1891 differentially expressed genes (DEGs) were obtained in flower buds and 819 in leaves in response to light in shading treatment compared to the control sample by RNA-Seq. After shading treatment, the content of CGA in LM leaves decreased significantly by 1.78-fold, the carotenoid content increased, and the soluble sugar and starch contents significantly decreased. WGCNA and the expression of related genes verified by qRT‒PCR revealed that CGA synthesis pathway enzyme genes form a co-expression network with genes for carbohydrate synthesis, photosynthesis, light signalling elements, and transcription factor genes (TFs) that affect the accumulation of CGA. Through a virus-induced gene silencing (VIGS) system and CGA assay in Nicotiana benthamiana (NB), we determined that downregulation of NbHY5 expression decreased the CGA content in NB leaves. In this study, we found that light provides energy and material for the accumulation of CGA in LM, and light affects the expression of CGA accumulation-related genes. Our results show that different light intensities have multiple effects on leaves and flower buds in LM and are able to coregulate LmHY5 expression and CGA synthesis.

Endophytic bacterium Bacillus aryabhattai induces novel transcriptomic changes to stimulate plant growth.

In nature, plants interact with a wide range of microorganisms, and most of these microorganisms could induce growth through the activation of important molecular pathways. The current study evaluated whether the endophytic bacterium Bacillus aryabhattai encourages plant growth and the transcriptional changes that might be implicated in this effect. The endophytic bacterium promotes the growth of Arabidopsis and tobacco plants. The transcriptional changes in Arabidopsis plants treated with the bacterium were also identified, and the results showed that various genes, such as cinnamyl alcohol dehydrogenase, apyrase, thioredoxin H8, benzaldehyde dehydrogenase, indoleacetaldoxime dehydratase, berberine bridge enzyme-like and gibberellin-regulated protein, were highly expressed. Also, endophytic bacterial genes, such as arginine decarboxylase, D-hydantoinase, ATP synthase gamma chain and 2-hydroxyhexa-2,4-dienoate hydratase, were activated during the interaction. These findings demonstrate that the expression of novel plant growth-related genes is induced by interaction with the endophytic bacterium B. aryabhattai and that these changes may promote plant growth in sustainable agriculture.

Programmable therapeutic nanoscale covalent organic framework for photodynamic therapy and hypoxia-activated cascade chemotherapy.

Clinical photodynamic therapy (PDT) only has a limited cancer therapeutic effect and typically leads to a more hypoxic milieu owing to the hypoxic conditions of the solid tumor microenvironment that limit the singlet oxygen (1O2), generation. To address this issue, the PDT, in combination with hypoxia-activated prodrugs, has recently been investigated as a possible clinical treatment modality for cancer therapy. By cross-linking the photosensitizer tetra(4-hydroxyphenyl)porphine (THPP) and a 1O2-cleavable thioketal (TK) linker, a multifunctional nanoscale covalent organic framework (COF) platform with a high porphyrin loading capacity was synthesized, which significantly improve the reactive oxygen species (ROS) generation efficiency and contributes to PDT. As-synthesized THPPTK-PEG nanoparticles (NPs) possess a high THPP photosensitizer content and mesoporous structure for further loading of the hypoxia-responsive prodrug banoxantrone (AQ4N) into the COF with a high-loading content. The nano-carriers surfaces are coated with a thick PEG coating to promote their dispersibility in physiological surroundings and therapeutic performance. When exposed to 660 nm radiation, such a nanoplatform can efficiently create cytotoxic 1O2 for PDT. Similarly, oxygen intake may exacerbate the hypoxic environment of the tumor, inducing the activation of AQ4N to achieve hypoxia-activated cascade chemotherapy and increased treatment efficacy. This study provides a new nanoplatform for photodynamic-chemical synergistic therapy and offers critical new insights for designing and developing a multifunctional supramolecular drug delivery system. STATEMENT OF SIGNIFICANCE: Here, we designed a laser-activated hypoxia-responsive nanoscale COF nanoplatform for hypoxia-activated cascade chemotherapy and PDT. When exposed to laser light, thus this nanoplatform can efficiently create cytotoxic 1O2 for PDT while consuming oxygen at the tumor location. However, increased oxygen consumption can exacerbate the tumor's hypoxic environment, causing AQ4N to become active, allowing for programmed hypoxia-triggered cascade chemotherapy and improved therapeutic efficacy. In addition, this innovative nanoscale COF nanoplatform allows for laser-controlled drug delivery in specific areas, which dramatically improves tumor inhibition. This research suggests a method for attaining ultrasensitive drug release and effective cascade therapy for cancer treatments.

