Search Results (187)

Background/Objectives: This study aimed to evaluate the immediate effects of a 2-hinged expander activated with the alternate rapid maxillary expansion–constriction (Alt-RAMEC) protocol on craniofacial structures and the soft tissue periodontium in adolescents with skeletal Class III malocclusion characterized by maxillary retrusion. Methods: Lateral cephalograms obtained at baseline (T0) and immediately after treatment (T1) from 15 adolescents (6 females, 9 males; mean ages 12.6–13.1 years) treated with a 2-hinged expander using a 9-week Alt-RAMEC protocol were analyzed. A control group consisted of 27 untreated Class III individuals (7 females, 20 males; mean ages 12.5–12.6 years). Sagittal and vertical skeletal, dental, and soft tissue measurements were assessed using a Cartesian coordinate system. Periodontal parameters of supporting teeth were evaluated at T0 and T1. Statistical analysis was performed using the Mann–Whitney U and Wilcoxon tests (p < 0.05). Results: Significant anterior maxillary displacement was observed in the treatment group compared with controls (p < 0.01), accompanied by increases in overjet and Wits appraisal (p < 0.05), while mandibular position remained unchanged. The upper lip advanced in accordance with skeletal changes (p < 0.05). Gingival index, bleeding index, and probing pocket depth increased significantly in supporting teeth (p < 0.05), whereas plaque index remained stable (p > 0.05). Conclusions: The 2-hinged expander combined with a 9-week Alt-RAMEC protocol induces immediate skeletal maxillary advancement in growing Class III patients with minimal dental compensation. Short-term periodontal changes suggest a transient inflammatory response associated with appliance therapy. Full article

Objective: To investigate the effects of three-bite plane appliance (TBP) therapy on maximal occlusal force (MOF) in growing patients. Methods: This study included 120 children (aged 9–10 years) diagnosed with Class I, Class II, or Class III malocclusion. All subjects presented with a deep bite and a normodivergent growth pattern. MOF was recorded at baseline (T0) and after 12 months of treatment (T1). A standardized multi-bite protocol was used to improve reproducibility. Paired t-tests or Wilcoxon tests assessed intragroup differences, while Welch’s ANOVA with Games–Howell post hoc testing evaluated intergroup variation. Results: Significant intragroup differences were found for all groups (p < 0.001). Class I subjects demonstrated a reduction in MOF (Δ = −138.3 N; p < 0.001), whereas Class II (Δ = 113.35 N; p < 0.001) and Class III (Δ = 145.6 N; p < 0.001) subjects showed significant increases. Intergroup comparison revealed a significant overall difference in MOF change (F = 41.35; p < 0.001). Post hoc analysis confirmed significant differences between Class I and both Class II and III, while no significant difference was detected between Class II and III. Conclusions: Treatment with a three-bite plane appliance modifies MOF in growing patients, showing malocclusion-specific adaptation patterns. The reduction observed in Class I contrasts with the functional enhancement detected in Class II and Class III subjects. Full article

Background/Objectives: Tissue-agnostic therapy has transformed oncology by enabling treatment selection based on molecular alterations rather than tumor origin. Since 2017, nine U.S. Food and Drug Administration approvals across six biomarker classes have defined this paradigm. Thoracic and head and neck (H&N) cancers have been underrepresented in the registrational evidence supporting these approvals. This review systematically evaluated biomarker representation, histologic distribution, and clinical applicability of tissue-agnostic therapies in thoracic and H&N malignancies. Methods: A narrative systematic review was conducted using PubMed, ClinicalTrials.gov, and regulatory documents for all tissue-agnostic approvals between January 2017 and October 2025. Data were extracted from pivotal trials, including total enrollment, objective response rate (ORR), histologic distribution, and thoracic/H&N representation. Emerging biomarkers and resistance mechanisms were assessed from phase I–III studies and basket trials. Results: Nine tissue-agnostic approvals encompassing six biomarkers were identified: MSI-H/dMMR, TMB-High, NTRK, RET, BRAF V600E, and HER2 (IHC 3+). Across pivotal datasets (3800 patients), thoracic and H&N cancers accounted for fewer than 8% (n = 290) of enrolled patients. Thoracic representation was dominated by non-small-cell lung cancer (NSCLC) in RET, NTRK, and HER2 programs (150 patients, 4%), while small-cell lung, mesothelioma, and thymic carcinomas contributed <1% combined. H&N cancers comprised 140 patients (3–4%), primarily secretory salivary carcinoma in NTRK trials (n = 12–20), thyroid carcinoma in BRAF (n = 36) and RET (n = 45) programs, and rare HER2-positive salivary duct carcinomas. Conventional HNSCC and sinonasal cancers were limited to 1–2 cases per trial. Only two of nine trials (22%) reported prespecified CNS endpoints, and RNA-based fusion testing was employed in <40%, underscoring diagnostic variability and limited applicability. Conclusions: Although tissue-agnostic therapy has expanded the reach of precision oncology, thoracic and H&N cancers remain underrepresented in registrational evidence. Most approvals rely on single-arm basket studies with small, heterogeneous subsets that preclude histology-specific conclusions. Future research should prioritize histology-enriched trial designs, standardized molecular diagnostics, and real-world validation to establish reliable, equitable standards of care for these underrepresented malignancies. Full article

