CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to most chemotherapy drugs, leading to poor chemotherapy efficacy. Recently, Trametinib and Palbociclib have promising prospects in the treatment of pancreatic cancer. This article aims to explore the effects of Trametinib on pancreatic cancer and address the underlying mechanism of resistance as well as its reversal strategies. The GDSC (Genomics of Drug Sensitivity in Cancer) and CTD2 (Cancer Target Discovery and Development) were utilized to screen the potential drug candidate in PDAC cell lines. The dose-increase method combined with the high-dose shock method was applied to induce the Trametinib-resistant PANC-1 and MIA PaCa-2 cell lines. The CCK8 proliferation assay, colony formation assay, flow cytometry, and western blot were conducted to verify the inhibitory effect of Trametinib and Palbociclib. RNA-seq was performed in resistant PDAC cell lines to find the differential expression genes related to drug resistance and predict pathways leading to the reversal of Trametinib resistance. The GDSC and CTD2 database screening revealed that Trametinib demonstrates a significant inhibitory effect on PDAC. We found that Trametinib has a lower IC50 than Gemcitabine in PDAC cell lines. Both Trametinib and Gemcitabine can decrease the proliferation capacity of pancreatic cells, induce cell cycle arrest, and increase apoptosis. Simultaneously, the phosphorylation of the AKT and ERK pathways were inhibited by the treatment of Trametinib. In addition, the RNA-seq of Trametinib-induced resistance PDAC cell lines reveals that the cyclin-dependent kinase (CDK)-RB-E2F regulatory axis and G2/M DNA damage checkpoint might lead the drug resistance. Besides, the combination of Trametinib with Palbociclib could inhibit the proliferation and cell cycle of both resistant cells lines and also restore the sensitivity of drug-resistant cells to Trametinib. Last but not least, the interferon-α and interferon-γ expression were upregulated in resistance cell lines, which might lead to the reversal of drug resistance. The study shows Trametinib has a critical inhibitory effect on PDAC. Besides, the combination of Trametinib with Palbociclib can inhibit the proliferation of PDAC-resistant cells.

The hemostatic and comforting effects of oral adhesive bandages in tooth extraction: a randomized controlled clinical study.

OBJECTIVES: To compare oral adhesive bandages with the classic compression method and evaluate the clinical efficacy of this wound dressing material in improving postoperative comfort, wound healing, and hemostasis in tooth extraction. MATERIALS AND METHODS: The study was designed as a randomized controlled clinical trial. A total of 120 patients were recruited and randomly assigned to the study group and the control group. In the study group, oral adhesive bandages were used as wound dressing. In the control group, patients bit on cotton balls and gauze, as usual. Hemorrhage, comfort, and healing levels were evaluated at postoperative 1 h, 24 h, and 7 days. The adhesion time of the oral adhesive bandages was also recorded. RESULTS: The average adhesion time of the oral adhesive bandages was 26.6 h. At postoperative 1 and 24 h, the hemostatic levels of the oral adhesive bandage group were significantly higher than those of the control group. The oral adhesive bandage group also reported significantly higher comfort scores than the control group. Both groups had similar healing levels and side effects. But the mean score for wound healing was slightly higher in the oral adhesive bandage group. CONCLUSIONS: Oral adhesive bandages were more effective than cotton balls and gauze in providing hemostatic and comfort effects on extraction wounds. CLINICAL RELEVANCE: Oral adhesive bandages possess clinical value in the management of extraction wounds.

A novel GSK3ß inhibitor 5n attenuates acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3ß is widely expressed in the kidneys. In acute models of injury, GSK3ß promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3ß inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3ß inhibited cell injury and inflammation induced by cisplatin. We found that GSK3ß interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3ß inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic.

