Resistance Pathways Research Articles

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

A concise review of the effect of efflux pump on biofilm intensity in bacteria with a special view to Mycobacterium

Abstract Excessive, arbitrary, self-medication, and misuse of antibiotics have caused widespread antibiotic resistance, but with the emergence of multiple antibiotic resistances, these concerns have increased. Efflux pumps are an important pathway involved in antibiotic resistance and can send the drug used in clinical cases out of the bacterial cell. Many studies show the role of these pumps in biofilm formation as well as increasing biofilm formation. Considering the effective relationship between antibiotic resistance from the efflux pump pathway and biofilm increase in bacteria, the purpose of this study was to investigate various aspects of the efflux pump pathway in biofilm exacerbation, especially in Mycobacterium. For this purpose, we studied more than 60 articles with keywords efflux pump, antibiotic resistance, biofilm formation, and Mycobacterium tuberculosis from valuable data sources such as PubMed, Scopus, Google Scholar, and Web of Science. Through the investigation, we came to the conclusion that the efflux pump is one of the main pathways of antibiotic resistance in bacteria, especially M. tuberculosis, which can increase the formation of biofilm in them, and as a result of this cooperation, the treatment process can become much more difficult. We suggest that all drug resistance pathways and their genes are investigated in the occurrence of other diseases, not only tuberculosis, in different geographical areas.

Updates on altered signaling pathways in tumor drug resistance

Curing cancer has always presented a formidable clinical challenge. Among the various treatment strategies for combating tumors, the combination of targeted therapy and immunotherapy has recently assumed significant importance. Regrettably, while targeted drugs demonstrate efficiency in the early stages of cancer treatment, patients inevitably develop drug resistance as treatment progresses, ultimately resulting in treatment failure and death. Currently, effective countermeasures against drug-resistant tumor cells remain limited, and research into the mechanisms of drug resistance continues to garner profound interest. The current understanding of drug resistance primarily focuses on two aspects: intrinsic or primary drug resistance, and acquired or secondary drug resistance. Further explanations delve into molecular mechanisms, including acquired gene mutations, epigenetic modifications, the plasticity of cancer stem cells, and the mediation of exosomes. With the advancement of single-cell analysis, our understanding of these potential mechanisms has become more comprehensive. In this review, we initially explore classical signaling pathways related to tumorigenesis and cancer cell progression. Additionally, we summarize recent findings regarding gene mutations and modifications related to drug resistance in cancer. Finally, we discuss the plasticity of cancer stem cells and the latest research on exosome-mediated tumor drug resistance.

Association of COX-inhibitors with cancer patients' survival under chemotherapy and radiotherapy regimens: a real-world data retrospective cohort analysis.

We conducted an extensive, sex-oriented real-world data analysis to explore the impact and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) on cancer treatment outcomes. This is particularly relevant given the role of the COX-2/PGE2 pathway in tumor cell resistance to chemotherapy and radiotherapy. The study applied a retrospective cohort design utilizing the TriNetX research database consisting of patients receiving cancer treatment in 2008-2022. The treated cohorts included patients who were prescribed with coxibs, aspirin or ibuprofen, while individuals in the control cohort did not receive these medicines during their cancer treatment. A 1:1 propensity score matching technique was used to balance the baseline characteristics in the treated and control cohorts. Then, Cox proportional hazards regression and logistic regression were applied to assess the mortality and morbidity risks among patient cohorts in a 5-year follow-up period. Use of coxibs (HR, 0.825; 95% CI 0.792-0.859 in females and HR, 0.884; 95% CI 0.848-0.921 in males) and ibuprofen (HR, 0.924; 95% CI 0.903-0.945 in females and HR, 0.940; 95% CI 0.917-0.963 in males) were associated with improved survival. Female cancer patients receiving aspirin presented increased mortality (HR, 1.078; 95% CI 1.060-1.097), while male cancer patients also had improved survival when receiving aspirin (HR, 0.966; 95% CI 0.951-0.980). Cancer subtype specific analysis suggests coxibs and ibuprofen correlated with survival, though ibuprofen and aspirin increased emergency department visits' risk. Secondary analyses, despite limited by small cohort sizes, suggest that COX inhibition post-cancer diagnosis may benefit patients with specific cancer subtypes. Selective COX-2 inhibition significantly reduced mortality and emergency department visit rates. Further clinical trials are needed to determine the optimal conditions for indication of coxibs as anti-inflammatory adjuvants in cancer treatment.