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis (TB), primarily MDR-TB and extensively drug-resistant XDR-TB. Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus). Tedizolid phosphate was the second commercially available oxazolidinone antibiotic approved, followed by other oxazolidinones (contezolid, radezolid, ranbezolid, sutezolid, delpazolid, cadazolid, TBI-233 and MK-7762) that are in clinical study. Contezolid is approved in China and cadazolid has entered phase III clinical trials. This comprehensive review intends to provide an overview of the compounds belonging to this class already in use in therapy and/or clinical studies and to portray the most significant and recent outcomes regarding new oxazolidinones under study. Three literature databases, i.e., PubMed/MEDLINE, Google Scholar and Scopus, were used for the literature search, particularly focusing on the last five years, and screened using different keywords. The design of new drugs belonging to this class may be of considerable interest to researchers and clinicians, contributing to the discovery of new antibiotics that retain antibacterial activity but have fewer side effects. Full article

Objective: External apical root resorption is a frequent complication of orthodontic treatment, and the response of endodontically treated teeth remains controversial. This study aimed to compare external apical root resorption (EARR) in endodontically treated teeth and vital teeth following fixed orthodontic treatment in patients with Angle Class I, II, and III malocclusions using digital panoramic radiography. Methods: This retrospective longitudinal study included 60 patients (mean age: 16.3 ± 2.4 years) who underwent non-extraction fixed orthodontic treatment. A paired contralateral within-subject design was used, whereby each patient contributed one endodontically treated tooth and its symmetrical untreated vital counterpart. Root length was measured on calibrated panoramic radiographs obtained before (T0) and after treatment (T1). Differences were analyzed using the Wilcoxon signed-rank and Kruskal–Wallis tests (p < 0.05). Results: Both endodontically treated and vital teeth exhibited statistically significant reductions in root length between T0 and T1 (mean reduction: 1.02 ± 1.36 mm and 1.11 ± 1.79 mm, respectively; p < 0.001). No significant difference was observed between the two tooth types regarding the magnitude of resorption. Similarly, no significant differences were detected among Angle Class I, II, and III malocclusion groups. The observed mean reduction of approximately 1 mm suggests limited apical shortening within the range generally considered clinically moderate. Conclusions: Endodontically treated teeth exhibited a degree of EARR comparable to that of vital teeth following fixed orthodontic treatment, suggesting that properly treated endodontic teeth do not pose an increased risk of clinically relevant apical root resorption during orthodontic therapy. Full article

Background/Objectives: Bisphosphonates, a class of drugs that are widely used in the treatment of neoplastic diseases, can lead to the development of medication-related osteonecrosis of the jaw (MRONJ). This condition is challenging to manage due to the high incidence of postoperative complications: superinfections, local wound dehiscence, or fractures in pathological bone. The aim of this study is to evaluate the therapeutic role of bovine-derived xenografts in the management of MRONJ. Methods: This retrospective observational study evaluates the clinical outcomes of patients with confirmed stage II or III MRONJ, after surgical treatment with Bio-Oss application. All patients had received zoledronic acid therapy, which was discontinued for a minimum of four months prior to surgical intervention. The surgical protocol included local debridement, sequestrectomy, and grafting of the residual defect with a bone substitute, followed by periodic clinical evaluations and monitoring of local healing with a follow-up period of up to one year. Results: Of the total number of patients treated according to this surgical protocol, 85.71% achieved favorable healing without complications at 8 weeks. Cases with poor local healing results were more likely to have prolonged zoledronic acid administration. Conclusions: Within the limits of this retrospective observational study, the use of bovine-derived xenografts following sequestrectomy in stage II–III MRONJ was associated with satisfactory local healing in several cases. However, considering the limited sample size and lack of a comparator group, these findings should be interpreted cautiously. To better understand the connection between the length of antiresorptive therapy, surgical management techniques, and postoperative outcomes, more prospective, multicenter trials with bigger patient cohorts are needed. Full article

