Blockage during the pipeline transport of cemented paste backfill (CPB) causes significant economic losses to mining operations. Suspending agent (SA) addition has been proposed as an easily implementable and low-cost method to mitigate the risk of pipeline blockage caused by sedimentation during the transportation of CPB. However, the effects of SAs on the rheological and sedimentation properties of CPB are not yet fully understood. This study investigated the rheological and sedimentation characteristics of CPB with different types of SAs. CPB mixtures were prepared with three types of SAs (hydroxypropyl methylcellulose (HPMC), polyacrylamide (PAM), and xanthan gum (XG)) at concentrations of 1.5, 3.0, and 6.0 g/L. The rheological properties (yield stress and viscosity) and sedimentation characteristics (bleeding and monitored via layered electrical conductivity) were measured over 0-2 h. Additionally, zeta potential and microstructural analyses were conducted. SA addition increased the yield stress and viscosity of CPB. Concurrently, the SAs inhibited bleeding and sedimentation. Furthermore, the SAs appeared to significantly inhibit the sedimentation of cement particles. The findings develop CPB technology utilizing SAs and provide important guidance for ensuring smooth pipeline transportation.
Based on the health benefits of polyphenols and their synergistic properties, using four common polyphenols as research subjects, the best antioxidant combination (Q: CA = 1:5) was screened by the combined index. In vitro digestion results showed that the combined polyphenols improved stability and bioaccessibility of the individual polyphenols to some extent, but the effect was not significant. Therefore, SC was chosen as the wall material to construct a nano-encapsulation system by ethanol-induced self-assembly. The optimum ethanol concentration was determined by morphology and encapsulation performance. The structural changes and encapsulation mechanisms were elucidated by spectroscopy and chromatography, involving ethanol-induced exposure of the hydrophobic region of SC and static binding of polyphenols to SC by hydrophobic interaction, hydrogen bonding, and electrostatic interaction. After digestion, the retention and bioaccessibility reached up to 74.41% and 53.69%, respectively, with excellent antioxidant activity. The present study provides valuable insights into the preparation of efficient nanocarriers for polyphenols.
This work reports the development of epoxy-based biocomposites via the valorization of coconut fiber, with tailored thermal and mechanical properties obtained by varying the reinforcement and curing system. An organosolv process was used to extract lignin from natural coconut fiber (NCF) using a 90% v/v aqueous acetic acid solution combined with 2% v/v HCl at 110 °C for 1 h, yielding organosolv coconut fiber lignin (OCFL) and modified coconut fiber (MCF). The polymeric matrix was composed of diglycidyl ether of bisphenol A containing 0 or 50 wt% OCFL, while NCF and MCF were used as reinforcements. The biocomposites were prepared with a matrix-to-reinforcement mass ratio of 80:20 and cured with either a protic or an aprotic ionic liquid, specifically 10 wt% [HMIM][HSO4] at 180 °C or 10 wt% [BMIM][PF6] at 220 °C for 1 h. The biocomposites were characterized by thermogravimetry, constant-pressure calorimetry, gel content, water absorption, chemical resistance, scanning electron microscopy and dynamic mechanical analysis. The results show that the thermal, thermos-oxidative, chemical, and mechanical properties of the biocomposites can be modulated by controlling the type of reinforcement, the lignin content in the matrix, and the curing ionic liquid. The valorization of coconut solid residues through a sustainable organosolv-based route thus enables the design of thermosetting materials with high glass transition temperatures, high gel content, and self-extinguishing behavior suitable for high-performance applications, with potential to partially replace petroleum-derived materials in selected sectors of the chemical industry.
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder with rising global prevalence. Current treatments such as corticosteroids and antibiotics often lead to side effects, drug resistance, and limited long-term safety. Natural compounds, including extracts from Selaginella, offer multi-targeted anti-inflammatory and antioxidant benefits but suffer from poor solubility and low bioavailability. To overcome these limitations, carbon nanodots using selaginella extract as the sole precursor (SSE-CDs) were synthesized. The SSE-CDs (2.5 ± 1.5 nm) possess abundant surface functional groups, negative surface charge and good enzyme-like activity. In vitro, SSE-CDs reduced reactive oxygen species, alleviated inflammation, and promoted proliferation in damaged HaCaT cells. In vivo, in an AD mouse model, SSE-CDs restored immune cell balance and normalized inflammatory cytokine expression. Mechanistic studies revealed that SSE-CDs inhibited phosphorylation of key proteins in the NF-κB and MAPK signaling pathways. Furthermore, a skincare lotion formulated with SSE-CDs showed therapeutic efficacy in an AD mouse model, suggesting its potential for dermatological applications. This study provides a preliminary demonstration of carbon nanodots as a promising anti-inflammatory strategy for AD management.
