Biopolymer-based hydrogels are attractive therapeutic carriers, offering tunable physicochemical properties and therapeutic release kinetics. Major limitations include low rheological strength, poor physical and thermal stability, limited swelling, and achieving controlled therapeutic delivery. To address these challenges, a library of innovative metal-organic framework (MOF)-biopolymer-based hydrogels was developed. The MOFs, zeolitic imidazole framework-8 (ZIF-8), and zinc adeninate framework (ZAF) were integrated into chitosan/alginate (C/A) and chitosan/gelatin (C/G) hydrogels, at increasing chitosan content. The MOF-hydrogels presented distinct immunoglobulin G (IgG) release rates and greater rheological strengths, swelling capabilities, and thermostabilities compared to the MOF lacking hydrogels. The MOF-C/A-hydrogels showed higher rheological strengths compared to the MOF-C/G-hydrogels. The ZIF-8-hydrogels presented greater rheological strengths, yet lower thermostabilities, and higher IgG release rates compared to the ZAF-hydrogels. This is attributed to the greater flexibility of ZAF, containing bulky adenine groups, which could lead to steric hindrance and limited zinc ion-dipole interactions. Holistically, exploiting ion-dipole, electrostatic, and hydrogen bonding interactions between the MOFs and biopolymers enabled therapeutic release rate control and balanced the typical trade-off between hydrogel swelling and rheological strength. The MOF-hydrogels offer adaptable platforms, advancing the design of next-generation MOF-biopolymer-based carriers for target applications.
The overall response of colorectal cancer (CRC) to immune checkpoint blockade remains limited, particularly in patients with microsatellite-stable disease. One important underlying mechanism is the involvement of myeloid-derived suppressor cells (MDSCs) in shaping an immunosuppressive TME. Under the influence of tumor-associated genetic alterations, chronic inflammation, the intestinal microbiota, metabolic stress, and therapeutic pressure, MDSCs undergo aberrant expansion and functional skewing. By remodeling the local immune ecology, they attenuate T cell- and natural killer (NK) cell-mediated antitumor responses. Concurrently, MDSCs are also implicated in angiogenesis, barrier disruption, stromal remodeling, premetastatic niche formation, and therapeutic tolerance. Thus, MDSCs are not only critical mediators of immune evasion but also key components of CRC progression and treatment resistance. Current clinical translation in this field remains constrained by the ambiguous definition of human MDSCs, phenotypic overlap, insufficient functional validation, and imprecise patient stratification. Future studies should integrate single-cell omics, spatial omics, metabolic profiling, and microbiome analyses to establish more functionally oriented biomarkers. On this basis, combination therapeutic strategies targeting MDSC recruitment, suppressive function, or reprogramming states should be further developed.
Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.
Osteoarthritis (OA) is increasingly recognized as a whole-joint disease driven by a dysregulated osteoimmune microenvironment, rather than mere mechanical wear. Despite the high prevalence of OA, current pharmacotherapies are largely palliative, failing to halt cartilage degeneration or reverse chondrocyte death. Consequently, the development of Disease-Modifying Osteoarthritis Drugs (DMOADs) targeting the underlying pathology remains an urgent unmet need. Natural products, distinguished by their pleiotropic nature, have emerged as promising candidates capable of functioning as "network regulators" to restore joint homeostasis. This review systematically elucidates the multi-dimensional mechanisms by which natural products prevent regulated cell death (RCD) in chondrocytes. We highlight their capacity to orchestrate upstream immune responses by repolarizing synovial macrophages, blocking inflammatory cascades (e.g., NLRP3 inflammasome), and restoring downstream cellular defenses. Special attention is given to emerging mechanisms, including the inhibition of ferroptosis and the reversal of metabolic reprogramming via the modulation of the HIF-1α/HIF-2α switch and the NAD+/SIRT1 axis. Furthermore, we extend the discussion to the subchondral bone, emphasizing the restoration of the osteochondral unit. To bridge the gap between preclinical success and clinical translation, we discuss current challenges such as bioavailability and propose future strategies involving biomimetic nanodelivery systems and precision medicine based on OA endotypes. Collectively, this review provides a comprehensive framework for utilizing natural products to rewire the osteoimmune microenvironment, highlighting their potential as promising candidates for future DMOAD development.