Bispecific antibody targets and therapies in multiple myeloma.

Recently, several bispecific antibodies (BsAbs) have been approved for the treatment of relapsed multiple myeloma (MM) after early phase trials in heavily pre-treated patients demonstrated high response rates and impressive progression-free survival with monotherapy. These BsAbs provide crucial treatment options for relapsed patients and challenging decisions for clinicians. Evidence on the optimal patient population, treatment sequence, and duration of these therapeutics is unknown and subject to active investigation. While rates of cytokine release syndrome and neurotoxicity appear to be lower with BsAbs than with CAR T-cells, morbidity from infection is high and novel pathways of treatment resistance arise from the longitudinal selection pressure of chronic BsAb therapy. Lastly, a wealth of novel T-cell engagers with unique antibody-structures and antigenic targets are under active investigation with promising early outcome data. In this review, we examine the mechanism of action, therapeutic targets, combinational approaches, sequencing and mechanisms of disease relapse for BsAbs in MM.

Estrogen Receptor Is Required for Metformin-Induced Apoptosis in Breast Cancer Cells Under Hyperglycemic Conditions.

About 25% to 30% of estrogen receptor (ER)-positive breast cancer patients develop resistance to endocrine therapy. Human epidermal growth factor receptor 2 (HER2) has been shown to cooperate with several growth factors that regulate cellular energy metabolism, including the insulin-like growth factor 1 receptor (IGF-1R). As the first-line therapy for type 2 diabetes mellitus (T2DM) patients, metformin is widely known to inhibit the metabolic reprogramming of cancer cells. This study aims to investigate metformin's efficacy in inhibiting endocrine resistance related to genes regulating energy metabolism in both ER-positive and ER-negative breast cancer cell lines under hyperglycemic conditions. MDA-MB-361 (ER-positive, HER2-positive) and SKBR3 (ER-negative, HER2-positive) cancer cell lines were used to represent ER status. Cell viability and cell survival rate were measured using the colorimetric assay of Cell Counting Kit-8. All mRNA levels were quantified using real-time quantitative polymerase chain reaction preceded by reverse transcription. A P value of <.05 was considered statistically significant. Unlike MDA-MB-361, SKBR3 were found to acquire resistance upon metformin treatment in hyperglycemic conditions. Moreover, the mRNA expression of IGF-1R and its downstream signaling, such as the mammalian target of rapamycin (mTOR), was not affected by metformin. Meanwhile, the mRNA expression level of ribosomal S6 kinase 1 (S6K1) was upregulated, whereas forkhead box O1 (FOXO1) was downregulated after metformin treatment in hyperglycemic conditions. This preliminary study suggests that an alternative pathway of metformin resistance may exist in the absence of ERα. Therefore, relying solely on metformin may be inadequate to inhibit the aggressiveness of breast cancer cells.

Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.

Synergistic Anti-Tumor Efficacy Achieved by Reversing Drug Resistance through the Regulation of the Tumor Immune Microenvironment with IL-12 and Osimertinib Combination Therapy.

The objective of this study was to investigate the role of IL-12 in enhancing the anti-tumor efficacy of the small molecule targeted drug osimertinib in resistant tumor models and reversing resistance mechanisms. We utilized paired non-small cell lung cancer H1975 tumor tissues, establishing mouse tumor models with diverse tumor immune microenvironments. Analytical methods including immunohistochemistry and immunofluorescence were employed to compare immune cell infiltration, cytokines, effector molecules, and protein changes in resistant signaling pathways in tumor tissues, shedding light on IL-12's mechanism of action in enhancing osimertinib efficacy and reversing resistance. Results showed that osimertinib monotherapy had limited tumor suppression, whereas IL-12 exhibited more significant anti-tumor effects. Combination therapy groups demonstrated even greater tumor suppression with increased immune cell infiltration, elevated immune-related factor secretion, reduced immunosuppressive MDSCs, and decreased resistance-related signaling pathway markers. In conclusion, IL-12 enhances anti-tumor efficacy and reverses osimertinib resistance through various mechanisms, including increased immune cell infiltration, reduced immunosuppressive MDSCs, enhanced immune cell granzyme and IFN-γ release, decreased PDL-1 expression, improved tumor microenvironment, restored immune surveillance, and heightened cancer cell sensitivity to osimertinib.

