USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer.

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

In Situ Defect Engineering in Carbon by Atomic Self-Activation to Boost the Accessible Low-Voltage Insertion for Advanced Potassium-Ion Full-Cells.

Enhancing the low-potential capacity of anode materials is significant in boosting the operating voltage of full-cells and constructing high energy-density energy storage devices. Graphitic carbons exhibit outstanding low-potential potassium storage performance, but show a low K+ diffusion kinetics. Herein, in situ defect engineering in graphitic nanocarbon is achieved by an atomic self-activation strategy to boost the accessible low-voltage insertion. Graphitic carbon layers grow on nanoscale-nickel to form the graphitic nanosphere with short-range ordered microcrystalline due to nickel graphitization catalyst. Meanwhile, the widely distributed K+ in the precursor induces the activation of surrounding carbon atoms to in situ generate carbon vacancies as channels. The graphite microcrystals with defect channels realize reversible K+ intercalation at low-potential and accessible ion diffusion kinetics, contributing to high reversible capacity (209 mAh g-1 at 0.05 A g-1 under 0.8 V) and rate capacity (103.2 mAh g-1 at 1 A g-1). The full-cell with Prussian blue cathode and graphitic nanocarbon anode maintains an obvious working platform at ca. 3.0 V. This work provides a strategy for the in situ design of carbon anode materials and gives insights into the potassium storage mechanism at low-potential for high-performance full-cells.

Recent advances of m6A methylation in skeletal system disease.

Skeletal system disease (SSD) is defined as a class of chronic disorders of skeletal system with poor prognosis and causes heavy economic burden. m6A, methylation at the N6 position of adenosine in RNA, is a reversible and dynamic modification in posttranscriptional mRNA. Evidences suggest that m6A modifications play a crucial role in regulating biological processes of all kinds of diseases, such as malignancy. Recently studies have revealed that as the most abundant epigentic modification, m6A is involved in the progression of SSD. However, the function of m6A modification in SSD is not fully illustrated. Therefore, make clear the relationship between m6A modification and SSD pathogenesis might provide novel sights for prevention and targeted treatment of SSD. This article will summarize the recent advances of m6A regulation in the biological processes of SSD, including osteoporosis, osteosarcoma, rheumatoid arthritis and osteoarthritis, and discuss the potential clinical value, research challenge and future prospect of m6A modification in SSD.

Chemokines in colon cancer progression.

Colon cancer is a major human cancer accounting for about a tenth of all cancer cases thus making it among the top three cancers in terms of incidence as well as mortality. Metastasis to distant organs, particularly to liver, is the primary reason for associated mortality. Chemokines, the chemo-attractants for various immune cells, have increasingly been reported to be involved in cancer initiation and progression, including in colon cancer. Here we discuss the available knowledge on the role of several chemokines, such as, CCL2, CCL3, CCL5, CXCL1, CXCL2, CXCL8 in colon cancer progression. CCL20 is one chemokine with emerging evidence for its role in influencing colon cancer tumor microenvironment through the documents effects on fibroblasts, macrophages and immune cells. We focus on CCL20 and its receptor CCR6 as promising factors that affect multiple levels of colon cancer progression. They interact with several cytokines and TLR receptors leading to increased aggressiveness, as supported by multitude of evidence from in vitro, in vivo studies as well as human patient samples. CCL20-CCR6 bring about their biological effects through regulation of several signaling pathways, including, ERK and NF-κB pathways, in addition to the epithelial-mesenchymal transition. Signaling involving CCL20-CCR6 has profound effect on colon cancer hepatic metastasis. Combined with elevated CCL20 levels in colon tumors and metastatic patients, the above information points to a need for further evaluation of chemokines as diagnostic and/or prognostic biomarkers.

Targeting syndecan-1: new opportunities in cancer therapy.

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles in developing new therapeutic methods, offering our perspective on the future directions to target SDC1 for cancer treatment.

Synthesis and Antibacterial Activity Evaluation of Biphenyl and Dibenzofuran Derivatives as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria.