Background: The prognostic value of preoperative hemoglobin A1c (HbA1c) in patients undergoing cardiac surgery remains uncertain. This study investigated the association between preoperative HbA1c levels and the risk of postoperative low cardiac output syndrome (LCOS) and in-hospital mortality in patients undergoing elective cardiac and/or thoracic aortic surgery. Methods: This single-center retrospective cohort study included consecutive adult patients who underwent elective cardiac and/or thoracic aortic surgery between 1 November 2019 and 30 June 2021. Patients younger than 18 years, pregnant, or lacking a preoperative HbA1c measurement within one week before surgery were excluded. A total of 728 patients were analyzed. Baseline clinical characteristics, operative variables, and postoperative outcomes were collected. Associations between HbA1c and perioperative parameters were assessed using univariate analyses, and independent predictors of LCOS and in-hospital mortality were identified using multivariate logistic regression. Results: Higher HbA1c levels were associated with greater body mass index (BMI; r = 0.08, p = 0.025), higher New York Heart Association (NYHA) functional class (III vs. I–II: 6.86 ± 1.60% vs. 6.15 ± 1.13%, p = 0.001), postoperative LCOS (7.05 ± 1.72% vs. 6.15 ± 1.13%, p = 0.013), and in-hospital mortality (6.79 ± 1.50% vs. 6.15 ± 1.13%, p = 0.011). In multivariate analysis, HbA1c independently predicted LCOS (odds ratio [OR] 1.52; 95% confidence interval [CI] 1.09–2.12; p = 0.015), together with reduced left ventricular ejection fraction and postoperative atrial fibrillation. Independent predictors of in-hospital mortality included BMI, HbA1c (OR 1.81; 95% CI 1.19–2.74; p = 0.005), EuroScore II, prolonged cardiopulmonary bypass time, impaired glomerular filtration rate, postoperative septicemia, continuous renal replacement therapy, re-intubation, and prolonged mechanical ventilation. Conclusions: Higher preoperative HbA1c levels were independently associated with an increased risk of postoperative LCOS and in-hospital mortality in patients undergoing elective cardiac and/or thoracic aortic surgery. These findings support the role of HbA1c as a prognostic biomarker and its potential integration into preoperative risk stratification models for cardiac surgery. Full article

Background/Objectives: Progress in diagnostic and therapeutic strategies has resulted in an increasing prevalence of adults with congenital heart disease (ACHD), including those involving genetically determined syndromes. This study aimed to characterize prevalence, congenital phenotypes, heart failure (HF) stages, comorbidity burden, and current medical management of ACHD and concomitant genetically determined syndromes enrolled in a prospective HF-focused registry. Methods: The PATHFINDER-CHD Registry is a German-based (est. 2022) multicenter observational registry. This web-based platform consecutively tracks ACHD patients across the heart failure spectrum, including those with current or prior HF, as well as those at high structural or functional risk. HF stage was classified using a modified ACC/AHA scheme adapted for CHD; functional capacity was graded according to the Perloff classification. Baseline demographics, CHD anatomy, prior surgical/interventional treatment, cardiac and extracardiac comorbidities, and medication were collected from medical records. Results: Among 1987 enrolled ACHD, 107 (5.4%) had a genetic syndrome (n = 65, 60.7% women; mean age 33.5 ± 9.4 years; range 18–68). Most common syndromes were trisomy 21 (n = 49; 45.8%) and 22q11.2 deletion (n = 27; 25.2%); 31 patients (30.0) had rarer syndromes. Predominant CHD diagnoses were atrioventricular septal defect (n = 42, 39.3%), tetralogy of Fallot (n = 19, 17.8%), and pulmonary atresia with ventricular septal defect (n = 7, 6.5%). A systemic left ventricle was present in 102 (95.3%); 40 (37.4%) had primarily cyanotic CHD, and 7 (6.5%) an Eisenmenger physiology. Most patients (n = 71; 66.4%) had undergone definite surgical repair; 25 patients (23.3%) had at least one catheter intervention, including transcatheter valve implantation in 17 cases (15.9%). HF stage was mainly B (n = 30, 28.0%) or C (n = 75, 70.1%). Perloff functional class I/II was present in 97 (90.7%). Leading cardiac comorbidities included intrinsic aortopathy (n = 49, 45.8%), pulmonary arterial hypertension (n = 12, 11.2%), and arrhythmias (n = 10, 9.3%). Frequent extracardiac comorbidities were thyroid dysfunction (n = 34, 31.8%), kidney disease (n = 16, 15.0%), hyperuricemia (n = 13, 12.1%), and depression (n = 15, 14.0%). Pharmacotherapy was used in 66 patients (61.7%). Beta-blockers (n = 25, 23.4%) were common, while ACEi/ARB (n = 9, 8.4%), diuretics (n = 10, 9.3%), MRAs (n = 8, 7.5%), and SGLT2 inhibitors (n = 3; 2.8%) were infrequently prescribed; no patient received ARNI or digitalis. For targeted treatment of pulmonary arterial hypertension, phosphodiesterase-5 inhibitors (n = 7, 6.5%), endothelin receptor antagonists (n = 6, 5.6%), or prostacyclin analogues (n = 1, 0.9%) were used. As oral anticoagulants, vitamin K antagonists or direct oral anticoagulants (DOACs) were prescribed in 17 cases (15.9%). Forty-one patients (38.3%) received thyroid hormone replacement. Conclusions: Syndromic ACHD constitute a small but clinically high-risk subgroup within an HF-oriented registry, marked by complex CHD, substantial cardio–extracardiac multimorbidity (notably aortopathy, PAH, thyroid disease, renal dysfunction, depression), and low utilization of contemporary HF therapies. These data support specialized, interdisciplinary, longitudinal care pathways and prospective studies addressing outcomes and evidence-based HF management in syndromic ACHD. Full article