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (ML), and it is also known as Hansen's disease. It is transmitted mainly through prolonged close contact with an untreated infected person. The disease primarily affects the skin and peripheral nerves. Leprosy can, however, present with a broad spectrum of clinical manifestations depending on the host's immune response, ranging from localized tuberculoid disease to disseminated lepromatous disease. Diagnosis of leprosy relies primarily on clinical findings and is supported by histopathological examination of a skin biopsy. Management requires multidrug therapy (MDT), treatment of lepra reactions, and rehabilitation. We report the case of a 27-year-old female with lepromatous leprosy complicated by a severe type two lepra reaction involving multiple organ systems. The treatment regimen was complicated by hemolysis caused by dapsone therapy despite normal glucose-6-phosphate dehydrogenase (G6PD) activity. This report highlights significant therapeutic challenges and provides important insights into the management of leprosy reactional states.
Liver fibrosis is a dynamic pathological process characterized by excessive extracellular matrix (ECM) deposition, primarily driven by the activation of hepatic stellate cells (HSCs). Recent advances in liver fibrosis research have identified critical pathways, such as oxidative stress, inflammation and transforming growth factor-β (TGF-β) signaling, which drive disease progression. Concurrently, innovative drug delivery systems (e.g., liposomes, micelles and nanocrystals) have emerged to enhance therapeutic efficacy and targeting. These systems enable precise delivery of antifibrotic agents to HSCs or fibrotic tissues, minimizing off-target effects and improving pharmacokinetic profiles. This review summarizes current understanding of liver fibrosis pathogenesis and recent advances in drug delivery strategies, highlighting clinical transformation opportunities and future research directions. Combining molecular insights with advanced delivery technologies represents a promising avenue for developing effective antifibrotic therapies.
Oral implantology has experienced substantial digital transformation over the past two decades. The adoption of cone-beam computed tomography (CBCT), computer-assisted surgery, and artificial intelligence (AI) has improved diagnostic accuracy, treatment planning, and procedural precision. However, clinical decision-making remains largely dependent on conventional radiographic interpretation and clinician experience. We propose the concept of Implanomics (Implant-Omics) as an integrative framework combining radiomics, AI, and digital workflows. Radiomics, which converts medical images into quantitative data, offers new opportunities to extract imaging biomarkers from routine CBCT examinations. By characterizing bone morphology, trabecular architecture, and image texture beyond visual assessment, radiomics may support more objective evaluation of implant sites and improve prediction of treatment outcomes. When combined with machine-learning algorithms, these imaging-derived features can be incorporated into predictive models for risk assessment, implant planning, and longitudinal monitoring. In this Perspective, we discuss the evolution of implant dentistry from experience-based planning toward imaging-driven decision support and examine the emerging role of radiomics and AI in precision implant care. We highlight current applications, key challenges, and future directions for integrating quantitative imaging analysis into clinical workflows. Although substantial validation and implementation challenges remain, the convergence of radiomics, artificial intelligence, and digital implant technologies may contribute to more individualized and evidence-informed treatment strategies in implant dentistry.