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, a series of biphenyl and dibenzofuran derivatives were designed and synthesized by Suzuki-coupling and demethylation reactions in moderate to excellent yields (51-94% yield). Eleven compounds exhibited potent antibacterial activities against the prevalent antibiotic-resistant Gram-positive and Gram-negative pathogens, among which compounds 4'-(trifluoromethyl)-[1,1'-biphenyl]-3,4,5-triol (6i) and 5-(9H-carbazol-2-yl) benzene-1,2,3-triol (6m) showed the most potent inhibitory activities against methicillin-resistant Staphylococcus aureus and multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 3.13 and 6.25 µg/mL, respectively. Compounds 3',5'-dimethyl-[1,1'-biphenyl]-3,4,4',5-tetraol (6e), 4'-fluoro-[1,1'-biphenyl]-3,4,5-triol (6g), and 4'-(trifluoromethyl)-[1,1'-biphenyl]-3,4,5-triol (6i) showed comparable inhibitory activities with ciprofloxacin to Gram-negative bacterium carbapenems-resistant Acinetobacter baumannii. Study of the structure-activity relationship indicated that a strong electron-withdrawing group on the A ring and hydroxyl groups on the B ring of biphenyls were beneficial to their antibacterial activities, and for benzo-heterocycles, N-heterocycle exhibited optimal antibacterial activity. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.

Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial.

BACKGROUND: Painless gastrointestinal endoscopy is widely used for the diagnosis and treatment of digestive diseases. At present, propofol is commonly used to perform painless gastrointestinal endoscopy, but the high dose of propofol often leads to a higher incidence of cardiovascular and respiratory complications. Studies have shown that the application of propofol combined with ketamine in painless gastrointestinal endoscopy is beneficial to reduce the dosage of propofol and the incidence of related complications. Esketamine is dextrorotatory structure of ketamine with a twice as great anesthetic effect as normal ketamine but fewer side effects. We hypothesized that esketamine may reduce the consumption of propofol and to investigate the safety of coadministration during gastrointestinal endoscopy. METHODS: A total of 260 patients undergoing painless gastrointestinal endoscopy (gastroscope and colonoscopy) were randomly divided into P group (propofol + saline), PK1 group (propofol + esketamine 0.05 mg/kg), PK2 group (propofol + esketamine 0.1 mg/kg), and PK3 group (propofol + esketamine 0.2 mg/kg). Anesthesia was achieved by 1.5 mg/kg propofol with different doses of esketamine. Propofol consumption per minute was recorded. Hemodynamic index, pulse oxygen saturation, operative time, induction time, awakening status, orientation recovery time, adverse events, and Mini-Mental State Examination (MMSE) were also recorded during gastrointestinal endoscopy. RESULTS: Propofol consumption per minute was 11.78, 10.56, 10.14, and 9.57 (mg/min) in groups P, PK1, PK2, and PK3, respectively; compared with group P, groups PK2 and PK3 showed a decrease of 13.92% (P = 0.021) and 18.76% (P = 0.000), respectively. In all four groups, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), but not pulse oxygen saturation (SpO2) significantly decreased (P = 0.000) immediately after administration of induction, but there were no significant differences between the groups. The induction time of groups P, PK1, PK2, and PK3 was 68.52 ± 18.394, 64.83 ± 13.543, 62.23 ± 15.197, and 61.35 ± 14.470 s, respectively (P = 0.041). Adverse events and psychotomimetic effects were observed but without significant differences between the groups. CONCLUSIONS: The combination of 0.2 mg/kg esketamine and propofol was effective and safe in painless gastrointestinal endoscopy as evidenced by less propofol consumption per minute, shorter induction time, and lower incidence of cough and body movement relative to propofol alone. The lack of significant differences in hemodynamic results, anesthesia-related indices, adverse events, and MMSE results showed the safety to apply this combination for painless gastrointestinal endoscopy. Trial registration This study was registered with China Clinical Trial Registration on 07/11/2020 (registration website: chictr.org.cn; registration numbers: ChiCTR https://clinicaltrials.gov/ct2/show/2000039750 ).

