Annals of medicine最新文献

Background: Tumour microenvironment and cancer cells have constant interaction affecting cancer progression. Tumour-stroma ratio (TSR) in the tumour centre and desmoplastic reaction (DR) classification at the invasive margin are prognostic factors based on stroma evaluation on H&E slides. However, their combined value and immunological associations remain poorly defined. This study examines the prognostic and immunological value of TSR, DR, and their combination in two large colorectal cancer cohorts.

Methods: Two colorectal cancer cohorts (N = 1,876) were analyzed. We introduced a three-tiered Stromal Maturity and Proportion Score (SMAPS) based on the presence of high (>50%) TSR and myxoid stroma (immature DR classification). Alcian blue staining was used to further quantify myxoid stroma. Multiplex immunohistochemistry combined with digital image analyses, was utilized to study immune cell densities associated with SMAPS, TSR, DR, and Alcian blue intensity.

Results: In the study cohort (N = 1,100), SMAPS was a stronger predictor of cancer-specific mortality [HR for high (vs. low) SMAPS 2.01 (95% CI 1.47-2.75), p < 0.0001] compared to TSR [HR for stroma-high (vs. stroma-low) 1.49 (95% CI 1.15-1.93), p = 0.003] and DR classification [HR for immature (vs. mature) 1.84 (95% CI 1.39-2.45), p < 0.0001]. High SMAPS, stroma-high TSR, and immature DR correlated with lower densities of CD3⁺ T cells, B cells, M1-like macrophages, CD66B⁺ granulocytes, and mast cells. Alcian blue staining was associated with immature DR and corresponding immune cells. The validation cohort (N = 776) confirmed the association of SMAPS with survival and T cell densities.

Conclusions: TSR and DR are independent prognostic factors for cancer-specific survival. SMAPS is a promising prognostic tool that integrates stromal maturity at the invasive margin and stromal proportion in the tumour centre. SMAPS has stronger prognostic value compared to TSR and DR classifications alone. A high stromal proportion and myxoid content are associated with an immunosuppressive microenvironment characterized by lower densities of antitumourigenic immune cells.

Patients with the most common chronic inflammatory dermatoses, namely psoriasis and atopic dermatitis, gained access to state-of-the-art therapeutic options providing spectacular improvement of skin lesions. Although generally safe, biological agents and small molecular drugs have also side effects which may be mild and irrelevant to the therapy course, but sometimes, of a greater extent and influencing further therapeutic decisions. In this review, we summarize the molecular explanation for the most common adverse effects of drugs used in the treatment of psoriasis and atopic dermatitis. Biologics used in psoriasis predominantly target TNFα, IL-17, 23, while in AD inhibit IL-4,13,31. Janus kinase (JAK) inhibitors represent small-molecule therapies effective in both conditions, although more prominently in AD. TNFα inhibitors are associated with increased susceptibility to infections, paradoxical psoriasis, eczematoid lesions, and reactivation of tuberculosis. IL-17 inhibitors may cause fungal infections and possibly trigger inflammatory bowel disease. IL-4/13 blockade in AD treatment has been linked to eosinophilia, conjunctivitis, arthritis, and facial erythema, likely due to a shift toward IL-17-driven inflammation. JAK inhibitors may cause infections, acne, dyslipidemia, and, in selected cases, cardiovascular events. This review emphasizes the importance of understanding the pathogenetic background of drug-related complications to introduce appropriate clinical management and patient selection.

Purpose: To investigate the relationship between first-trimester maternal serum iodine concentration (SIC) and foetal ultrasound biometric parameters as well as neonatal size at birth in Chinese pregnant women.

Materials and methods: A birth cohort study of 1881 women from 2022 to 2024 in Zhejiang Province, China, was conducted. SIC in the first trimester was measured using inductively coupled plasma mass spectrometry. Foetal biometric parameters in mid-pregnancy were measured using ultrasound scanning techniques. Neonatal anthropometric measurements were obtained immediately after delivery. Linear regression models were used to explore the association between maternal SIC and both foetal ultrasound biometric parameters as well as birth size indicators.