GSH-Responsive Metal-Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy.

Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8+ T cells and reduce Treg cells to result in highly effective immunotherapy. In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors: A Randomized Clinical Trial.

Importance: Prevention of chemotherapy-induced neutropenia (CIN) and its clinical consequences is an unmet need for which plinabulin, a selective immunomodulating microtubule-binding agent, is being tested. Objective: To demonstrate noninferiority between plinabulin and pegfilgrastim for days of severe neutropenia in cycle 1 in patients with solid tumors treated with docetaxel. Design, Setting, and Participants: The Plinabulin vs Pegfilgrastim for the Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors (PROTECTIVE-1) double-blind phase 3 randomized clinical trial was performed in multiple centers in China, Russia, Ukraine, and the US. Participants included patients with breast, prostate, or non-small cell lung cancer treated with single-agent docetaxel chemotherapy. Data were collected from June 1, 2018, to January 31, 2019. The database was locked on February 18, 2021. Data analysis was based on intention to treat and safety and performed from October 5, 2018, to February 23, 2021. Interventions: Plinabulin, 40 mg, plus placebo or pegfilgrastim, 6 mg, plus placebo. Main Outcomes and Measures: The primary end point was day of severe neutropenia in cycle 1. Additional end points included clinical consequences of CIN (febrile neutropenia, hospitalizations, infections, antibiotic use, and modifications of chemotherapy dose), patient-reported outcomes for bone pain score, markers for immune suppression (neutrophil-to-lymphocyte ratio [NLR] of >5), immature neutrophils (band, promyelocyte, and myelocyte counts >0), and safety. Results: Among the 105 patients included in the analysis (65 [6.19%] women; median age, 59 [range, 31-81] years), the primary end point was met within a noninferiority margin of 0.65 days, with a mean difference of 0.52 days (98.52% CI, 0.40-0.65 days). Grade 4 neutropenia frequency in cycle 1 was not significantly different. Plinabulin had earlier onset of action with less grade 4 neutropenia in week 1 of cycle 1. Plinabulin had fewer adverse clinical consequences with rates of febrile neutropenia (0 of 52 vs 1 of 53 [1.9%]), infections (4 of 52 [7.7%] vs 8 of 53 [15.1%]), chemotherapy dose delay of more than 7 days (2 of 52 [3.8%] vs 3 of 53 [5.7%]), and permanent chemotherapy discontinuation (7 of 52 [13.5%] vs 14 of 53 [26.4%]). Patients receiving plinabulin had significantly less bone pain (difference, -0.67 [95% CI, -1.17 to -0.16]; P = .01) and a better immunosuppressive profile (NLR >5 at day 8, 2 of 52 [3.8%] vs 24 of 51 [46.0%]; P < .001). Plinabulin was well tolerated, with comparable safety to pegfilgrastim. Conclusions and Relevance: Plinabulin has comparable efficacy to pegfilgrastim for the prevention of CIN, with better safety and a better immunosuppressive profile. Plinabulin's same-day dosing compared with pegfilgrastim's next-day dosing offers distinct advantages, including reducing use of health care services. Trial Registration: ClinicalTrials.gov Identifier: NCT03102606.

Efficacy and Safety of First-Line Chemotherapies for Patients With Advanced Biliary Tract Carcinoma: A Systematic Review and Network Meta-Analysis.