Efficient analysis of adverse drug events and toxicological mechanisms of newly marketed drugs by integrating pharmacovigilance and network toxicology: selumetinib as an example.

To integrate pharmacovigilance and network toxicology methods to explore the potential adverse drug events (ADEs) and toxic mechanisms of selumetinib, and to provide a reference for quickly understanding the safety and toxicological mechanisms of newly marketed drugs. Taking selumetinib as an example, this study integrated pharmacovigilance methods based on real-world data and network toxicology methods to analyze its ADE and its potential toxicological mechanism. First, the ADE reports of selumetinib were extracted from the US Food and Drug Administration (FDA) adverse event reporting system (FAERS), and the ADE signals were detected by reporting odds ratio (ROR) and UK medicines and healthcare products regulatory agency (MHRA) methods. The ADE signals were classified and described according to the preferred terms (PTs) and system organ class (SOC) derived from the Medical Dictionary for Regulatory Activities (MedDRA). The network toxicology method was used to analyze the toxicological mechanism of the interested SOCs. The specific steps included predicting the potential targets of selumetinib using TOXRIC, STITCH, ChEMBL, CTD, SwissTargetPreditcion, and Super-PRED databases, collecting the targets of SOC using GeneCards database, conducting protein-protein interaction (PPI) analysis through STRING database, conducting gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis through DAVID database, and testing the molecular affinity using AutoDock software. A total of 1388 ADE reports related to selumetinib were extracted, and 53 positive signals were detected by ROR and MHRA methods, of which 20 signals were not mentioned in the package insert, including ingrowing nail, hyperphosphatemia, cardiac valve disease, hematuria, neutropenia, etc. Analysis of the toxicological mechanism of six SOCs involved in positive ADE signals revealed that the key targets included EGFR, STAT3, AKT1, IL6, BCL2, etc., and the key pathways included PI3K/Akt pathway, apoptosis, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance, etc. Molecular docking assays showed spontaneous binding of selumetinib to key targets in these pathways. The pharmacovigilance analysis identified some new potential ADEs of selumetinib, and the network toxicology analysis showed that the toxic effects of selumetinib may be related to PI3K/Akt pathway, apoptosis, ErbB signaling pathway, EGFR tyrosine kinase inhibitor resistance and other pathways.

Cuproptosis in cancer therapy: mechanisms, therapeutic application and future prospects.

Cuproptosis is a regulated form of cell death induced by the accumulation of metal ions and is closely linked to aspects of cellular drug resistance, cellular metabolism, and signalling pathways. Due to its crucial role in regulating physiological and pathological processes, cuproptosis has gained increasing significance as a potential target for anticancer drug development. In this review, we introduce the definition of cuproptosis and provide a comprehensive discussion of the mechanisms of cuproptosis. In addition, the methods for the detection of cuproptosis are summarized, and recent advances in cuproptosis in cancer therapy are reviewed, mainly in terms of elesclomol (ES)-mediated cuproptosis and disulfiram (DSF)-mediated cuproptosis, which provided practical value for applications. Finally, the current challenges and future development of cuproptosis-mediated cancer therapy are discussed. In summary, this review highlights recent progress on cuproptosis in cancer therapy, offering novel ideas and strategies for future research and applications.