A systematic review of preclinical studies on the taurine role during diabetic nephropathy: focused on anti-oxidative, anti-inflammation, and anti-apoptotic effects.

Diabetic nephropathy is one of the most important and growing diseases globally and the leading cause of cardiovascular mortality in these patients. Taurine is an amino acid that has pleiotropic protective properties on some diseases. This study aimed to investigate the potential role of taurine in the treatment of diabetes-induced nephropathy. To achieve the aim of the present study, a comprehensive systematic search based on PRISMA guidelines has been conducted up to August 2021. A total of 382 articles were found in the electronic databases based on search keywords. After doing the screening, 14 articles were included in the present systematic review. The dated demonstrated elevation of oxidative stress, inflammatory and apoptotic pathways, and changes in other molecules' function plays an essential role in diabetes-induced renal tissue damage. Due to its multiple protective effects, taurine significantly prevented the activation of the pathways mentioned above and altered the function of molecules involved in these pathways, resulting in alleviating diabetic nephropathy. According to the obtained results, it was found that taurine can mitigate diabetes-induced nephropathy, mainly through its anti-oxidant activity, which is an essential factor in activating inflammation and apoptosis pathways.

Impurity identification and quantification for arginine vasopressin by liquid chromatography/high-resolution mass spectrometry.

RATIONALE: For pharmaceutical quality control, impurities may have unexpected pharmacological or toxicological effects on quality, safety, and efficacy of drugs. Arginine vasopressin (AVP) is an important cyclic peptide drug that is mainly used for the treatment of diabetes insipidus and esophageal varices bleeding. With the advancement made in analytical techniques, liquid chromatography/high-resolution mass spectrometry (LC/HRMS) has emerged as a critical technique for the identification and quantification of structurally related peptide impurities in AVP. METHODS: An LC/HRMS/MS-based method using a quadrupole ion trap-Orbitrap mass spectrometer operated in the positive ion electrospray ionization mode was developed for the determination and quantification of structurally related peptide impurities in AVP. RESULTS: Under optimized experimental conditions, three deamidation products, ([Glu4 ]AVP, [Asp5 ]AVP, and AVP acid), two amino acid deletion impurities (des-Pro7 -AVP and des-Gly9 -AVP), one amino acid insertion impurity (endo-Gly10a -AVP), one end chain reaction product (N-acetyl-AVP), and one AVP isomer were detected. Subsequent quantification using an external standard method estimated the total mass fraction of all structurally related peptide impurities in the AVP study material to be 30.3 mg/g with an expanded uncertainty of 3.0 mg/g (k = 2). CONCLUSIONS: This study complements the AVP impurity profile and improves the separation and discovery of other potential impurities in vasopressin analogues.

The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers.

Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD-1 is an important immunomodulatory protein, the blockade of PD-1 and its ligand PD-L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD-1/PD-L1 interaction in gastrointestinal tract cancers. Targeting PD-1 and PD-L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD-1/PD-L1-associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD-1/PD-L1-targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies.

The Increasing Diagnostic Role of Exosomes in Inflammatory Diseases to Leverage the Therapeutic Biomarkers.

Inflammatory diseases provide substantial worldwide concerns, affecting millions of people and healthcare systems by causing ongoing discomfort, diminished quality of life, and increased expenses. In light of the progress made in treatments, the limited effectiveness and negative side effects of present pharmaceuticals need a more comprehensive comprehension of the underlying processes in order to develop more precise remedies. Exosomes, which are tiny vesicles that play a vital role in cell communication, have been identified as prospective vehicles for effective delivery of anti-inflammatory medicines, immunomodulators, and gene treatments. Vesicles, which are secreted by different cells, have a crucial function in communicating between cells. This makes them valuable in the fields of diagnostics and therapies, particularly for inflammatory conditions. Exosomes have a role in regulating the immune system, transporting cytokines, and influencing cell signaling pathways associated with inflammation. They consist of proteins, lipids, and genetic information that have an impact on immune responses and inflammation. Scientists are now investigating exosomes as biomarkers for inflammatory disease. This review article aims to develop non-invasive diagnostic techniques with improved sensitivity and specificity. Purpose of this review is a thorough examination of exosomes in pharmacology, specifically emphasizing their origin, contents, and functions, with the objective of enhancing diagnostic and therapeutic strategies for inflammatory conditions. Gaining a comprehensive understanding of the intricate mechanisms involved in exosome-mediated interactions and their impact on immune responses is of utmost importance in order to devise novel approaches for tackling inflammatory disease and enhancing patient care.