Alveolar osteitis (AO), or dry socket, is a painful postoperative complication caused by the premature loss of the blood clot from the extraction site. Current treatments rely on irrigation and temporary dressings, however these approaches offer limited therapeutic benefits and often require repeated interventions. This work describes a customizable, dual-function biomaterials platform based on 3D-printed gelatin gels incorporating the antimicrobial quaternary ammonium compound, benzyldimethyldodecylammonium (BDMDAC), and the analgesic lidocaine enabling sustained infection control and localized pain management. 3D-printed gels were optimized for printability, mechanical stability, and controlled drug release, and their physicochemical properties were characterized through swelling, degradation, and release studies. Both hydrated and freeze-dried gels were evaluated to assess how architecture influences transport behavior and therapeutic performance. Antimicrobial efficacy was evaluated against clinically relevant oral pathogens, including Porphyromonas gingivalis, Enterococcus faecalis, and Streptococcus mutans which are key pathogens associated with oral infections. Cytocompatibility and inflammatory responses were assessed using human gingival fibroblasts (HGF-1s) as well as Interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) expression. The 3D-printed gels sustained antimicrobial activity, achieving complete planktonic pathogen eradication and biofilm inhibition within 24 h, independent of lidocaine incorporation. Analysis of pro-inflammatory cytokine markers showed a minimal response in most gel formulations, with a slight increase at high lidocaine concentrations (30 mg/mL), whereas freeze-dried gels produced a more pronounced early inflammatory response at this concentration. Finally, 3D printed anatomical patient-specific molar-shaped gels preserved antimicrobial efficacy comapred with grid-printed controls, confirming that therapeutic performance is maintained across complex geometries. Overall, these results demonstrate that on-demand fabrication of patient specific, antimicrobial, and analgesic 3D printed gels has the potential to be used for localized management of AO.
Bilateral breast cancer is uncommon, accounting for 2%-5% of cases, and presents additional clinical challenges when tumors exhibit discordant molecular subtypes. Metachronous tumors, occurring sequentially, require individualized therapeutic strategies, especially when one tumor is triple-negative and the other is hormone-responsive. We report on a 37-year-old woman who initially presented with a left-sided breast lump during her fifth pregnancy. Histopathology revealed invasive carcinoma of no special type (NST), progesterone receptor (PR)-positive (90%), estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2)-negative, with a high proliferative index (Ki-67 = 90%), staged T2N2M0 (stage IIB/IIIA). Subsequently, she developed a right-sided breast mass, confirmed as triple-negative invasive carcinoma (T4N3M0, stage IIIC). The patient was initiated on neoadjuvant chemotherapy with the adriamycin and cyclophosphamide (AC) regimen and received supportive care, including ondansetron, morphine, and bisacodyl. Her Eastern Cooperative Oncology Group (ECOG) performance status was 1, and she experienced significant weight loss (from 68 to 46 kg in 4 months). Post-chemotherapy imaging will guide surgical planning. This case highlights the rarity and complexity of metachronous bilateral breast cancer with discordant receptor status. Therapeutic prioritization is guided by the more aggressive tumor, in this instance, the triple-negative carcinoma, while simultaneously addressing the hormone-responsive lesion. Neoadjuvant chemotherapy allows tumor downstaging, assessment of chemosensitivity, and individualized surgical planning. Multidisciplinary management is essential to optimize outcomes and address prognostic variability between tumors. Metachronous bilateral breast cancer with discordant molecular subtypes presents significant diagnostic and management challenges. Individualized, biology-driven treatment strategies are critical, emphasizing the importance of systemic therapy guided by the more aggressive tumor and careful post-chemotherapy surgical planning.
Although the RNA-dependent RNA polymerase (RdRp) complex is a therapeutic target for influenza, evidence on the pharmacology, resistance, and clinical impact of RdRp-targeting inhibitors in high-risk populations remains fragmented. This scoping review on RdRp-targeting inhibitors identifies the research gaps and characterizes their mechanisms of action, pharmacokinetics, efficacy, safety, and resistance patterns. Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews" guidelines, a comprehensive search for studies was conducted across PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang, and ClinicalTrials.gov from inception to October 2025. Preclinical and clinical studies on influenza RdRp-targeting inhibitors were included, with data charted across eight domains. From 1,282 identified records (English: 1197; Chinese: 85), 156 articles were included. PA inhibitors emerged as the most extensively documented class. Preclinical findings demonstrated potent antiviral activity of PA inhibitors and emerging PB1/PB2 analogs, with variability in pharmacokinetic profiles. Clinical evidence showed PA inhibitors consistently shorten the time to symptom relief and accelerate viral RNA clearance compared with standard therapy. RdRp-targeting inhibitors showed an acceptable tolerability profile. Resistance was a notable challenge, primarily involving PA-I38 substitutions. Evidence on drug-drug interactions was limited to early-phase trials. A significant evidence gap remains for high-risk populations; baloxavir being the only agent widely studied in high-risk adults. RdRp-targeting antivirals represent a promising frontier for influenza treatment, with PA inhibitors being the most extensively validated class. While PB1 and PB2 inhibitors diversify the therapeutic pipeline, their development is hindered by the need for multiple-dose regimens and the emergence of drug resistance. Future research should prioritize inhibitor designs that minimize resistance, as well as combination regimens, to accelerate clinical translation.