Transcriptional alterations of the resistant potato genotype ‘Cruza 148’ in response to Ralstonia solanacearum infection

AbstractRalstonia solanacearum, a highly destructive phytopathogen causing bacterial wilt disease, poses a substantial risk to the potato value chain, putting global food security at risk and impeding potato production. ‘Cruza 148’, a locally adapted potato genotype, has been reported to exhibit resistance when cultivated in areas with a background of bacterial wilt occurrences. This study aimed to acquire a deeper understanding of the factors influencing resistance and susceptibility in ‘Cruza 148’ and ‘Shangi’ potato genotypes respectively. To achieve this, RNA‐seq was deployed to detect DEGs in ‘Cruza 148’ and ‘Shangi’ potato genotypes at 6 h, 24 h, 48 h, and 72 h post‐inoculation with Ralstonia solanacearum. A total of 54.2% of the DEGs were upregulated and 45.8% were downregulated in the roots of the ‘Cruza 148’ potato genotype, while 45.5% and 54.5% of DEGs were upregulated and downregulated in the roots of the susceptible potato genotype ‘Shangi’ respectively. The gene ontology (GO) enrichment analysis indicated that the ‘Cruza 148’ genotype consistently displayed the ‘defence response’ category throughout every stage of infection. The analysis of enriched GO terms revealed 225 terms, with 132 related to biological processes, 16 linked to cellular components and 12 linked to molecular functions. The ‘Cruza 148’ genotype had the highest gene counts in peptide metabolic processes and cellular component assembly, while the ‘Shangi’ genotype had the greatest number of gene counts that responded to chemicals and cellular component assembly. Defence genes identified, included leucine‐rich repeat protein, MYB transcription factor, glucan endo‐1,3‐beta‐glucosidase, serine/threonine‐protein kinase, ethylene‐responsive transcriptional coactivator and disease resistance protein, which could help explain the mechanisms and pathways of resistance to R. solanacearum. This study presents a fundamental understanding of the transcriptional alterations that occur during pathogen interactions with potato. It will also assist in identifying potential useful genes induced during the resistance and susceptibility processes.

Comparative Genomics and Characterization of Shigella flexneri Isolated from Urban Wastewater.

Shigella species are a group of highly transmissible Gram-negative pathogens. Increasing reports of infection with extensively drug-resistant varieties of this stomach bug has convinced the World Health Organization to prioritize Shigella for novel therapeutic interventions. We herein coupled the whole-genome sequencing of a natural isolate of Shigella flexneri with a pangenome ana-lysis to characterize pathogen genomics within this species, which will provide us with an insight into its existing genomic diversity and highlight the root causes behind the emergence of quick vaccine escape variants. The isolated novel strain of S. flexneri contained ~4,500 protein-coding genes, 57 of which imparted resistance to antibiotics. A comparative pan-genomic ana-lysis revealed genomic variability of ~64%, the shared conservation of core genes in central metabolic processes, and the enrichment of unique/accessory genes in virulence and defense mechanisms that contributed to much of the observed antimicrobial resistance (AMR). A pathway ana-lysis of the core genome mapped 22 genes to 2 antimicrobial resistance pathways, with the bulk coding for multidrug efflux pumps and two component regulatory systems that are considered to work synergistically towards the development of resistance phenotypes. The prospective evolvability of Shigella species as witnessed by the marked difference in genomic content, the strain-specific essentiality of unique/accessory genes, and the inclusion of a potent resistance mechanism within the core genome, strengthens the possibility of novel serotypes emerging in the near future and emphasizes the importance of tracking down genomic diversity in drug/vaccine design and AMR governance.

Citrus transcription factor CsERF098 cooperates with CsWRKY70 to participate in response of fruit to green mold