Platelet Membrane Coated Cu9S8-SNAP for Targeting NIR-II Mild Photothermal Enhanced Chemodynamic/Gas Therapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and uncommon subtype of breast cancer with a poor prognosis. It is crucial to prioritise the creation of a nanotherapeutic method that is highly selective and actively targeting TNBC. This study explores a new nanosystem, Cu9S8-SNAP@PM (C-S@P), composed of Cu9S8-SNAP coated with a platelet membrane (PM). The purpose of this nanosystem is to cure TNBC using multimodal therapy. The utilisation of PM-coated nanoparticles (NPs) enables active targeting, leading to the efficient accumulation of C-S@P within the tumour. The Cu9S8 component within these NPs serves the potential to exert photothermal therapy (PTT) and chemodynamic therapy (CDT). Simultaneously, the S-Nitroso-N-Acetylvanicillamine (SNAP) component enables nitric oxide (NO) gas therapy (GT). Furthermore, when exposed to NIR-II laser light, Cu9S8 not only increases the temperature of the tumour area for PTT, but also boosts CDT and stimulates the release of NO through thermal reactions to improve the effectiveness of GT. Both in vitro and in vivo experimental results validate that C-S@P exhibits minimal side effects and represents a multifunctional nano-drug targeted at tumors for efficient treatment. This approach promises significant potential for TNBC therapy and broader applications in oncology.

Exploring negative thermal expansion materials with bulk framework structures and their relevant scaling relationships through multi-step machine learning.

Discovering new negative thermal expansion (NTE) materials is a great challenge in experiment. Meanwhile, the machine learning (ML) method can be another approach to explore NTE materials using the existing material databases. Herein, we adopt the multi-step ML method with efficient data augmentation and cross-validation to identify around 1000 materials, including oxides, fluorides, and cyanides, with bulk framework structures as new potential NTE candidate materials from ICSD and other databases. Their corresponding coefficients of negative thermal expansion (CNTE) and temperature ranges are also well predicted. Among them, about 57 materials are predicted to have an NTE probability of 100%. Some predicted NTE materials were tested by the first-principles calculations with quasi-harmonic approximation (QHA), which indicates that the ML results are in good agreement with the first principles calculation results. Based on the comprehensive analysis of the existing and predicted NTE materials, we established three universal relationships of CNTE with an average electronegativity, porosity, and temperature range. From these, we also identified some important critical values characterizing the NTE property, which can serve as an important criterion for designing new NTE materials.

CYLD alleviates NLRP3 inflammasome-mediated pyroptosis in osteoporosis by deubiquitinating WNK1.

BACKGROUND: Osteoporosis (OP) is the result of bone mass reduction and bone structure disorder. Bone marrow mesenchymal stem cells (BMSCs) are the main source of osteogenic precursor cells involved in adult bone remodeling. The involvement of the deubiquitinating enzyme CYLD in OP has recently been discovered. However, the detailed role and mechanism of CYLD remain unknown. METHODS: The OP mouse model was established by performing ovariectomy (OVX) on mice. Hematoxylin and eosin staining, Masson and Immunohistochemical staining were used to assess pathologic changes. Real-time quantitative PCR, Western blot, and immunofluorescence were employed to assess the expression levels of CYLD, WNK1, NLRP3 and osteogenesis-related molecules. The binding relationship between CYLD and WNK1 was validated through a co-immunoprecipitation assay. The osteogenic capacity of BMSCs was determined using Alkaline phosphatase (ALP) and alizarin red staining (ARS). Protein ubiquitination was evaluated by a ubiquitination assay. RESULTS: The levels of both CYLD and WNK1 were decreased in bone tissues and BMSCs of OVX mice. Overexpression of CYLD or WNK1 induced osteogenic differentiation in BMSCs. Additionally, NLRP3 inflammation was activated in OVX mice, but its activation was attenuated upon overexpression of CYLD or WNK1. CYLD was observed to reduce the ubiquitination of WNK1, thereby enhancing its protein stability and leading to the inactivation of NLRP3 inflammation. However, the protective effects of CYLD on osteogenic differentiation and NLRP3 inflammation inactivation were diminished upon silencing of WNK1. CONCLUSION: CYLD mitigates NLRP3 inflammasome-triggered pyroptosis in osteoporosis through its deubiquitination of WNK1.

Carbon wet deposition flux and river carbon output in a forest watershed in permafrost region of the Da Xing'an Mountains.