Arts-based programs have re-emerged as a focus of population mental health policy, with the World Health Organisation Healing Arts initiative and social prescribing programs across the UK, Australia, USA, and Canada signaling growing interest in scalable, accessible approaches to mental health prevention. With this growing trend there is an opportunity for seeking complementary scalable approaches implemented during childhood to prevent mental-ill health. The aim of this study was to provide a broad overview of the nature of the relationships between participation in arts programs and mental health and wellbeing outcomes during middle childhood, with a specific emphasis on the mechanisms that may underlie this relationship. This review also aimed to identify program characteristics and the context in which this relationship exists. This systematic review was performed according to PRISMA guidelines with a focus on studies examining the relationships between arts participation and mental health and wellbeing outcomes among children in the general population during the middle childhood years (6 to 12 years). A total of 34 studies were included, made up of primarily quantitative studies. The evidence base reviewed suggests therapeutic approaches in non-clinical settings led by specialists over shorter periods of implementation (typically 4-10 weeks) shows preliminary signs of promise. Recreational programs showed inconsistent effects across outcome domains: some studies reported benefits to wellbeing and stress, while others reported no effect on internalising or externalising symptoms, with no consistent pattern across program features. Psychological and biological constructs were the most commonly identified mechanisms of change. The certainty of evidence across all mental health outcomes was rated as low or very low. This first systematic review of arts-inclusive programs in middle childhood points to preliminary signs of promise, particularly for therapeutic approaches in non-clinical settings, although the certainty of evidence is low. Future research should focus on conducting high quality studies in school contexts with a focus on pedagogical design and facilitator expertise. This would address cost effectiveness for scaling at the general population level for prevention. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024581364.
Adult granulosa cell tumor (aGCT) is a rare ovarian malignancy with frequent late recurrences and limited systemic treatment options. Emerging evidence suggests that dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma (Rb) axis contributes to aGCT biology, while hormone receptor expression supports the potential role of endocrine therapy. We performed a scoping review to map available evidence on CDK4/6 inhibition in aGCT. A literature search was conducted in PubMed/MEDLINE, Embase and Web of Science, complemented by searches of trial registries, conference abstracts and citation searching. Eligible reports included translational, preclinical and clinical studies addressing CDK4/6 pathway dysregulation or CDK4/6 inhibition in aGCT. Evidence on endocrine therapy was synthesized narratively to contextualize combination strategies. Twenty-three reports were included. Translational and genomic studies showed recurrent abnormalities affecting cell-cycle regulation, including alterations in CDK inhibitors, Rb-associated signaling and other proliferation-related pathways. Preclinical studies demonstrated that CDK4/6 inhibition, particularly with abemaciclib, reduced cell viability and tumor growth in GCT models. Clinical evidence was limited to small retrospective case series, which suggested clinically meaningful disease control in a subset of patients with recurrent disease. An ongoing phase II trial is expected to provide the first systematic evaluation of this therapeutic strategy. Available evidence supports CDK4/6 inhibition as a biologically plausible therapeutic strategy in aGCT. Although current clinical data remain limited, the combination of CDK4/6 inhibitors with endocrine therapy appears promising and warrants prospective evaluation.