As plant-specific transcription factors (TFs), AP2/ERF can participate in regulating disease resistance in plants. Currently, researches on regulation of disease resistance of AP2/ERF TFs were mainly focused on model plants, and the regulatory mechanisms in non-model plants such as citrus fruit, an important economical fruit which is seriously infected by Penicillium digitatum, are still unclear. In this study, transcriptional activator CsERF098 overexpression enhanced the resistance of citrus fruit against green mold. Transcriptome sequencing revealed that CsERF098 was involved in four disease resistance pathways, including salicylic acid (SA) signaling pathway, lignin and waxy biosynthesis pathway, chitinase and jasmonic acid signaling pathway. CsERF098 could bind to promoter of SA pathway CsSAMT and CsSABP2, activate the transcriptional activities of CsSAMT, CsSABP2, CsTLP1b and CsTLP. Furthermore, the interaction of CsERF098 and CsWRKY70 was confirmed, which enhanced the trans-activation of CsERF098 on CsSAMT and CsSABP2. These results indicated that CsERF098 could mediate salicylic acid signaling pathway and enhance the synergistic regulation of CsSAMT and CsSABP2 through interaction with CsWRKY70, thereby in controlling the resistance of citrus fruit to Penicillium digitatum. The present study provides new thoughts on the role and mechanism of AP2/ERF transcription factor involved in regulating citrus disease resistance.

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes.

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become resistant to multiple classes of antibiotics. New antibiotics are costly to develop and deploy, and they have a limited effective lifespan. Antibiotic adjuvants are molecules that potentiate existing antibiotics through nontoxic mechanisms. We previously reported that loratadine, the active ingredient in Claritin, potentiates multiple cell-wall active antibiotics in vitro and disrupts biofilm formation through a hypothesized inhibition of the master regulatory kinase Stk1. Loratadine and oxacillin combined repressed the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional genes involved in antibiotic resistance, biofilm formation, and other cellular pathways would be modulated when looking transcriptome-wide. To test this, we used RNA-seq to quantify transcript levels and found significant effects in gene expression, including genes controlling virulence, antibiotic resistance, metabolism, transcription (core RNA polymerase subunits and sigma factors), and translation (a plethora of genes encoding ribosomal proteins and elongation factor Tu). We further demonstrated the impacts of these transcriptional effects by investigating loratadine treatment on intracellular ATP levels, persister formation, and biofilm formation and morphology. Loratadine minimized biofilm formation in vitro and enhanced the survival of infected Caenorhabditis elegans. These pleiotropic effects and their demonstrated outcomes on MRSA virulence and survival phenotypes position loratadine as an attractive anti-infective against MRSA.

From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC).

Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood-brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.

Artificial SEI Layer Combined with Single-Ion Polymer Electrolytes to Prevent Dendrite Growth in Lithium Metal Batteries

Li-metal batteries have the potential to become the next generation of batteries since they can provide an increased energy density vs. Li-ion batteries. However, the safety issue caused by the inhomogeneous Li deposition and Li dendrite growth greatly limits their commercial application. Several methods have been proposed to address this issue. On the one hand, when Li ions are released from one electrode and consumed at the other electrode, it causes a salt concentration gradient. Besides, the electrical migration of anions in the opposite direction aggravates the concentration of gradient since anions do not react at the electrodes. Fast dendritic growth then occurs when the current is high enough to fully deplete the Li+ ion at the anode during charge. Thus, suppressing concentration gradient by immobilizing the anions would in principle solve the fast dendritic growth issue. On the other hand, the Solid Electrolyte Interphase (SEI) plays a crucial role in the operation of Li metal batteries since it prevents further reduction and continuous electrolyte reaction. SEI derives from the passivation layer formed onto the surface of Li metal under dry air during lithium foil extrusion and then evolves further in contact with the electrolytes and during subsequent electrochemical Li stripping/plating. The SEI is inhomogeneous and since it contains lower resistance pathways for Li+ transport, it favors inhomogeneous deposition at any current. Thus, SEI engineering, in order to favor the homogeneity of current density and enhanced mechanical properties to confine lithium could, in principle, improve the performance of Li metal batteries.Thus, we studied the use of single-ion conducting polymers with high cationic transference numbers (tLi+ close to 1) as artificial SEIs (art-SEIs) since they include immobile anions and thus prevent Li+ depletion during charge and, at the same time, improve lithium metal confinement and the homogeneity of current density. Our results show much improved homogeneity of Li deposition and cycling stability after single-ion art-SEI coating using an ether-based liquid electrolyte combined with a separator. Nevertheless, it could not enable long-term cycling as the separator does not enable homogeneous pressure and current density onto the lithium anode. Thus, the use of a single-ion conducting solid polymer electrolyte was combined with a single-ion conducting art-SEI (as illustrated in Figure 1). This strategy allows the suppression of salt concentration gradients, inhomogeneous pressure and current density, thus enables homogeneous Li deposition and long-term cycling of Li metal anode. Figure 1

A Novel Resistive Sensor Network Utilizing an SAP-Enhanced Ionic Layer and CNT Doping for Multipoint Pressure Measurement.