Carbon wet deposition and river carbon output in river basins are important components of global carbon cycle. The assessment of both properties is of great significance for regional carbon budget. However, research on these topics in high-latitude permafrost regions in China is still lacking. We conducted dynamic monitoring of carbon wet deposition and carbon output in the river from May 28th to October 30th, 2022, in Laoyeling watershed, a typical forested watershed in the Da Xing'an Mountains permafrost region. We analyzed the variations of carbon component concentrations and fluxes in precipitation and river water, and estimated the contribution of carbon wet deposition to carbon output in the watershed. The results showed that wet deposition fluxes of dissolved organic carbon (DOC), dissolved inorganic carbon (DIC), and total dissolved carbon (TDC) in the Laoyeling watershed were 1354.86, 684.59, and 2039.45 kg·km-2, respectively. The fluxes of DOC, DIC, TDC, particulate organic carbon (POC), particulate inorganic carbon (PIC), and total carbon (TC) in the river were 601.75, 1977.30, 2579.05, 125.13, 21.99, and 2726.17 kg·km-2, respectively. The contribution of TDC wet deposition to the river TDC output was 9941.89 kg, accounting for 17.6% of total output. The DIC concentration in the river showed significant seasonal differences, with increased runoff resulting from precipitation leading to a decrease in DIC concentration in the river and showing a clear dilution effect, while the concentrations of DOC, POC, and PIC increased, mainly due to erosion effect. In conclusion, carbon wet deposition flux in the Laoyeling watershed was mainly determined by precipitation, and its contribution to river carbon output was relatively small compared to other factor. Runoff was the dominant factor affecting river carbon output. The results would provide important insights into carbon cycling and carbon budget balance in permafrost regions under climate change.

Review of predicting protein stability changes upon variations.

Forecasting alterations in protein stability caused by variations holds immense importance. Improving the thermal stability of proteins is important for biomedical and industrial applications. This review discusses the latest methods for predicting the effects of mutations on protein stability, databases containing protein mutations and thermodynamic parameters, and experimental techniques for efficiently assessing protein stability in high-throughput settings. Various publicly available databases for protein stability prediction are introduced. Furthermore, state-of-the-art computational approaches for anticipating protein stability changes due to variants are reviewed. Each method's types of features, base algorithm, and prediction results are also detailed. Additionally, some experimental approaches for verifying the prediction results of computational methods are introduced. Finally, the review summarizes the progress and challenges of protein stability prediction and discusses potential models for future research directions.

Identification of Protein-Protein Interaction Associated Functions Based on Gene Ontology.

Protein-protein interactions (PPIs) involve the physical or functional contact between two or more proteins. Generally, proteins that can interact with each other always have special relationships. Some previous studies have reported that gene ontology (GO) terms are related to the determination of PPIs, suggesting the special patterns on the GO terms of proteins in PPIs. In this study, we explored the special GO term patterns on human PPIs, trying to uncover the underlying functional mechanism of PPIs. The experimental validated human PPIs were retrieved from STRING database, which were termed as positive samples. Additionally, we randomly paired proteins occurring in positive samples, yielding lots of negative samples. A simple calculation was conducted to count the number of positive samples for each GO term pair, where proteins in samples were annotated by GO terms in the pair individually. The similar number for negative samples was also counted and further adjusted due to the great gap between the numbers of positive and negative samples. The difference of the above two numbers and the relative ratio compared with the number on positive samples were calculated. This ratio provided a precise evaluation of the occurrence of GO term pairs for positive samples and negative samples, indicating the latent GO term patterns for PPIs. Our analysis unveiled several nuclear biological processes, including gene transcription, cell proliferation, and nutrient metabolism, as key biological functions. Interactions between major proliferative or metabolic GO terms consistently correspond with significantly reported PPIs in recent literature.

The protective effects of BMSA1 and BMSA5-1-1 proteins against Babesia microti infection.

The intracellular parasite Babesia microti is among the most significant species causing human babesiosis and is an emerging threat to human health worldwide. Unravelling the pathogenic molecular mechanisms of babesiosis is crucial in developing new diagnostic and preventive methods. This study assessed how priming with B. microti surface antigen 1 (BHSA 1) and seroreactive antigen 5-1-1 (BHSA 5-1-1) mediate protection against B. microti infection. The results showed that 500 µg/ml rBMSA1 and rBMSA5-1-1 partially inhibited the invasion of B. microti in vitro by 42.0 ± 3.0%, and 48.0 ± 2.1%, respectively. Blood smears revealed that peak infection at 7 days post-infection (dpi) was 19.6%, 24.7%, and 46.7% in the rBMSA1, rBmSA5-1-1, compared to the control groups (healthy mice infected with B. microti only), respectively. Routine blood tests showed higher white blood cell, red blood cell counts, and haemoglobin levels in the 2 groups (BMSA1 and BMSA5 5-1-1) than in the infection control group at 0-28 dpi. Moreover, the 2 groups had higher serum interferon-γ, tumor necrosis factor-α and Interleukin-17A levels, and lower IL-10 levels than the infection control group throughout the study. These 2 potential vaccine candidate proteins partially inhibit in vitro and in vivo B. microti infection and enhance host immunological response against B. microti infection.

Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Water-compatible cross-linked pyrrolidone acrylate pressure-sensitive adhesives with persistent adhesion for transdermal delivery: Synergistic effect of hydrogen bonding and electrostatic force.

Poor skin adhesion and mechanical properties are common problems of pressure-sensitive adhesive (PSA) in transdermal drug delivery system (TDDS). Its poor water compatibility also causes the patch to fall off after sweating or soaking in the application site. To solve this problem, poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl)acrylamide) (PENH), a cross-linked pyrrolidone polyacrylate PSA, was designed to improve the adhesion and water resistance of PSA through electrostatic force and hydrogen bonding system. The structure of PENH was characterized by 1H NMR, FTIR, DSC, and other methods. The mechanism was studied by FTIR, rheological test, and molecular simulation. The results showed that the PENH patch could adhere to human skin for more than 10 days without cold flow, and it could still adhere after sweating or water contact. In contrast, the commercial PSA Duro-Tak® 87-4098 and Duro-Tak® 87-2852 fell off completely on the 3rd and 6th day, respectively, and Duro-Tak® 87-2510 showed a significant dark ring on the second day. Mechanism studies have shown that the hydrogen bond formed by 2-ethylhexyl acrylate (2-EHA), N-vinyl-2-pyrrolidinone (NVP), and N-(2-Hydroxyethyl)acrylamide (HEAA) enhances cohesion, the interaction with skin improves skin adhesion, and the electrostatic interaction with water or drug molecules enhances the ability of water absorption and drug loading. Due to the synergistic effect of hydrogen bonds and electrostatic force, PENH can maintain high cohesion after drug loading or water absorption. PENH provides a choice for the development of water-compatible patches with long-lasting adhesion. STATEMENT OF SIGNIFICANCE: Based on the synergistic effect of hydrogen bonding and electrostatic force, a hydrogen-bonded, cross-linked pyrrolidone acrylate pressure-sensitive adhesive for transdermal drug delivery was designed and synthesized, which has high adhesion and cohesive strength and is non-irritating to the skin. The patch can be applied on the skin surface continuously for more than 10 days without the phenomenon of "dark ring", and the patch can remain adherent after the patient sweats or bathes. This provides a good strategy for choosing a matrix for patches that require prolonged administration.

Periodic magnetic modulation enhanced electrochemical analysis for highly sensitive determination of genomic DNA methylation.

DNA methylation aberrations have a strong correlation with cancer in early detection, diagnosis, and prognosis, which make them possible candidate biomarkers. Electrochemical biosensors offer rapid protocols for detecting DNA methylation status with minimal pretreatment of samples. However, the inevitable presence of background current in the time domain, including electrochemical noise and variations, limits the detection performance of these biosensors, especially for low concentration analytes. Here, we propose an ultrasensitive frequency-domain electrochemical analysis strategy to effectively separate the weak signals from background current. To achieve this, we employed periodic magnetic field modulation of magnetic beads (MBs) on and off the electrode surface to generate a periodic electrochemical signal for subsequent frequency-domain analysis. By capturing labeled MBs with as low as 0.5 pg of DNA, we successfully demonstrated a highly sensitive electrochemical method for determination of genome-wide DNA methylation levels. We also validated the effectiveness of this methodology using DNA samples extracted from three types of hepatocellular carcinoma (HCC) cell lines. The results revealed varying genomic methylation levels among different HCC cell lines, indicating the potential application of this approach for early-stage cancer detection in terms of DNA methylation status.

Melatonin alleviates glyphosate-induced testosterone synthesis inhibition via targeting mitochondrial function in roosters.