Extracellular vesicles (EVs) are cell-secreted phospholipid bilayer vesicles that play a key role in intercellular communication by transporting molecular cargo and engaging in surface-level signaling. Due to their intrinsic biological features, EVs not only reflect the functional attributes of their originating cells but also hold promise as both therapeutic agent and natural carriers for targeted delivery. In recent years, plant-derived nanovesicles (PDNVs) containing bioactive molecules have attracted the attention of researchers because of their better biocompatibility, low immunogenicity, wide range of sources, and ability to act as natural therapeutic agents for diseases. PDNVs play an increasingly important role in human-plant interactions, as they are able to enter the human system and deliver effector molecules to cells, which in turn modulate cellular signaling pathways. PDNVs play a critical role in human health and disease. This review provides a comprehensive overview of PDNVs, encompassing their biogenesis, methods of isolation and purification, physicochemical characterization, stability, and storage strategies. It further explores their routes of administration, internalization, and biodistribution as therapeutic agents, highlighting their potential in the treatment of conditions such as inflammation, cancer, tissue regeneration, viral infections, liver and brain disorders, and osteoporosis. Lastly, the review examines current clinical applications of PDNVs and the key challenges hindering their broader implementation. We look forward to further exploration of the functions of PDNVs to facilitate their clinical translation and increase their benefits in humans.
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant brain tumors, largely due to the restrictive nature of the blood-brain barrier (BBB). This barrier significantly limits the efficient delivery of therapeutic agents to the tumor site, thereby reducing treatment efficacy. This review evaluates the potential of dextran (Dex)-based nanoparticles (NPs) as an advanced platform for enhancing BBB penetration and enabling targeted GBM therapy. Dex, a biocompatible and biodegradable polysaccharide, offers key advantages including ease of functionalization, high drug-loading capacity, and improved systemic stability. Recent studies demonstrate that Dex-based nanocarriers enhance drug transport across the BBB via receptor-mediated and adsorptive transcytosis mechanisms, resulting in improved accumulation at tumor sites. Furthermore, surface engineering strategies facilitate active targeting of GBM cells, thereby increasing therapeutic efficacy while reducing systemic toxicity. Comparative evidence indicates that Dex-based nanocarriers outperform conventional delivery systems in terms of targeting efficiency, biocompatibility, and tailored drug release. These systems also show potential for co-delivery of multiple therapeutic agents, supporting combination treatment approaches for improved clinical outcomes. Emerging preclinical studies highlight improved survival outcomes and enhanced pharmacokinetic profiles associated with Dex-based nanocarriers, reinforcing their therapeutic relevance. Despite these promising findings, challenges related to large-scale manufacturing, reproducibility, and regulatory approval remain significant barriers to clinical translation. Future research should focus on clinical validation, scalable synthesis approaches, and long-term safety assessment to facilitate successful translation into clinical practice. Overall, Dex-based NPs represent a versatile and highly promising strategy to overcome existing limitations in GBM treatment and advance targeted nanomedicine approaches for brain cancer therapy.
Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation, and sequencing with ICIs remain unresolved. This meta-analysis evaluates the impact of biologically effective dose (BED), treatment timing, and ICI agents on progression-free survival (PFS) and safety in advanced cancers. A systematic search of PubMed, Embase, Web of Science, and Cochrane Library (2010-2024) identified 18 studies (727 patients). Pooled PFS and treatment-related adverse events (TRAEs) were analyzed using random-effects models. Subgroup analyses stratified outcomes by cancer type, RT regimen, BED (low: ≤50; moderate: 50-100; high: >100), treatment sequence (concurrent/sequential), and ICI agents. This study was registered on PROSPERO (CRD420251044176). The synthesis of PFS revealed extreme between study heterogeneity, with a wide 95% prediction interval ranging from 0.90 to 41.21 months. Despite this variance, reconstructed individual patient data suggested that moderate BED regimens between 50 and 100 showed a more favorable median PFS compared to low or high dose regimens. Concurrent administration of radiotherapy and immunotherapy demonstrated a longer reconstructed median PFS than sequential strategies. Furthermore, PD-1 and PD-L1 based regimens appeared to perform better than CTLA-4-only approaches. The pooled incidence of grade 3 or higher TRAEs was 0.22, indicating a manageable overall safety profile. This descriptive meta-analysis and reconstructed individual patient data synthesis provide hypothesis-generating insights into combined radioimmunotherapy. Concurrent administration of moderate BED radiotherapy with PD-1 and PD-L1 inhibitors suggests a plausible balance of efficacy and safety. However, extreme heterogeneity limits direct clinical application, underscoring the critical need for standardized dose protocols and rigorous sequencing in future randomized trials.
