Chimeric Antigen Receptors (CAR) T-cell therapy is a ground-breaking discovery in immunotherapy, mainly known for its exceptional results in treating haematological malignancies. The latest research has revealed that the potential of CAR T-cell therapy extends far beyond its current capabilities and could represent a novel therapeutic approach for treating various cancers. This review aims to summarize the latest innovations in CAR T-cell therapy applied in cancer treatment, including multiple myeloma, osteosarcoma, glioblastoma, melanoma and various childhood malignancies. However, several challenges limit success of CAR T-cell therapy, including the antigen escape phenomenon, 'on-target off-tumour' toxicity, penetration into solid tumour tissue, alongside the cost-effectiveness concerns. The improvement of cancer immunotherapies currently available requires an increase in the effectiveness of CAR T-cells in managing refractory and solid cancers. This could be achieved by using CAR T-cells to target various antigens, enhancing their local delivery and tumour infiltration capabilities and utilizing CAR T-cells in combination with checkpoint blockade and immunotherapy, such as PD-1 blockade and CD19 CAR T-cell combined therapy. Although CAR T-cell treatment offers a lot of promise, its cost needs to be taken into account, especially in healthcare systems with limited funding. More importantly, frameworks for Health Technology Assessment (HTA) must adapt to incorporate ethical, sociological and psychological aspects. Reducing CAR T-cell toxicity is also essential, as it remains among biggest obstacles to their widespread application in clinical practice. Future research should therefore focus on enhancing our understanding of CAR T-cell therapy and expanding the application of immunotherapy in treatment.

Steatosis extends beyond the liver to the pancreas, heart, and skeletal muscle, yet prevailing definitions remain narrowly organ-focused. This narrative review introduces the Metabolic Steatotic Axis (MSA) as a framework that captures the dynamic, bidirectional interactions among these organs, driving systemic metabolic dysfunction. We synthesize evidence linking lipotoxicity, inflammatory signaling, and endocrine cross-talk into a self-amplifying network accelerating insulin resistance, β-cell failure, and cardiometabolic risk. The MSA concept provides a rationale for axis-based staging systems and composite biomarker panels to quantify cumulative disease burden better and refine risk stratification. We highlight phenotypic heterogeneity within MSA stages, the possible hierarchy of organ vulnerability, and the implications for prognosis and therapy. Viewing pharmacological and lifestyle interventions through the MSA lens reframes them as systemic modulators rather than organ-specific treatments, underscoring the need for multi-organ endpoints in clinical trials. Finally, we outline priorities for longitudinal imaging, multi-omics integration, and global harmonization to translate the MSA from a conceptual construct to a clinically actionable paradigm. By unifying fragmented observations into a systemic model, the MSA has the potential to reshape disease classification, therapeutic strategies, and precision medicine in metabolic disorders.

ABSTRACT Introduction Interindividual variability in drug response remains a significant clinical challenge, leading to therapeutic failure and toxicity. Much of this variability is unexplained by classical host-centric pharmacokinetic (PK) models, highlighting a critical gap in understanding of drug disposition. This review addresses this gap by establishing the gut microbiome as an important determinant of drug fate. Areas covered This narrative review with scoping approach examines how microbial enzymes affect therapeutics through comprehensive analysis of mechanistic and clinical studies. Key examples discussed include irinotecan, digoxin, and sulfasalazine. We highlight specific situations where the influence of gut bacteria is particularly significant, such as with low-bioavailability drugs and in patients with an ileocolonic anastomosis, where gut bacteria directly impact drug absorption and metabolism. Additionally, we address the limitations of current PK models and explore the potential of new integrated approaches. Expert opinion We propose that the gut microbiome should be recognized as a ‘fifth pillar’ of PKs. This shift in perspective is crucial for advancing personalized medicine. In this new model, a ‘PK profile card’ integrating microbial, genomic, and clinical data will help guide dosing. We anticipate microbiome analysis to become a standard clinical tool to optimize drug efficacy and safety.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of cartilage, as well as by extra-articular manifestations. Rheumatoid nephropathy is a common complication of RA and its principal target is the renal corpuscle. Vitamin D and its analogs exert immunomodulatory actions throughout the body due to the widespread of their receptors. Our study aimed to compare the effects of cholecalciferol (vitamin D3) and alfacalcidol on renal corpuscle changes in pristane-induced RA model following a 28-day treatment, using geometric morphometrics. Forty female Wistar rats (190–210 g; 12–13 weeks old) were randomly assigned to four groups: the control (Cont) group (n = 10) received saline i.c., the PIA group (n = 10) was administered pristane i.c., PIA-ALF group (n = 10) was administered pristane i.c. and alfacalcidol orally, and the PIA-CH group (n = 10) was injected i.c. with pristane and received cholecalciferol orally. Pristane administration was used for RA induction. At the end of the experiment, the left kidneys were removed and processed by standard histological procedures for geometric morphometric analysis. Geometric morphometric analysis demonstrated that, compared with the control group, the architecture of the renal corpuscles was altered in the PIA (p < 0.0001) and PIA-CH (p = 0.0065) groups. In contrast, no statistically significant differences were observed in the PIA-ALF group (p = 0.3011). Geometric morphometric analysis demonstrated that alfacalcidol, but not cholecalciferol, exertedaprotective effect on the renal corpuscle architecture in pristane-induced rheumatoid arthritis in rats.