BACKGROUND: At present, chemotherapy is still the primary treatment for advanced biliary tract carcinoma, but it is challenging to balance the efficacy and side effects. Network meta-analysis (NMA) is a better way to identify the protocol, and the advantage is that it can be combined with direct and indirect evidence to judge the best treatment regimens. Therefore, we conducted NMA on the searched randomized controlled trials (RCTs). METHODS: NMA was conducted regarding the searched RCTs by comparing progression-free survival (PFS), overall survival (OS), objective remission rates (ORRs), and adverse events (AEs) of different chemotherapy protocols. RESULTS: We screened 24 studies that met the inclusion criteria for further analysis. Compared with other regimens, the best supportive care (BSC) or FUFA protocol has a worse OS. Folfox4, GEMOX+erlotinib, and C+GEMOX can improve patients' PFS compared with BSC. Patients receiving GP+cediranib protocol have higher ORRs. There was reduced neutropenia grade ≥3 when adopting GP+cediranib, GS, C+GEMOX, RAM+GP, and MER+GP than when using FUFA protocol. The probability of vomiting of XELOX is lower than that of GEM+XELOX. There is a lower diarrhea incidence of XELOX than that of GEMOX+erlotinib. The results of cluster grade analysis illustrated that GEMOX+erlotinib owned a higher ORR and a higher surface under the cumulative ranking (SUCRA) of neutropenia and vomiting but also had a lower SUCRA of diarrhea and fatigue. Meanwhile, both GEMOX and C+GEMOX have a better ORR and a higher AE SUCRA. CONCLUSION: The NMA demonstrated that chemotherapy combined with targeted therapy has better efficacy and lower incidence of AEs than chemotherapy alone.

Heat-killed endophytic bacterium induces robust plant defense responses against important pathogens.

Stress caused by pathogens strongly damages plants. Developing products to control plant disease is an important challenge in sustainable agriculture. In this study, a heat-killed endophytic bacterium (HKEB), Bacillus aryabhattai, is used to induce plant defense against fungal and bacterial pathogens, and the main defense pathways used by the HKEB to activate plant defense are revealed. The HKEB induced high protection against different pathogens through the salicylic and jasmonic acid pathways. We report the presence of gentisic acid in the HKEB for the first time. These results show that HKEBs may be a useful tool for the management of plant diseases.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606.

Redox Responsive Metal Organic Framework Nanoparticles Induces Ferroptosis for Cancer Therapy.

Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu-SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide-thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh-7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu-SS not only allows the MOF to be used as a contrast agent for T1 -weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near-infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging.

Expression significance and potential mechanism of hypoxia-inducible factor 1 alpha in patients with myelodysplastic syndromes.

OBJECTIVE: To investigate the expression level and potential mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in patients with myelodysplastic syndromes (MDS). METHODS: Immunohistochemistry (IHC) techniques were used to examine the protein expression of HIF-1α in paraffin-embedded myeloid tissues from 82 patients with MDS and 33 controls (patients with lymphoma that is not invading myeloid tissues). In addition, the associations between the protein expression of HIF-1α and clinical parameters were examined. To further investigate the significance of HIF-1α expression in MDS patients, the researchers not only extracted the data about HIF-1α expression from MDS-related microarrays but also analyzed the correlation between the level of HIF-1α expression and MDS. The microRNA (miRNA) targeting HIF-1α was predicted and verified with a dual luciferase experiment. RESULTS: Immunohistochemistry revealed that the positive expression rate of HIF-1α in the bone marrow of patients with MDS was 90.24%. This rate was remarkably higher than that of the controls (72.73%) and was statistically significant (P < .05), which indicated that HIF-1α was upregulated in the myeloid tissues of MDS patients. For the GSE2779, GSE18366, GSE41130, and GSE61853 microarrays, the average expression of HIF-1α in MDS patients was higher than in the controls. Particularly for the GSE18366 microarray, HIF-1α expression was considerably higher in MDS patients than in the controls (P < .05). It was predicted that miR-93-5p had a site for binding with HIF-1α, and a dual luciferase experiment confirmed that miR-93-5p could bind with HIF-1α. CONCLUSION: The upregulated expression of HIF-1α was examined in the myeloid tissues of MDS patients. The presence of HIF-1α (+) suggested an unsatisfactory prognosis for patients, which could assist in the diagnosis of MDS. In addition, miR-93-5p could bind to HIF-1α by targeting, showing its potential to be the target of HIF-1α in MDS.

Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling.