The perioperative management of antithrombotic (AT) therapy during lumboperitoneal shunting (LPS) for idiopathic normal pressure hydrocephalus (iNPH) remains controversial, and evidence to guide decisions regarding continuation of AT therapy is limited. We retrospectively analyzed patients with iNPH who underwent LPS at our institution. Patients were classified according to AT agent use on the day of surgery into a Continued AT therapy group and a Discontinued/No AT therapy group. Symptomatic hemorrhagic complications, chronic subdural hematoma (CSDH), and thromboembolic events within 1 month after surgery were evaluated. A total of 203 patients were included in the analysis, of whom 164 (80.8%) were classified into the Discontinued/No AT therapy group and 39 (19.2%) into the Continued AT therapy group. Symptomatic hemorrhagic complications excluding CSDH occurred in 2 patients (1.2%) in the Discontinued/No AT therapy group and in 1 patient (2.6%) in the Continued AT therapy group (odds ratio [OR], 2.13; 95% confidence interval [CI], 0.19-24.1). CSDH developed in 8 patients (4.9%) in the Discontinued/No AT therapy group and in 2 patients (5.1%) in the Continued AT therapy group (OR, 1.05; 95% CI, 0.21-5.17). Symptomatic thromboembolic complications occurred in 1 patient (0.6%) in the Discontinued/No AT therapy group and in none of the patients who continued AT therapy. The overall incidence of hemorrhagic complications was low in both groups, regardless of AT agent use. These findings demonstrate the rarity of such events, which presents a fundamental obstacle to conducting adequately powered prospective trials on perioperative antithrombotic management in this population.
Near-infrared fluorescence (NIRF) can deliver high-contrast, video-rate, non-contact imaging of tumor-targeted contrast agents with the potential to guide surgeries excising solid tumors. However, it has been met with skepticism for wide-margin excision due to sensitivity and resolution limitations at depths larger than ~ 5 mm in tissue. To address this limitation, fast-sweep photoacoustic-ultrasound (PAUS) imaging is proposed to complement NIRF. In an exploratory in vitro feasibility study using dark-red bovine muscle tissue, we observed that PAUS scanning can identify tozuleristide, a clinical stage investigational imaging agent, at a concentration of 20 µM from the background at depths estimated to be of up to ~ 34 mm, highly extending the capabilities of NIRF alone. The capability of spectroscopic PAUS imaging was tested by direct injection of 20 µM tozuleristide into bovine muscle tissue at a depth of ~ 8 mm. Experimental results demonstrate that multi-point laser fluence compensation and strong clutter suppression enabled by the unique capabilities of the fast-sweep approach greatly improve spectroscopic accuracy and the PA detection limit and strongly reduce image artifacts. Thus, the complementary NIRF-PAUS approach can be promising for comprehensive pre- (with PA) and intra- (with NIRF) operative solid tumor detection and wide-margin excision in optically guided solid tumor surgery.
Both basic and clinical consciousness research aims to find objective measures that reliably distinguish conscious from unconscious brain states. Electroencephalogram (EEG) measures are widely used, although they may be affected by interference from electrical signals such as those generated by muscles. To assess this source of error, we investigated the impact of neuromuscular blockade (NMB) on proposed measures of awareness (spectral slope, Lempel-Ziv complexity (LZc), connectivity, alpha peak frequency, power in canonical EEG frequency bands) computed from spontaneous high-density EEG recorded from six healthy volunteers in three different conditions: (1) awake-unparalysed (normal wakefulness), (2) awake-paralysed (complete paralysis caused by neuromuscular blocking agent (NMBA)), and (3) sedated-paralysed (deep sedation with propofol, with paralysis by NMBA). The measures we investigated distinguished awake-unparalysed states from sedated-paralysed with close to perfect accuracy in accordance with past findings. However, our analysis revealed a serious failure of most measures to recognise the awake-paralysed condition as an aware state. Errors ranged from 7% of awake-paralysed time segments predicted as unaware (using alpha power) to 100% (using LZc). Using a unique high-density EEG data set, this study clearly demonstrates that many EEG-based measures fail to recognise awareness in awake subjects under the influence of muscle relaxants. These results highlight critical limitations of current EEG-based measures at detecting awareness.