Results: Log-transformed maternal SIC showed a significant positive association with biparietal diameter (BPD) (β = 0.102, 95% CI: 0.029, 0.174), but significant negative associations with birth length (β = -0.337, 95% CI: -0.608, -0.066) and birth weight (β = -0.091, 95% CI: -0.171, -0.012). Further sex-stratified analysis revealed that among male foetuses, SIC was significantly positively associated with BPD (β = 0.158, 95% CI: 0.053, 0.263), head circumference (HC) (β = 0.414, 95% CI: 0.074, 0.754) and abdominal circumference (AC) (β = 0.490, 95% CI: 0.111, 0.870). but negatively associated with neonatal length (β = -0.402, 95% CI: -0.742, -0.062) and birth weight (β = -0.120, 95% CI: -0.234, -0.005). These associations were attenuated and non-significant in female foetuses. Maternal age stratification showed significantly stronger positive associations between SIC and foetal BPD in women aged <29 years (β = 0.150, 95% CI: 0.036, 0.265) compared to those ≥29 years.

Conclusions: Our findings suggest that first-trimester maternal SIC shows a positive association with foetal BPD but a potential negative association with neonatal anthropometric measures, with these relationships appearing stronger in male foetuses and younger mothers.

Background: This study aimed to profile the molecular signatures of post-traumatic elbow heterotopic ossification (HO) to identify key regulators and potential therapeutic targets.

Methods: Total RNA from post-traumatic elbow HO tissues (n=4) and normal bone tissues (n=6) was subjected to high-throughput sequencing to identify differentially expressed mRNAs (DEGs), microRNAs (DEMs), and lncRNAs (DELs). Bioinformatics analyses included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction network construction, and transcription factor (TF)-microRNA-mRNA network analysis. The expression trends of four most upregulated and four most downregulated DEGs were validated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Results: We identified 2,138 DEGs, 40 DEMs, and 905 DELs. DEGs were significantly enriched in biological process "bone mineralization," cellular component "plasma membrane," molecular function "integrin binding," and pathways including PI3K-Akt, NF-κB, JAK-STAT, and TNF signaling pathways. Hub genes with high connectivity included MMP9, IL6, MMP3, CTSK, and BGLAP. Integrated network analysis highlighted the transcription factor JUN and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b). The qRT-PCR results confirmed the expression trends of selected DEGs.

Conclusions: This study, for the first time, profiled the differentially expressed mRNAs, microRNAs, and lncRNAs in post-traumatic elbow HO using high-throughput RNA sequencing. These findings provide valuable insights into the molecular mechanisms of HO following elbow trauma. The identified hub genes (MMP9, IL6, MMP3, CTSK, and BGLAP), key TF (JUN), and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b) may serve as potential therapeutic targets for preventing and treating post-traumatic elbow HO.

Background: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC.

Methods: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening.

Discussion: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies.

Conclusion: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Objective: To systematically review and evaluate published risk prediction models for perioperative blood transfusion in patients undergoing total hip or knee arthroplasty (THA/TKA).

Methods: We systematically searched PubMed, Web of Science, the Cochrane Library, and Embase from inception to May 31, 2025. Two researchers independently screened the literature, extracted data, and assessed the risk of bias and applicability using the Prediction model Risk Of Bias Assessment Tool (PROBAST). The area under the receiver operating characteristic curve (AUC) values were pooled via a meta-analysis using Stata 18.0.

Results: d Fourteen studies containing 36 prediction models were included. The incidence of blood transfusion among THA/TKA patients ranged from 3.2% to 30.8%. Preoperative hemoglobin (Hb) level, tranexamic acid (TXA) use, operative duration, intraoperative blood loss, and age were the most frequently incorporated predictors. Model sensitivity ranged from 58% to 94.5%, and specificity ranged from 71.3% to 94%. Meta-analysis showed that the pooled AUC value of the 13 validated models was 0.87 (95% CI: 0.85-0.90), suggesting good discriminatory performance. All models were rated as having a high risk of bias. The applicability of four studies was rated as unclear.

Conclusion: Although the included studies demonstrated promising discriminative ability of prediction models for blood transfusion in THA/TKA, all were assessed as having a high risk of bias using the PROBAST tool. Therefore, future research should prioritize the development of models with larger sample sizes, rigorous study designs, and multicenter external validation.