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Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes, obesity and cardiorenal disease. Beyond their established glycaemic and weight-lowering effects, both drug classes consistently lower blood pressure (BP), a benefit that remains relatively underrecognized. This review provides an integrated synthesis of trial evidence, real-world data and meta-analyses examining the antihypertensive effects of SGLT2is and GLP-1 RAs. Across cardiovascular, heart failure, renal and obesity trials, modest but clinically meaningful BP reductions have been observed in diverse populations, including individuals without diabetes. These effects appear largely independent of glycaemic control and offer additive value in high-risk patients with overlapping comorbidities. The totality of evidence supports the strategic incorporation of these agents into future antihypertensive frameworks, warranting further investigation in dedicated blood pressure-focused trials.

Introduction: Polycystic ovary syndrome (PCOS) represents a state of androgen-driven metabolic dysregulation where visceral adiposity and inflammation critically define cardiometabolic risk. Visceral adiposity is not a bystander in PCOS; it is an active endocrine organ driving insulin resistance, low-grade inflammation, and androgen persistence. Interventions that reverse adipocyte hypertrophy and inflammatory signaling may therefore alter the metabolic trajectory of PCOS. Beyond its chronobiotic role, melatonin exerts profound metabolic actions via MT1/MT2 receptors in adipose tissue, modulating oxidative stress and inflammatory gene expression. Yet its direct impact on androgen-induced visceral adiposity remains unclear. Aim: The present study aimed to evaluate the effects of melatonin, metformin, and their combination on visceral fat accumulation in a testosterone-induced PCOS rat model. Material and methods: Thirty prepubertal female Wistar rats were randomized into five groups (n=6): control, PCOS (testosterone 20 mg/kg/day), PCOS+metformin (500 mg/kg/day), PCOS+melatonin (2 mg/kg/day), and PCOS+melatonin+metformin. Treatments lasted 36 days. Estrous cyclicity was monitored by daily vaginal cytology, and somatometric parameters were recorded weekly. On day 36, serum, ovaries, and visceral fat were collected for biochemical and histological analysis. Results: Vaginal smear changes and ovarian pathological alteration due to prolonged testosterone exposure confirmed the successful induction of the PCOS model. Measures of central adiposity, including abdominal circumference and the TC/AC ratio, were significantly higher in the PCOS model than in controls (p < 0.001). Abdominal circumference (AC) increase was greatest in the PCOS model (p < 0.001), while all treatment groups showed significant reductions, most notably in the melatonin + metformin group, followed by melatonin monotherapy and then metformin (all p < 0.001 vs. PCOS). Melatonin was more effective than metformin (p=0.029). AC/TC reduction was greatest in the combined treatment group (p < 0.05). Total weight gain among groups did not reach statistical significance. While total visceral fat weight did not differ among groups, histology revealed a marked reduction in adipocyte number in treated animals, most pronounced in the melatonin group (p < 0.033). Conclusion: Our findings identify melatonin as a metabolic modulator of androgen-driven adiposity, supporting its potential as an adjunctive therapy targeting visceral fat and inflammation in PCOS

Small intestinal bacterial overgrowth (SIBO) is a major yet underrecognized driver of gastrointestinal morbidity in systemic sclerosis (SSc). Disordered motility, fibrosis, and dysbiosis promote microbial stasis, malabsorption, and malnutrition, contributing substantially to impaired quality of life and survival. Diagnostic accuracy remains limited: jejunal aspirate culture is invasive, whereas breath testing offers only moderate sensitivity and specificity. Empirical antibiotic therapy yields transient symptom relief, but recurrence is common, and evidence guiding optimal eradication strategies is sparse. Adjunctive measures, including probiotics, prokinetics, and dietary interventions, remain variably applied, with heterogeneous outcomes across studies. Novel microbiome-targeted, neuromodulatory, and antifibrotic therapies are emerging as promising mechanism-based options. Bearing this in mind, this narrative review aims to consolidate current knowledge on SIBO eradication in SSc. We first outline the pathophysiological rationale and clinical relevance of bacterial overgrowth. We then synthesize available evidence for treatment strategies, appraise barriers to durable remission, and discuss implications for multidisciplinary management. Finally, we highlight emerging approaches, including microbiome-directed therapies, novel prokinetics, and antifibrotic interventions, and define priorities for future clinical research.

Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.