Amidst the rapid advancements in flexible electronics, flexible pressure sensors have achieved widespread applications in fields such as wearable devices and motion monitoring. Nevertheless, it is still a challenge to design a sensor with high sensitivity, cost-effectiveness, and a simplified manufacturing process. This paper introduces a piezoresistive sensor built upon a composite conductive filler. The sensor incorporates a super absorbent polymer (SAP) to absorb a phosphoric acid solution and doped carbon nanotubes as the composite conductive filler. In contrast to conventional rigid conductive fillers, the elastic polymer SAP enhances the sensor's stability significantly by exhibiting superior compatibility with the polydimethylsiloxane matrix, all the while reducing its Young's modulus. This work aims to theoretically elucidate the underlying principles that enable the sensor to achieve high sensitivity. It focuses on the induction of charge carriers due to pressure, which leads to the formation of a conductive pathway and subsequent changes in resistance, thus facilitating precise pressure detection. The paper also discusses the effects of piezoresistive layers with varying thicknesses and conductive fillers on the sensor's output performance. The results highlight the sensor's high sensitivity (0.094 kPa-1), rapid response time (105 ms), and exceptional cyclic load/unload stability (>5000 cycles). Furthermore, this paper establishes a versatile sensing network by integrating a portable inductance, capacitance, and resistance instrument with a programmable logic controller module. Compared to individual sensors, this system enables multipoint measurements, offering high spatial resolution and real-time monitoring capabilities, significantly expanding its overall practicality.

A feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC

BackgroundHepatocellular carcinoma (HCC) is a principal type of liver cancer with high incidence and mortality rates. Regorafenib is a novel oral multikinase inhibitor for second-line therapy for advanced HCC. However, resistance to regorafenib is gradually becoming a dilemma for HCC and the mechanism remains unclear. In this study, we aimed to reveal the metabolic profiles of regorafenib-resistant cells and the key role and mechanism of the most relevant metabolic pathway in regorafenib resistance.MethodsMetabolomics was performed to detect the metabolic alteration between drug-sensitive and regorafenib-resistant cells. Colony formation assay, CCK-8 assay and flow cytometry were applied to observe cell colony formation, cell proliferation and apoptosis, respectively. The protein and mRNA levels were detected by western blot and RT-qPCR. Cell lines of Glucose-6-phosphate dehydrogenase(G6PD) knockdown in regorafenib-resistant cells or G6PD overexpression in HCC cell lines were stably established by lentivirus infection technique. G6PD activity, NADPH level, NADPH/NADP+ ratio, the ratio of ROS positive cells, GSH level, and GSH/GSSG ratio were detected to evaluate the anti-oxidative stress ability of cells. Phosphorylation levels of NADK were evaluated by immunoprecipitation.ResultsMetabonomics analysis revealed that pentose phosphate pathway (PPP) was the most relevant metabolic pathway in regorafenib resistance in HCC. Compared with drug-sensitive cells, G6PD enzyme activity, NADPH level and NADPH/NADP+ ratio were increased in regorafenib-resistant cells, but the ratio of ROS positive cells and the apoptosis rate under the conditions of oxidative stress were decreased. Furthermore, G6PD suppression using shRNA or an inhibitor, sensitized regorafenib-resistant cells to regorafenib. In contrast, G6PD overexpression blunted the effects of regorafenib to drug-sensitive cells. Mechanistically, G6PD, the rate-limiting enzyme of PPP, regulated the PI3K/AKT activation. Furthermore, PI3K/AKT inhibition decreased G6PD protein expression, G6PD enzymatic activity and the capacity of PPP to anti-oxidative stress possibly by inhibited the expression and phosphorylation of NADK.ConclusionTaken together, a feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC and targeting the feedback loop could be a promising approach to overcome drug resistance.