Inflammation is a shared biological process underlying diseases that are traditionally viewed as distinct, including viral infections, coronary artery disease, and metabolic disorders. Despite differing clinical presentations, these conditions are driven by common immune-inflammatory pathways. This review describes how interactions between the innate and adaptive immune systems can become dysregulated, leading to a self-amplifying inflammatory cycle characterized by persistent immune activation, cytokine signaling, and tissue injury. Within this framework, inflammasome activation and immunometabolic dysfunction emerge as central drivers of disease. The role of colchicine is then examined as a therapeutic model that targets upstream components of the inflammatory amplification cascade. Finally, emerging therapeutic strategies are discussed, along with key gaps that may help guide more targeted approaches to treatment in the future.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity and plays a critical role in inducing pro-inflammatory cytokines and type I interferons (IFN-I). This pathway has emerged as a promising target for cancer immunotherapy and antiviral treatments. Despite its promise, the clinical translation of STING agonists is hindered by several challenges, including structural instability, high production costs, and inefficient delivery systems. These barriers underscore the urgent need for further research and innovation to optimize STING-based therapies. This review provides a comprehensive overview of the cGAS-STING pathway, focusing on its activation mechanisms and recent advances aimed at enhancing its therapeutic efficacy. Alternative activators of STING, including metal ions, exogenous DNA, and endogenous DNA, are discussed for their potential to stimulate this pathway. Furthermore, synergistic therapeutic strategies combining cGAS-STING activation with reactive oxygen species (ROS)-based treatments, such as photodynamic therapy, radiotherapy, sonodynamic therapy, and chemodynamic therapy, are highlighted. Finally, recent progress in harnessing STING activation for antiviral defense against emerging pathogens, such as SARS-CoV-2 and influenza viruses, is summarized to provide insights into the future development of cGAS-STING-targeted immunotherapies.
Background Methicillin-resistant Staphylococcus aureus (MRSA) continues to pose a major global public health concern due to its resistance to commonly used antibiotics. Ceftaroline has emerged as a promising therapeutic agent against MRSA; however, local susceptibility data remain limited. This study evaluated the in vitro susceptibility of clinical MRSA isolates to ceftaroline using the E-test strip method and described antimicrobial susceptibility patterns and clinical characteristics of affected patients in a tertiary care setting. Methods This prospective, observational, cross-sectional study included non-repetitive MRSA-positive clinical samples obtained from patients aged ≥1 year over a two-year period. Identification and baseline antimicrobial susceptibility testing were performed using the VITEK 2 automated microbiological identification system. Ceftaroline susceptibility was determined using E-test minimum inhibitory concentration (MIC) strips. Results Out of 180 patients assessed, 167 MRSA isolates were included in the final analysis. The mean patient age was 34.51 ± 21.35 years, with 103 (61.7%) males. Surgical departments accounted for 99 (59.3%) of isolates, while most patients were admitted to wards (134; 80.2%). Surgical site infections (61; 36.5%) and skin and soft tissue infections (30; 18.0%) were the most frequent diagnoses. Pus samples constituted 90 (53.9%) of the isolates. Ceftaroline demonstrated high in vitro activity against MRSA, with 166 (99.4%) of isolates being susceptible and only one (0.6%) resistant. Most MIC values ranged from 0.1 to 0.4 µg/mL. Tetracycline, vancomycin, linezolid, and daptomycin also demonstrated sensitivity rates above 80%. Conclusions These findings demonstrate excellent in vitro susceptibility of MRSA isolates to ceftaroline and support further multicenter studies incorporating clinical outcome data to evaluate its therapeutic role in tertiary care settings. Its clinical use should, however, be reserved for MRSA infections resistant to other antimicrobials.