Burkholderia pseudomallei, an environmental Gram-negative saprophyte is the causative agent of melioidosis, a potentially fatal yet treatable clinical entity. We report an unusual colony morphology of the organism to minimize misidentification and enable accurate diagnosis.
Colorectal cancer (CRC) is one of the most significant global health concerns, necessitating innovative therapeutic strategies for its effective management. Despite advances in treatment therapies, chemotherapy remains the mainstay of CRC treatment, with 5-Fluorouracil (5-FU) as a standard first-line agent. However, its clinical effectiveness is hindered by drug resistance, rapid clearance and systemic toxicity, underscoring the need for innovative drug delivery strategies. In this context, the current work involves engineering of a bioinspired nanocomplex (NX) comprising zein and a biological macromolecule, such as chitosan, using a Quality by Design (QbD) approach. The resulting NX was characterized for particle size (186.13 ± 8.61 nm), polydispersity index (0.194 ± 0.03), and %entrapment of 5-FU (54.39 ± 3.1%) and silibinin (97.44 ± 1.16%), respectively. SEM and TEM analysis revealed the smooth and spherical nature of NX. Thermal analysis was performed using TGA and DSC and XRD was employed for structural characterization. Subsequently, spectroscopic investigations were carried out using FTIR, Raman and fluorescence spectroscopy to examine the potential interactions between the drugs and polymers used in the formulation of the NX system. In vitro studies confirmed controlled drug release with Weibull release kinetic model. The dual-drug-loaded-NX exhibited a significant increase in cytotoxicity compared to individual 5-FU and silibinin, and achieving nearly a 5-fold increase in cytotoxicity compared to silibinin. The NX demonstrated apoptosis induction, S/G2 cell cycle arrest, and improved cellular uptake compared to control group. The current investigation suggests that QbD-engineered zein-chitosan-based-NX could be a promising therapeutic strategy for managing CRC.
The diagnostic accuracy of computed tomography angiography (CTA) and its appropriate clinical indications remain unclear. We aimed to assess the diagnostic performance of CTA and identify clinical predictors to determine the optimal clinical indications for its use in patients with acute gastrointestinal (GI) bleeding. This large cohort study included patients who underwent CTA for suspected acute GI bleeding in Korea between October 2011 and December 2023. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CTA were assessed. Multivariate analysis was conducted to identify the predictors of positive CTA findings, and a predictive nomogram was developed and validated. Of the 5,525 patients identified, 1,770 were included in the final analysis. CTA demonstrated low sensitivity (44.9%) and PPV (52.4%), with relatively high specificity (88.3%) and NPV (84.9%). Multivariate analysis identified male sex, use of antithrombotic agents, low hemoglobin level (<9.6 g/dL), elevated blood urea nitrogen level (≥29.9 mg/dL), hemodynamic instability, and presentation with hematemesis or hematochezia as independent predictors of positive CTA findings. A nomogram incorporating these variables showed good discrimination. The selective application of CTA based on clinical risk factors improved diagnostic sensitivity (47.3% at predicted probability ≥0.1, 56.5% at ≥0.2, and 69.5% at ≥0.3; all P < 0.001). Although CTA may be unsuitable as an initial diagnostic modality for acute GI bleeding, its selective use-guided by a clinical prediction model-can help identify patients most likely to benefit, thereby reducing inappropriate use and improving the diagnostic yield of CTA.