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

Background/Objectives: Antimicrobial peptides (AMPs), evolutionarily conserved components of innate immunity characterized by their broad-spectrum efficacy and minimal resistance development, are increasingly recognized as promising therapeutic candidates. This review aims to integrate current knowledge concerning natural and synthetic antimicrobial peptides and their therapeutic effectiveness in addressing gastrointestinal infections. Methods: A literature review was performed, evaluating recent peer-reviewed studies on AMPs. The research concentrated on their molecular mechanisms of action, antimicrobial spectrum, and their interactions with standard antibiotics. More in detail, the peptide classes examined herein included defensins, cathelicidins, histatins, and various natural peptides such as lactoferricin, protamines, RegIII, and hepcidin, along with synthetic analogs like WR12, D-IK8, MSI-78, and IMX942. Results: Natural AMPs demonstrated significant antimicrobial and immunomodulatory effects against Escherichia coli, Klebsiella pneumoniae, Salmonella spp., and Shigella spp. Beyond direct antimicrobial activity, antimicrobial peptides act as integrated anti-infective agents not only by modulating host–microbiota interactions, but also preserving epithelial barrier integrity, and limiting inflammation, thereby offering a multifaceted strategy to control gastrointestinal infections. On the other hand, synthetic peptides showed improved stability, reduced cytotoxicity, and synergistic interactions with antibiotics, which suggests that they could be used either alone or in combination with other treatments. Conclusions: AMPs constitute a promising category endowed with anti-infective activity, especially for therapy of intestinal diseases, which is attributed to their distinctive anti-infective mechanisms, immune-modulating characteristics, and a relatively low propensity for resistance development compared to conventional antibiotics. However, more clinical trials and improvements to their formulation are needed to translate promising in vitro results into reliable patient outcomes. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design. Full article