Persistent low back pain is a known complication of long construct fusions, often resulting in long term impacts on patients' physical function. While available treatment options manage patients' pain, there are few options available that also work to improve the patients' physical function. Prior studies have demonstrated the benefit of restorative stimulation of the multifidus muscles on patients' pain, function, and disability levels. This case hypothesizes that medial branch restorative neuromodulation at the L2 segment may be therapeutic for the patient's chronic lumbar spine pain, and potentially protective through improved multifidi stability. A 70-year-old female with a past medical history of rheumatoid arthritis, scoliosis status post multiple long-construct spinal fusions now fused to T10 to Pelvis, presented with significant chronic lumbar spine and leg pain. The patient presented to the clinic with 9/10 pain around the T9-T10 level and bilateral iliac crests. Her current pain management regimen included chronic hydrocodone and duloxetine, with minimal benefit for pain, and a home exercise program. Physical exam was significant for flat back kyphosis and S-shaped scoliosis with associated paraspinal muscle spasm. Prone instability and multifidus lift testing were positive bilaterally, and there was magnetic resonance imaging (MRI) evidence of multifidus atrophy. She underwent a permanent peripheral nerve stimulator placement, with lead placement at the L2 medial branches bilaterally, to provide restorative motor stimulation of the multifidus muscle. She completed 30-minute, twice daily restorative motor stimulation sessions. At her most recent follow-up visit, she reports pain is now 6/10, with improvement in several Patient-Reported Outcomes Measurement Information System (PROMIS)-29 domains. Additionally, the patient reports experiencing notable strong contractions of multifidus muscles bilaterally during stimulation sessions. She reports improvements in her quality of life, ability to walk without her cane, and less difficulty with activities of daily living. Restorative neuromodulation using motor programming may represent a potential adjunctive intervention for management of post-fusion pain in select patients by improving segmental stability. The device implantation is minimally invasive, and therapeutic sessions are aligned with functional restoration. Further study is needed to better define its role, mechanisms, and expected outcomes in post-surgical populations.
The PACIFIC regimen (consolidation durvalumab following chemoradiotherapy) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). With the publication of data from the phase III LAURA trial and the emergence of real-world evidence regarding sequential toxicity, concurrent chemoradiotherapy followed by sequential targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) is recommended for patients with EGFR mutations. However, the optimal combination regimen remains to be determined. We systematically searched the PubMed, Embase, Cochrane Library, and Web of Science databases to identify randomized controlled trials (RCTs) and high-quality retrospective studies comparing various therapeutic strategies for unresectable stage III EGFR-mutated NSCLC. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while secondary endpoints included the objective response rate (ORR) and safety profiles. A network meta-analysis (NMA) was performed using a Bayesian random-effects model. Hazard ratios (HRs), odds ratios (ORs), and their corresponding 95% credible intervals (CrIs) were calculated. A total of 12 studies involving 1,529 patients were analyzed to compare six therapeutic strategies: consolidation durvalumab following chemoradiotherapy (CRT+Durva), CRT alone, consolidation EGFR-TKIs after CRT (CRT+EGFR-TKI), EGFR-TKI monotherapy, EGFR-TKI in combination with chemotherapy (EGFR-TKI+Chemo), and EGFR-TKI integrated with radiotherapy (EGFR-TKI+RT) via induction, concurrent, or consolidation sequencing. NMA revealed that CRT+EGFR-TKI was the only strategy to demonstrate a statistically significant improvement in OS compared to CRT alone (HR = 0.63, 95% CrI: 0.41-0.94), while also achieving the highest ORR. EGFR-TKI+RT (chemotherapy-free regimen) ranked first for PFS (HR = 0.14, 95% CrI: 0.06-0.33) and exhibited a favorable safety profile, associated with the lowest risk of severe radiation pneumonitis (RP). Notably, CRT+Durva failed to yield a survival benefit (PFS: HR = 0.75; OS: HR = 0.82) and was characterized by higher toxicity. An RCT-only sensitivity analysis demonstrated consistent PFS benefits and a comparable OS trend (HR = 0.68, 95% CrI: 0.33-1.4), validating the integration of real-world data to maintain adequate statistical power. For unresectable stage III EGFR-mutated NSCLC, CRT+EGFR-TKI represents the optimal strategy for extending OS. Conversely, the EGFR-TKI+RT (chemotherapy-free regimen) approach provides a superior balance between prolonged PFS and clinical tolerability. https://www.crd.york.ac.uk/prospero/, identifier CRD420261285935.