Complications after pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) are associated with delays or omission of adjuvant chemotherapy (AC). Similar data for patients who undergo distal pancreatectomy (DP) are lacking. A retrospective cohort study was conducted using the SEER-Medicare database to identify patients who underwent upfront DP for PDAC (2010-2019). Multilevel logistic regression and Cox proportional hazards models were used to evaluate the association of postoperative complications with AC omission and delay as well as survival endpoints based on receipt of AC. Of 1029 patients identified, 613 (59.6 %) received AC. Patients with complications had lower rates of AC (50.0 % vs 61.1 %; p = 0.013) and multi-agent AC (25.0 % vs 28.2 %; p = 0.039) and higher rates of delays in AC (42.9 % vs 21.4 %; p < 0.001) than those without complications. In multivariable analysis, complications were associated with a lower rate of AC (hazard ratio [HR], 0.67; 95 % confidence interval [CI], 0.54-0.84; p < 0.001) and a higher rate of delayed AC (odds ratio [OR], 3.36; 95 % CI 1.92-5.91; p < 0.001). For survival, receipt of AC overall (HR, 0.56; 95 % CI 0.47-0.67; p < 0.001), even when delayed (HR, 0.72; 95 % CI 0.57-0.90; p = 0.005), was associated with better overall survival (OS) than no AC. However, delayed AC was associated with worse OS than timely AC (HR, 1.27; 95 % CI 1.01-1.62; p = 0.04). Patients who experienced a postoperative complication after DP for left-side PDAC had lower rates of AC overall and higher rates of delayed AC, both associated with worse OS.
Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.
Hepatic fibrogenesis represents a significant and escalating global health challenge with few effective treatments. This research explored the anti-fibrotic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor Ipragliflozin (IPRA) in a rat model of hepatic fibrogenesis caused by thioacetamide (TAA), with a specific focus on critical pathways of inflammation, fibrosis, and oxidative stress. Groups were designated as follows: a control; a model group receiving TAA (100mg/kg, twice weekly for 6 weeks); and two therapeutic groups receiving TAA plus either a low (3mg/kg/day) or high (6mg/kg/day) oral dose of Ipragliflozin during the final 4 weeks. TAA administration induced severe liver fibrosis, characterized by significant increases in serum ALT, AST, triglycerides, cholesterol, oxidative stress (↓GSH, ↓CAT, ↑MDA), and pro-inflammatory/pro-fibrotic signaling (↑TLR4, ↑IL-1β, ↑NF-κB, ↑TGF-β1). Ipragliflozin treatment, particularly at the 6mg/kg dose, dose-dependently and significantly attenuated these changes. It restored liver function, normalized the lipid profile, reversed oxidative stress by boosting antioxidant defenses, and suppressed the core inflammatory and profibrotic TLR4/IL-1β/TGF-β1/NF-κB axis. Histopathological and immunohistochemical findings confirmed a reduction in fibrosis and inflammation. These findings highlight Ipragliflozin's promise as a multi-faceted therapeutic agent for liver fibrosis.
Monoclonal antibody-based therapies have substantially improved outcomes in breast cancer, particularly through HER2-directed treatment strategies, but have also introduced important cardiovascular toxicities that require careful recognition and management. This narrative review summarizes current evidence on cardiotoxicity associated with monoclonal antibody therapies used in breast cancer, with emphasis on HER2-targeted antibodies, antibody-drug conjugates, and selected immune checkpoint inhibitors.Trastuzumab remains the best-characterized monoclonal antibody associated with cancer therapy-related cardiac dysfunction, most commonly presenting as left ventricular systolic dysfunction, particularly in patients previously exposed to anthracyclines or with baseline cardiovascular risk factors. Pertuzumab and currently available antibody-drug conjugates have not shown a major increase in cardiotoxic risk beyond that observed with established HER2-directed therapy, although long-term data remain limited for some newer agents. Immune checkpoint inhibitors are less commonly associated with cardiovascular toxicity, but may rarely cause severe immune-mediated complications, particularly myocarditis and also non-immune mediated toxicity such as cardiac dysfunction.Contemporary evaluation of cardiotoxicity increasingly relies on an integrated cardio-oncology framework incorporating left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers, with growing recognition of subclinical dysfunction and right ventricular involvement. Current management strategies emphasize baseline cardiovascular risk assessment, risk-adapted surveillance, early initiation of heart failure therapy when indicated, and individualized multidisciplinary decision-making regarding continuation of anticancer treatment, including permissive cardiotoxicity in selected patients.As the use of monoclonal antibody therapies continues to expand, optimizing the balance between oncologic efficacy and cardiovascular safety remains a central goal of modern breast cancer care.