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials. In the present study, the potency of plinabulin to inhibit tubulin polymerization and growth of KRAS-driven cancer cells was characterized. In vivo efficacy of plinabulin was tested in two different mouse models; one being the RCAS/t-va gene transfer system and the other being a xenograft model. In vitro cell culture tubulin polymerization assays were used to complement the mouse models. There was improved survival in a KRAS-driven mouse gene transfer glioma model, but lack of benefit in a similar model, without constitutively active KRAS, which supports the notion of a KRAS-specific effect. This survival benefit was mediated, at least in part, by the ability of plinabulin to inhibit tubulin polymerization and disrupt endosomal recycling. It was proposed a mechanism of compromised endosomal recycling of displaced KRAS through targeting microtubules that yields inhibition of protein kinase B, but not extracellular signal regulated kinase (ERK) signaling, therefore lending rationale to combination treatments of tubulin- and ERK-targeting agents in KRAS-driven cancer.

In Vivo Imaging-Guided Photothermal/Photoacoustic Synergistic Therapy with Bioorthogonal Metabolic Glycoengineering-Activated Tumor Targeting Nanoparticles.

Developing multifunctional phototheranostics with nanoplatforms offers promising potential for effective eradication of malignant solid tumors. In this study, we develop a multifunctional phototheranostic by combining photothermal therapy (PTT) and photoacoustic therapy (PAT) based on a tumor-targeting nanoagent (DBCO-ZnPc-LP). The nanoagent DBCO-ZnPc-LP was facilely prepared by self-assembling of a single lipophilic near-infrared (NIR) dye zinc(II)-phthalocyanine (ZnPc) with a lipid-poly(ethylene glycol) (LP) and following modified further with dibenzyl cyclootyne (DBCO) for introducing the two-step chemical tumor-targeting strategy based on metabolic glycoengineering and click chemistry. The as-prepared DBCO-ZnPc-LP could not only convert NIR light into heat for effective thermal ablation but also induce a thermal-enhanced ultrasound shockwave boost to trigger substantially localized mechanical damage, achieving synergistic antitumor effect both in vitro and in vivo. Moreover, DBCO-ZnPc-LP can be efficiently delivered into tumor cells and solid tumors after being injected intravenously via the two-step tumor-targeting strategy. By integrating the targeting strategy, photoacoustic imaging, and the synergistic interaction between PTT and PAT, a solid tumor could be accurately positioned and thoroughly eradicated in vivo. Therefore, this multifunctional phototheranostic is believed to play an important role in future oncotherapy by the enhanced synergistic effect of PTT and PAT under the guidance of photoacoustic imaging.

Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members.

To gain a broader insight into the role of Bcl-2 proteins in apoptosis induced after mitotic arrest, we investigated the subcellular location, oligomeric structure, and protein interactions of Bax, Bcl-2, and Bcl-xL in vinblastine-treated KB-3 cells. Vinblastine induced the translocation of Bax from the cytosol to the mitochondria, which was accompanied by conformational activation and oligomerization of Bax. Bcl-2 was located in the mitochondria, underwent multisite phosphorylation after vinblastine treatment, and was strictly monomeric under all conditions. In contrast, in control cells, Bcl-xL existed in both monomeric (30 kDa) and oligomeric (150 kDa) forms. Treatment with agents that induced Bcl-xL phosphorylation (microtubule inhibitors) caused loss of the 150-kDa form, but this species was unaffected by apoptotic stimuli that did not stimulate phosphorylation. Vinblastine also promoted Bax activation and Bax oligomerization in HCT116 colon cancer cells. Both wild-type and Bax-deficient HCT116 cells expressed the 150-kDa form of Bcl-xL, which was depleted similarly in both cell lines upon vinblastine treatment. Co-immunoprecipitation studies revealed that in untreated KB-3 cells inactive cytosolic Bax interacted with Bcl-xL, whereas in vinblastine-treated cells, activated mitochondrial Bax did not interact with Bcl-xL. Interaction of Bcl-2 with Bax was not observed under any condition. Overexpression of Bcl-xL inhibited vinblastine-induced Bax activation and Bax dimerization and in parallel inhibited apoptosis. The results indicate that vinblastine-induced apoptosis requires translocation, activation, and oligomerization of Bax and is associated with specific changes in the oligomeric properties of Bcl-xL, which occur independently of Bax.