Association between MTHFR Ala222Val (rs1801133) polymorphism and bladder cancer susceptibility: a systematic review and meta-analysis.

Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. The association between the MTHFR Ala222Val polymorphism and bladder cancer has been widely reported, however, in general the data from published studies with individually low statistical power were controversial and underpowered. Hence, we performed a meta-analysis to investigate the association between bladder cancer and MTHFR Ala222Val in different inheritance models. Fourteen studies including a total of 3,570 bladder cancer cases and 3,926 controls for MTHFR rs1801133 polymorphism were included in the meta-analysis. Data were extracted from these studies and odds ratios with corresponding 95 % confidence intervals (95 % CI) were computed to estimate the strength of the association. Overall, the MTHFR Ala222Val polymorphism was not associated with the development of bladder cancer in all genetic models (Ala/Ala vs. Val/Val--OR = 0.961, 95 % CI = 0.763-1.209; Ala/Ala vs. Ala/Val--OR = 0.918, 95 % CI = 0.795-1.060--Ala/Val vs. Val/Val--OR = 1.022, 95 % CI = 0.852-1.227; dominant model--OR = 0.998, 95 % CI = 0.869-1.145; recessive model--OR = 0.921, 95 % CI = 0.794-1.069; Ala allele vs. Val allele--OR = 0.957, 95 % CI = 0.857-1.067). In the stratified analyses, no significant associations were found among different descent populations and sources of controls. Our meta-analysis suggests that the MTHFR Ala222Val polymorphism not contributes to the development of bladder cancer.

Enantioselective esterification of ibuprofen under microwave irradiation.

Enantioselective esterification of ibuprofen has been successfully carried out in an organic solvent catalyzed by recombinant APE 1547 (a thermophilic esterase from the archaeon Aeropyrum pernix K1). Here we used microwave irradiation (MW) as the mode of heating to improve the enzyme performance. Under the optimum conditions, the enzyme activity of APE 1547 was 4.16 µmol/mg/h and the enantioselectivity (E value) was 52.9. Compared with conventional heating, the enzyme activity and the enantioselectivity were increased about 21.9-fold and 1.4-fold, respectively. The results also indicated that APE 1547 can maintain 95% of its activity even after being used five times, suggesting that the enzyme is stable under low power MW conditions.

[ShRNA-mediated silencing of MDM2 inhibits growth of HepG2 hepatocellular carcinoma cells xenografted in nude mice].

OBJECTIVE: To construct a short hairpin (sh)RNA targeting the gene encoding the MDM2 oncoprotein in order to investigate its role in human hepatocellular carcinoma (HCC) and its potential for use as a gene therapy strategy to inhibit HCC growth in vivo. METHODS: Small interfering (si)RNAs were designed targeting the MDM2 gene (siMDM2-1 and siMDM2-2) and unrelated sequences (negative control) and cloned into the expression plasmid pGCSilencer-U6-neo-GFP. A HCC mouse model was established by subcutaneous inoculation of HepG2 cells (2 x 10(6) in 0.2 ml) into 20 nude mice. The inoculated mice were divided into four equal groups for tumor-localized injections of saline, negative control siRNA plasmid, siMDM2-1 plasmid, and siMDM2-2 plasmid. Tumor growth was observed daily (by caliper measurement) for one month, when mice were sacrificed by cervical dislocation. The tumor mass was resected for analysis of tumor inhibition rate (% = [(average tumor weight of control group - average tumor weight of treatment group) / average tumor weight of control group x 100]) and effects on MDM2 and p53 mRNA and protein expression (by reverse transcription- PCR and western blotting, both normalized to beta-actin). Significance of between-group differences was assessed by one-way ANOVA or LSD test; pairwise comparisons were made by the Chi-squared test. RESULTS: siMDM2-1 and siMDM2-2 suppressed the xenografted tumor growth remarkably (60.6% and 54.6% inhibition rates, respectively), significantly reduced the expression ofMDM2 gene (62.8% and 61.6%) and protein (60.7% and 59.5%), and significantly increased p53 gene (47.1% and 45.6%) and protein (45.9% and 44.3%) (all, P < 0.05). CONCLUSION: shRNA-mediated silencing of the MDM2 gene effectively inhibits HCC tumorigenesis of subcutaneously xenografted HepG2 cells in nude mice, and the mechanism may involve p53.

Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: Focused on host defense peptides.

The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs.

Putative cause of seizure-induced cognitive alterations: The oscillatory reconfiguration of seizure network.

Introduction: The dynamic reconfiguration of network oscillations is connected with cognitive processes. Changes in how neural networks and signaling pathways work are crucial to how epilepsy and related conditions develop. Specifically, there is evidence that prolonged or recurrent seizures may induce or exacerbate cognitive impairment. However, it still needs to be determined how the seizure brain configures its functional structure to shape the battle of strong local oscillations vs. slow global oscillations in the network to impair cognitive function. Methods: In this paper, we aim to deduce the network mechanisms underlying seizure-induced cognitive impairment by comparing the evolution of strong local oscillations with slow global oscillations and their link to the resting state of healthy controls. Here, we construct a dynamically efficient network of pathological seizures by calculating the synchrony and directionality of information flow between nine patients' SEEG signals. Then, using a pattern-based method, we found hierarchical modules in the brain's functional network and measured the functional balance between the network's local strong and slow global oscillations. Results and discussion: According to the findings, a tremendous rise in strong local oscillations during seizures and an increase in slow global oscillations after seizures corresponded to the initiation and recovery of cognitive impairment. Specifically, during the interictal period, local strong and slow global oscillations are in metastable balance, which is the same as a normal cognitive process and can be switched easily. During the pre-ictal period, the two show a bimodal pattern of separate peaks that cannot be easily switched, and some flexibility is lost. During the seizure period, a single-peak pattern with negative peaks is showcased, and the network eventually transitions to a very intense strong local oscillation state. These results shed light on the mechanism behind network oscillations in epilepsy-induced cognitive impairment. On the other hand, the differential (similarity) of oscillatory reorganization between the local (non) epileptogenic network and the global network may be an emergency protective mechanism of the brain, preventing the spread of pathological information flow to more healthy brain regions.

[Clinical and radiologic comparison between oblique lateral interbody fusion and minimally invasive transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis].

OBJECTIVE: To compare the short-term clinical efficacy and radiologic differences between oblique lateral interbody fusion(OLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for degenerative lumbar spondylolisthesis. METHODS: A retrospective analysis was performed on 58 patients with lumbar spondylolisthesis treated with OLIF or MIS-TLIF from April 2019 to October 2020. Among them, 28 patients were treated with OLIF (OLIF group), including 15 males and 13 females aged 47 to 84 years old with an average age of (63.00±9.38) years. The other 30 patients were treated with MIS-TLIF(MIS-TLIF group), including 17 males and 13 females aged 43 to 78 years old with an average age of (61.13±11.10) years. General conditions, including operation time, intraoperative blood loss, postoperative drainage, complications, lying in bed, and hospitalization time were recorded in both groups. Radiological characteristics, including intervertebral disc height (DH), intervertebral foramen height (FH), and lumbar lordosis angle (LLA), were compared between two groups. The visual analogue scale (VAS) and Oswestry disability index (ODI) were used to evaluate the clinical effect. RESULTS: The operation time, intraoperative blood loss, postoperative drainage, lying in bed, and hospitalization time in OLIF group were significantly less than those in the MIS-TLIF group (P<0.05). The intervertebral disc height and intervertebral foramen height were significantly improved in both groups after the operation (P<0.05). The lumbar lordosis angle in OLIF group was significantly improved compared to before the operation(P<0.05), but there was no significant difference in the MIS-TLIF group before and after operation(P>0.05). Postoperative intervertebral disc height, intervertebral foramen height, and lumbar lordosis were better in the OLIF group than in the MIS-TLIF group (P<0.05). The VAS and ODI of the OLIF group were lower than those of the MIS-TLIF group within 1 week and 1 month after the operation (P<0.05), and there were no significant differences in VAS and ODI at 3 and 6 months after the operation between the two groups(P>0.05). In the OLIF group, 1 case had paresthesia of the left lower extremity with flexion-hip weakness and 1 case had a collapse of the endplate after the operation;in the MIS-TLIF group, 2 cases had radiation pain of lower extremities after decompression. CONCLUSION: Compared with MIS-TLIF, OLIF results in less operative trauma, faster recovery, and better imaging performance after lumbar spine surgery.

KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

Regulatory effects of lncRNAs and miRNAs on the crosstalk between autophagy and EMT in cancer: a new era for cancer treatment.

PURPOSE: Autophagy and EMT (epithelial-mesenchymal transition) are the two principal biological processes and ideal therapeutic targets during cancer development. Autophagy, a highly conserved process for degrading dysfunctional cellular components, plays a dual role in tumors depending on the tumor stage and tissue types. The EMT process is the transition differentiation from an epithelial cell to a mesenchymal-like cell and acquiring metastatic potential. There is evidence that the crosstalk between autophagy and EMT is complex in cancer. In recent years, more studies have shown that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in autophagy, EMT, and their crosstalk. Therefore, accurate understanding of the regulatory mechanisms of lncRNAs and miRNAs in autophagy, EMT and their interactions is crucial for the clinical management of cancers. METHODS: An extensive literature search was conducted on the Google Scholar and PubMed databases. The keywords used for the search included: autophagy, EMT, crosstalk, lncRNAs, miRNAs, cancers, diagnostic biomarkers, and therapeutic targets. This search provided relevant articles published in peer-reviewed journals until 2021. Data from these various studies were extracted and used in this review. RESULTS: The results showed that lncRNAs/miRNAs as tumor inhibitors or tumor inducers could regulate autophagy, EMT, and their interaction by regulating several molecular signaling pathways. The lncRNAs/miRNAs involved in autophagy and EMT processes could have potential uses in cancer diagnosis, prognosis, and therapy. CONCLUSION: Such information could help find and develop lncRNAs/miRNAs based new tools for diagnosing, prognosis, and creating anti-cancer therapies.

Esketamine alleviates postoperative depression-like behavior through anti-inflammatory actions in mouse prefrontal cortex.

The rising incidence of postoperative depression (POD) in recent years has placed a heavy burden on patients' physical and mental health. At this point in time, however, POD pathogenesis remains poorly understood and novel therapeutic strategies are being sought. The present study aimed to clarify esketamine's protective effects and possible mechanisms of action in POD. To this avail, we used an animal model of postoperative depression to analyze behavioral, parameters, plus the inflammatory response in serum and in the medial prefrontal cortex (mPFC). Using immunofluorescence staining, we detected the number of microglia and parvalbumin (PV) in mPFC, and determined changes in neuronal dendritic spine density via Golgi staining. Expression of Iba1, PSD95 and NF-κB was examined by Western blot analysis. Our results show that esketamine can significantly improve depression-like symptoms caused by anesthesia and surgery. In addition, esketamine administration reversed the decrease in the density of PV neurons and restored synaptogenesis in mPFC which had been perturbed by inflammation. The evidence obtained suggests esketamine's anti-inflammatory effects may be mediated by the BDNF/TrkB signaling pathway and possibly by attenuation of the nuclear factor κB (NF-κB) pathway. These data warrant further investigations into the interplay of esketamine, and microglia in the modulation of POD symptomatology.