Ovarian carcinomas represent the second most common malignancy of the female genital tract; however, primary squamous cell carcinoma (SCC) is a rare subtype. Most of these tumors arise from malignant transformation of mature cystic teratoma (MCT), whereas others are associated with endometriosis or Brenner tumor. Preoperative diagnosis remains challenging because both clinical presentation and imaging findings are frequently nonspecific. Patients often present with symptoms related to the mass effect of the lesion, and metastatic disease may be present at the time of diagnosis. While pelvic ultrasonography and magnetic resonance imaging (MRI) are essential diagnostic adjuncts, histopathological examination remains the gold standard for establishing the diagnosis and guiding management. Current therapeutic strategies necessitate a multimodal approach, including surgical debulking and adjuvant chemotherapy or radiotherapy. We present the case of a 39-year-old woman diagnosed with ovarian SCC arising from a mature cystic teratoma, detailing her clinical presentation and subsequent management. This case highlights the diagnostic and therapeutic challenges associated with malignant transformation of MCTs, particularly in younger patients.
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disorder with complex and incompletely understood pathophysiology. This study aimed to investigate the therapeutic effects and underlying mechanisms of abdominal massage on diarrhea-predominant IBS-D using a rat model. IBS-D was induced in Sprague-Dawley rats through a combination of maternal separation and chronic stress. The experimental interventions consisted of abdominal massage and fecal microbiota transplantation (FMT) using donor microbiota obtained from IBS-D + abdominal massage rats. Assessments included fecal moisture content (FMC), Bristol stool scores, visceral hypersensitivity, intestinal motility, open field test, gut microbiota, short-chain fatty acids (SCFAs), inflammatory markers (LPS, TLR4/MyD88/NF-κB pathway), and intestinal barrier integrity (TEM, tight junction proteins, FITC-dextran permeability). Abdominal massage significantly improved diarrheal symptoms, visceral hypersensitivity, gastrointestinal motility, and anxiety-like behaviors in IBS-D rats. It restored gut microbiota diversity, reduced SCFA levels, and suppressed the TLR4/MyD88/NF-κB pathway, leading to decreased pro-inflammatory cytokines and LPS levels. FMT replicated these effects, suggesting the role of gut microbiota modulation. Moreover, abdominal massage also ameliorated barrier dysfunction in IBS-D rats by restoring ultrastructure, modulating MLCK and junctional proteins, and reducing macromolecular permeability. Abdominal massage alleviates IBS-D symptoms by modulating gut microbiota, inhibiting the TLR4/MyD88/NF-κB/MLCK signaling pathway, reducing inflammation, and restoring intestinal barrier function. These findings support its potential as a non-invasive therapeutic strategy for IBS-D.
Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma, with a substantial proportion of patients developing resistance to standard chemotherapy. Chromosomal translocations resulting in overexpression of the serine/threonine kinase Proviral Integration site for Moloney murine leukemia virus (PIM-1) contribute to disease progression, therapeutic resistance, and poor clinical outcomes, establishing PIM-1 as a promising molecular target. Unlike many kinases, the ATP-binding site of PIM-1 lacks a backbone hydrogen bond donor within the hinge region due to the presence of Pro123, conferring unique structural features relevant for selective inhibitor design. Although R-CHOP is the first-line treatment for DLBCL, approximately 30%-40% of patients develop refractory disease, highlighting the need for novel targeted therapies. In this study, an in-silico drug repurposing strategy was employed to investigate plerixafor analogues as potential ATP-competitive PIM-1 inhibitors. Quantitative Structure Activity Relationship (QSAR) modeling demonstrated strong predictive performance (R2 = 0.82), and molecular docking revealed favorable interactions within the ATP-binding pocket. Molecular dynamics simulations over 200 ns confirmed the dynamic stability of the compound 1-PIM-1 complex, as evidenced by stable Root-Mean Square Deviation (RMSD) values, reduced Root-Mean Square Fluctuation (RMSF) in the active site, and favorable Radius of Gyration (Rg) and Solvent Accessible Surface Area (SASA) profiles. Additional MM/GBSA, Principal Component Analysis (PCA), Dynamic Cross-Correlation Matrix (DCCM), and free energy landscape (FEL) analyses further supported complex stability and restricted conformational dynamics. Collectively, these findings identify plerixafor-derived compound 1 as a promising PIM-1 inhibitor and provide a robust computational framework for the development of targeted therapeutics against aggressive DLBCL, warranting further experimental validation.