Background: Seasonal affective disorder (SAD) is a major depressive disorder recurring in fall and winter due to daytime light deficiency. To investigate underlying mechanisms of SAD, we previously developed a diurnal model using Nile grass rats (Arvicanthis niloticus), in which a winter-like dim daylight condition (dimLD) increased depression-like behaviors and neuroinflammation, while attenuating central orexinergic activity compared to grass rats housed in a summer-like bright daylight condition (brLD).

Materials and methods: The present study tested the hypothesis that the behavioral and neuroinflammatory responses induced by the winter-like dimLD condition are due to attenuated central orexinergic output. Male and female grass rats housed in dimLD or brLD received intracerebroventricular orexin A (OXA) or vehicle (aCSF) 6 h every morning for one week while sleep/wakefulness were continuously monitored. A saccharin-solution preference test was performed on the last infusion day to assess anhedonia, followed by brain collection for analyzing neuroinflammatory markers in the medial prefrontal cortex, dorsal hippocampus, and basolateral amygdala.

Results: OXA treatment promoted daytime wakefulness in females, improved nighttime sleep quality in males, and reduced anhedonia in both sexes of dimLD animals to levels comparable to brLD-aCSF controls. Additionally, treating dimLD animals with OXA increased expression of anti-inflammatory cytokines IL-4 and IL-10, and reduced pro-inflammatory markers including IL-6, CD11b, and the number and inflammatory morphology of microgliadepending on sex and brain site.

Conclusions: These findings support the hypothesis that the orexinergic system mediates the effects of ambient light on sleep and affect, and may be a potential therapeutic target in SAD.

Objectives: To examine whether the JAK inhibitor tofacitinib alleviates secretory dysfunction and modulates Th17/Treg balance in a Sjögren's disease (SjD) murine model.

Methods: Integrated analysis of SjD transcriptome sequencing (GSE159574, GSE247662) identified key signalling pathways, potential therapeutic agents, and immune cell infiltration. NOD/ShiLtj mice were administered with or without tofacitinib. Secretory function and inflammation were assessed via fluorescein ocular surface staining, tear flow rate, histopathology (HE, Masson, Sirius Red), saliva flow rate, immunohistochemistry, immunofluorescence, flow cytometry, and cytokine measurement. Pearson's linear regression evaluated the correlation between Th17/Treg balance and secretory function.

Results: Bioinformatics analysis showed the JAK-STAT pathway and CD4+ T cells contribute to SjD pathogenesis. Tofacitinib reduced corneal fluorescein staining, increased tear break-up time and secretion, diminished salivary gland lymphocytic inflammation, improved saliva flow rate, and altered phospho-JAK3-STAT1 expression. It also reduced Th17 cell proportion, increased Treg cell proportion in salivary glands and spleens, decreased IL-17, and increased IL-10 and TGF-β in blood. A strong negative correlation existed between secretory function and Th17/Treg balance.

Conclusions: Tofacitinib potently attenuated secretory dysfunction and inflammation in SjD mice, possibly by modulating Th17/Treg balance, suggesting it may be a therapeutic agent for SjD.

Background: Neuropathic pain (NP), resulting from damage or disease affecting the somatosensory nervous system, severely impairs patients' quality of life and constitutes a substantial global disease burden. Recent evidence highlights the critical involvement of mechanosensitive ion channels in peripheral nociception.

Discussion: This review systematically examines the roles of key mechanosensitive channels in NP pathophysiology. TRPV4 mediates mechanical allodynia via ion flux modulation and neuroinflammation; TRPC6 enhances neuronal excitability through calcium dynamics and MAPK/mTOR signaling; TRPA1 regulates pain through neuronal and Schwann cell mechanisms involving the NOX1-oxidative stress-CXCL1 axis and myelin disruption; TREK channels attenuate pain by stabilizing resting membrane potential; TMEM family members modulate neuroimmune signaling; and Piezo2 critically contributes to mechanical and inflammatory hypersensitivity. These mechanisms reveal significant translational potential for analgesic development.

Conclusions: Targeted modulation of mechanosensitive ion channels represents a promising strategy for developing effective, non-addictive analgesics. This review establishes a theoretical foundation for understanding NP pathophysiology and identifies actionable therapeutic targets with substantial clinical relevance.