Characterization of intraocular pressure variability in conscious rats

Elevation of mean intraocular pressure (IOP) has long been recognized as a leading risk factor for glaucoma. Less is known about the possible contribution of moment-to-moment variations in IOP to disease development and progression due to limitations of tonometry, the prevailing method of IOP measurement. Tonometry provides good estimates of mean IOP but not IOP variance. The aim of this study was to quantitatively characterize IOP variability via round-the-clock IOP telemetry in conscious unrestrained rats. The anterior chamber of one eye was implanted with a microcannula connected to a wireless backpack telemetry system, and IOP data were collected every 4 s for one week. The cannula was then repositioned under the conjunctiva, and control data were collected for an additional week. IOP statistics were computed in 30-min intervals over a 24-h period and averaged across days. All animals exhibited a diurnal variation in mean IOP, while deviations about the mean were independent of time of day. Correlation analysis of the deviations revealed transient and sustained components, which were respectively extracted from IOP records using an event detection algorithm. The amplitude and interval distributions of transient and sustained events were characterized, and their energy content was estimated based on outflow tissue resistance of rat eyes. Transient IOP events occurred ∼231 times per day and were typically ≤5 mmHg in amplitude and 2–8 min in duration, while sustained IOP events occurred ∼16 times per day and were typically ≤5 mmHg in amplitude and 20–60 min in duration. Both persisted but were greatly reduced in control recordings, implying minor contamination of IOP data by motion-induced telemetry noise. Sustained events were also often synchronous across implanted animals, indicating that they were driven by autonomic startle and stress responses or other physiological processes activated by sensory signals in the animal housing environment. Not surprisingly, the total daily fluidic energy applied to resistive outflow pathways was determined primarily by basal IOP level. Nevertheless, transient and sustained fluctuations collectively contributed 6% and diurnal fluctuations contributed 9% to daily IOP energy. It is therefore important to consider the cumulative impact of biomechanical stress that IOP fluctuations apply over time to ocular tissues.

Troponin T1 silencing inhibits paclitaxel resistance and the development of breast cancer via suppressing rat sarcoma virus/rapidly accelerated fibrosarcoma 1 pathway.

We aimed to determine the role of Troponin T1 (TNNT1) in paclitaxel (PTX) resistance and tumor progression in breast cancer (BC). Differentially expressed genes were obtained from the GSE4298 and GSE90564 datasets. Hub genes were isolated from protein-protein interaction networks and further validated by real-time quantitative polymerase chain reaction. The effect of TNNT1 on PTX resistance was determined using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing, transwell, flow cytometry assays, and subcutaneous xenografted tumor model. Western blotting was used to detect proteins associated with PTX resistance, apoptosis, migration, invasion, and other key pathways. Hematoxylin-eosin and immunohistochemical staining were used to evaluate the role of TNNT1 in tumors. After comprehensive bioinformatic analysis, we identified CCND1, IGF1, SFN, INHBA, TNNT1, and TNFSF11 as hub genes for PTX resistance in BC. TNNT1 plays a key role in BC and is upregulated in PTX-resistant BC cells. TNNT1 silencing inhibited PTX resistance, proliferation, migration, and invasion while promoting apoptosis of PTX-resistant BC cells. Tumor xenograft experiments revealed that TNNT1 silencing suppresses PTX resistance and tumor development in vivo. In addition, TNNT1 silencing inhibited the expression of proteins in the rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma1 (RAF1) pathway in vivo. Treatment with a RAS/RAF1 pathway activator reversed the inhibitory effect of TNNT1 silencing on proliferation, migration, and invasion while promoting apoptosis of PTX resistance BC cells. Silencing of TNNT1 suppresses PTX resistance and BC progression by inhibiting the RAS/RAF1 pathway, which is a promising biomarker and therapeutic target for drug resistance in BC.