This study evaluated the polyphenol content of leaf extracts from Artemisia monosperma (AM) and investigated their antioxidant properties, cytotoxic effects, and potential to induce DNA damage in human cancer cell lines. High-performance liquid chromatography (HPLC) quantified polyphenols in methanolic (AMM), ethanolic (AME), and aqueous (AMA) extracts, identifying 13 compounds in AME and 12 in AMA. AMM exhibited the strongest antioxidant activity (IC50 = 24 µg/ml). Both AME and AMM demonstrated potent anticancer activity against HCT-116 (IC₅₀ = 0.38 µg/mL for AMM) and HUH-7 (IC₅₀ = 21.95 µg/mL for AMM) cells, while exhibiting minimal cytotoxicity toward normal skin fibroblast cells (BJ-1; IC₅₀ = 13.05 µg/mL for AMM), with AMM demonstrating particular selectivity for HCT-116 cells. AMM induced DNA fragmentation and modulated apoptosis-related gene expression (Bax, Bcl-2, p53) in HUH-7 cells and caused cell cycle arrest at G0/G1 phase in HCT-116 cells. Molecular docking further supported AMM's apoptosis activity. These results position A. monosperma as a rich source of bioactive polyphenols and antioxidants, with AMM showing promise as a therapeutic agent, especially for colorectal cancer.
KRAS mutations are commonly found in 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making it one of the deadliest cancers. Key oncogenic signaling networks, such as KRAS, TP53-MDM2, EGFR, and PI3K/AKT/mTOR, are frequently altered in this invasive disease. These networks function within a dense desmoplastic tumor environment that inhibits drug delivery and fosters therapeutic resistance. Although KRAS mutations are a primary oncogenic driver and occur in approximately 90% of patients with PDAC, variant-specific biology (e.g., G12D, G12R, G12V, and G12C) affects downstream signaling dependency and treatment response. Although specific KRASG12C inhibitors have been developed, their use in PDAC remains limited because of compensatory pathway activation and mutation prevalence. Similarly, whereas EGFR amplification and adaptive signaling bypass pathways decrease the durability of EGFR-targeted therapies, TP53 inactivation and MDM2 axis dysregulation contribute to genomic instability and treatment resistance. Although resistance to chemotherapy and targeted therapies, survival signaling, and metabolic reprogramming are all significantly affected by the PI3K/AKT/mTOR system, the therapeutic results with pathway inhibitors have been mixed. Significantly, these signaling pathways function within a coordinated, interdependent network, wherein single-agent approaches are compromised by crosstalk and feedback activation. This review synthesizes these main signaling axes, emphasizing molecular pathology, including mutation-specific biology, diagnostic techniques such as liquid biopsy and NGS, the role of natural compounds, the tumor microenvironment (TME) in pancreatic cancer (PC), and the limitations noted in therapeutic trials. Novel therapeutic approaches include KRAS-directed degradation techniques, pathway co-inhibition, rational combination methods, and therapy paradigms driven by the TME. To discover new molecules with long-lasting therapeutic effects, a system-level understanding of pathway interactions within the PDAC microenvironment is necessary.
Periprosthetic joint infection (PJI) remains a devastating complication following total joint arthroplasty, leading to substantial morbidity and increased healthcare costs. Cefazolin is the standard agent for perioperative antibiotic prophylaxis. However, the rising prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has prompted the use of dual prophylaxis with vancomycin and cefazolin. The efficacy and safety of this combined strategy remain controversial. A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered on the international prospective register of systematic reviews (ID CRD420251077695). A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library was performed. Randomized controlled trials and observational studies directly comparing cefazolin alone with combined vancomycin and cefazolin as intravenous prophylaxis in patients undergoing total joint arthroplasty were included. The primary outcome measures were PJI and SSI (surgical site infection), and secondary outcome measures were AKI (acute kidney injury). Eight studies including 1,041,058 patients met the inclusion criteria. Dual prophylaxis was associated with a higher risk of SSI (odds ratio [OR] =1.39; 95% confidence interval [CI] = 1.23 to 1.58), but a lower risk of PJI (OR = 0.64; 95% CI = 0.46 to 0.91). There was no significant difference in risk of AKI between regimens (OR = 1.30; 95% CI = 0.76 to 2.20), although substantial heterogeneity was observed among studies reporting renal outcomes. Routine addition of vancomycin to cefazolin does not reduce overall SSI rates and may increase superficial infections. However, it may decrease PJI risk without significantly increasing AKI. These findings support a selective, risk-stratified prophylactic strategy rather than universal dual antibiotic therapy in total joint arthroplasty.