Background and aims: Vericiguat lowers cardiovascular death or heart-failure hospitalization in recently worsened heart failure with reduced ejection fraction (HFrEF), but its effects on cardiac remodeling are less well characterized. Our aim was to evaluate whether the addition of vericiguat to guideline-directed medical therapy (GDMT) promotes reverse myocardial remodeling in patients with HFrEF and recent worsening. Methods: We conducted a prospective, non-randomized, single-center study enrolling 34 consecutive patients with HFrEF who had experienced recent worsening and were on stable GDMT for at least 3 months prior to decompensation. Clinical, biochemical, and echocardiographic assessments were performed at baseline and at 6 months. Results: A total of 24 patients completed the 6-month follow-up (mean age 63 ± 9 years; 92% male), 96% of whom were in New York Heart Association (NYHA) class III or IV. After 6 months of vericiguat therapy, right ventricular systolic function improved significantly, with an increase in tricuspid annular plane systolic excursion (TAPSE) from 18.5 ± 4.3 mm to 21.4 ± 4.8 mm (p = 0.003). Left ventricular systolic function improved, with a numerical increase in left ventricular ejection fraction (LVEF) (30.1 ± 5.9% to 32.2 ± 10.5%; p = 0.122) and a significant increase in left ventricular outflow tract velocity-time integral (LVOT VTI) (14.8 ± 3.7 cm to 16.1 ± 3.8 cm; p = 0.011). Functional improvements were accompanied by structural remodeling, including reductions in right ventricular internal diameter in diastole (RVIDd) (40.5 ± 5.8 mm to 37.9 ± 6.9 mm; p = 0.002) and left ventricular end-systolic volume (LVESV) (144.0 ± 40.3 mL to 132.4 ± 61.0 mL; p = 0.031). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels also decreased significantly (median 1829.0 ng/mL to 1241.0 ng/mL; p = 0.03). Conclusions: In patients with HFrEF and recent worsening, the addition of vericiguat to GDMT may be associated with reverse myocardial remodeling. Full article

Background/Objectives: Conduction system pacing (CSP) is a potential alternative to biventricular pacing (BVP) in heart failure with reduced ejection fraction (HFrEF) and left bundle branch block (LBBB) or non-LBBB. Available data also suggest that unlike BVP, CSP may improve clinical outcome in patients with right bundle branch block (RBBB), although its effects on cardiac mechanics and energetics are ill-defined. Herein, we report on echocardiographic and clinical outcomes of CSP in this patient cohort. Methods: CSP either with His bundle pacing or LBB area pacing was attempted as a primary strategy in patients with RBBB, QRS duration ≥ 130 ms, LVEF < 35% and NYHA II-IV symptoms after optimized medical therapy for 6 months. Data on functional status, NT-proBNP and echocardiographic parameters were collected at baseline and 6 months after CSP. Results: CSP performed in 16 patients reduced QRS duration from 155.3 ± 12.8 ms to 130 ± 16.5 ms (p < 0.001), increased LVEF from 27 ± 7% to 33 ± 9% (p = 0.01), improved LV global longitudinal strain from −7 ± 3% to −10 ± 4% (p = 0.004) and improved LV peak strain dispersion from 126 ± 28 ms to 96 ± 23 ms (p = 0.004). Global myocardial work index increased from 582 ± 277 mmHg% to 840 ± 306 mmHg% (p = 0.003), as did global constructive work (900 ± 374 mmHg% to 1203 ± 393 mmHg%; p = 0.006) and global work efficiency (from 71 ± 7% to 77 ± 8%; p = 0.004). NYHA class (12.5% with NYHA II, 87.5% with NYHA III before vs. 25% with NYHA I, 50% with NYHA II and 25% with NYHA III at 6 months; p = 0.002) and 6 min walk distance (from 354 ± 88 m to 411 ± 95 m; p = 0.003) improved, while NT-proBNP decreased (from 4093 ± 7215 ng/L to 2087 ± 2872 ng/L, p = 0.003). Conclusions: CSP improved functional capacity and echocardiographic parameters related to cardiac functions and myocardial work in HFrEF patients with RBBB. Nevertheless, these results await further confirmation by large-scale, multi-center randomized trials. Full article

In this study, we characterized the holin-like protein ORF70 from the cyanophage MaMV-DC, offering valuable insights into its role in phage-mediated host cell lysis. ORF70 shares key features with class III holins, such as a hydrophobic transmembrane domain and membrane-associated localization, which are crucial for its bacteriolytic activity. Subcellular localization studies suggested its association with the membrane, supporting its classification as a holin-like protein. Overexpression of ORF70 in E. coli resulted in significant growth inhibition, increased β-galactosidase leakage, and visual confirmation of cell death through live/dead staining. Additionally, ORF70’s sensitivity to the energy toxin 2,4-dinitrophenol (DNP) further indicated its holin-like activity by promoting membrane depolarization. Transmission electron microscopy and Gram staining revealed characteristic morphological changes in E. coli cells, including membrane disruption, consistent with damage caused by holins. These results suggest that ORF70 acts as a holin-like protein that disrupts the host membrane, leading to bacterial cell death. Our study provides evidence supporting the holin-like activity of ORF70 from cyanophage MaMV-DC. This research significantly enhances our understanding of phage-host interactions and opens new avenues for developing phage-based therapies, offering promising alternatives to traditional antibiotics amidst the growing challenge of antibiotic resistance. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2–6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation. Full article