Glyphosate (GLY) is a widely used herbicide that has been revealed to inhibit testosterone synthesis in humans and animals. Melatonin (MET) is an endogenous hormone that has been demonstrated to promote mammalian testosterone synthesis via protecting mitochondrial function. However, it remains unclear whether MET targets mitochondria to alleviate GLY-inhibited testosterone synthesis in avian. In this study, an avian model using 7-day-old rooster upon chronic exposure to GLY with the treatment of MET was designed to clarify this issue. Data first showed that GLY-induced testicular Leydig cell damage, structural damage of the seminiferous tubule, and sperm quality decrease were mitigated by MET. Transcriptomic analyses of the testicular tissues revealed the potentially critical role of mitophagy and steroid hormone biosynthesis in the process of MET counteracting GLY-induced testicular damage. Also, validation data demonstrated that the inhibition of testosterone synthesis due to GLY-induced mitochondrial dynamic imbalance and concomitant Parkin-dependent mitophagy activation is alleviated by MET. Moreover, GLY-induced oxidative stress in serum and testicular tissue were significantly reversed by MET. In summary, these findings demonstrate that MET effectively ameliorates GLY-inhibited testosterone synthesis by inhibiting mitophagy activation, which provides a promising remedy for the application of MET as a potential therapeutic agent to antagonize reproductive toxicity induced by GLY and similar contaminants.

A polyethylene glycol-grafted pullulan polysaccharide adhesive improves drug loading capacity and release efficiency.

In this study, polyethylene glycol was grafted onto pullulan polysaccharides, resulting in the development of a novel adhesive termed PLUPE, offering superior drug loading capacity and rapid release efficiency. The efficacy of PLUPE was rigorously evaluated through various tests, including the tack test, shear strength test, 180° peel strength test, and human skin adhesion test. The results demonstrated that PLUPE exhibited a static shear strength that was 4.6 to 9.3 times higher than conventional PSAs, ensuring secure adhesion for over 3 days on human skin. A comprehensive analysis, encompassing electrical potential evaluation, calculation of interaction parameters, and FT-IR spectra, elucidated why improved the miscibility between the drug and PSAs, that the significant enhancement of intermolecular hydrogen bonding in the PLUPE structure. ATR-FTIR, rheological, and thermodynamic analyses further revealed that the hydrogen bonding network in PLUPE primarily interacted with polar groups in the skin. This interaction augmented the fluidity and free volume of PSA molecules, thereby promoting efficient drug release. The results confirmed the safety profile of PLUPE through skin irritation tests and MTT assays, bolstering its viability for application in TDDS patches. In conclusion, PLUPE represented a groundbreaking adhesive solution for TDDS patches, successfully overcoming longstanding challenges associated with PSAs.

Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic-Immune Combination Therapy for Colorectal Cancer.

Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV-Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV-Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a "cold" into a "hot" tumor, it offers valuable insights for clinical translation and application.

Management of anastomotic biliary stricture through utilizing percutaneous transhepatic cholangioscopy.

AIM: Occurrence of anastomotic biliary stricture (AS) remains an essential issue following hepatobiliary surgeries, and percutaneous transhepatic cholangioscopy (PTCS) has great therapeutic significance in handling refractory AS for patients with altered gastrointestinal anatomy after cholangio-jejunostomy. This present study aimed to investigate feasibility of PTCS procedures in AS patients for therapeutic indications. MATERIALS AND METHODS: This study was a single-center, retrospective cohort study with a total number of 124 consecutive patients who received therapeutic PTCS due to AS. Clinical success rate, required number, and adverse events of therapeutic PTCS procedures as well as patients survival state were reviewed. RESULTS: These 124 patients previously underwent choledochojejunostomy or hepatico-jejunostomy, and there was post-surgical altered gastrointestinal anatomy. Overall, 366 therapeutic PTCS procedures were performed for these patients through applying rigid choledochoscope, and the median time of PTCS procedures was 3 (1-11). Among these patients, there were 34 cases (27.32%) accompanied by biliary strictures and 100 cases (80.65%) were also combined with biliary calculi. After therapeutic PTCS, most patients presented with relieved clinical manifestations and improved liver functions. The median time of follow-up was 26 months (2-86 months), and AS was successfully managed through PTCS procedures in 104 patients (83.87%). During the follow-up period, adverse events occurred in 81 cases (65.32%), most of which were tackled through supportive treatment. CONCLUSION: PTCS was a feasible, safe and effective therapeutic modality for refractory AS, which may be a promising alternative approach in clinical cases where the gastrointestinal anatomy was changed after cholangio-jejunostomy.

Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.

Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.