Medical sciences (Basel, Switzerland)最新文献

Background: Adoptive cell therapy using genetically engineered recombinant T cell receptors (rTCRs) expressed in T cells (TCR-T cell therapy) provides precision targeting of cancer cells expressing tumor-associated or tumor-specific antigens recognized by the rTCRs. Standardized analytical tools are lacking to easily quantify receptor expression.

Methods: To overcome this hindrance, a universal tagging system (UniTope & TraCR) was designed consisting of a minimal peptide epitope (UniTope) inserted into the constant region of the rTCR α or β chain and a high-affinity monoclonal antibody (TraCR) specific to this tag. Detailed biophysical, biochemical, and functional assays were performed to evaluate rTCR expression, folding, pairing, and antigen recognition, as well as antibody performance, using the UniTope & TraCR System.

Results: Tagged rTCRs were stably expressed in human T cells with surface densities comparable to untagged rTCRs. The TraCR antibody bound UniTope with nanomolar affinity and no detectable cross-reactivity was observed for endogenous proteins expressed by human cells of diverse origin, importantly, including T cells of the natural T cell repertoires of multiple human donors. Functional assays confirmed that UniTope-tagged rTCRs preserved their antigen-specific cytokine secretion and cytolytic activity upon antigen-specific stimulation. The UniTope & TraCR System enabled robust detection of rTCR-expressing T cells by flow cytometry, and rTCR protein expression by Western blot or immunoprecipitation, supporting the quantitative assessment of receptor copy number and structural integrity.

Conclusions: The UniTope & TraCR System provides a modular, construct-agnostic platform for monitoring engineered rTCRs, integrated into TCR-T cell therapies currently in development.

Background/Objectives: Since 1988, the IARC has classified alcohol as a type 1 carcinogen, causally linked to seven types of cancer (oral cavity, pharynx, larynx, esophagus, colorectum, liver and breast carcinomas). Several agencies, such as the WHO and the IARC, hold that there is a direct monotonic association between any gram of alcohol consumed and the risk of cancer, regardless of the drinking pattern. On the other hand, an expanding body of evidence indicates that drinking pattern may substantially modify the effect of alcohol consumption. The Mediterranean alcohol-drinking pattern (MADP) includes different aspects of alcohol consumption, such as preference for red wine, moderate alcohol consumption with meals, spreading consumption over the week and avoiding binge drinking. Conformity to this pattern has shown inverse associations with all-cause mortality, cardiovascular disease and diabetes. However, its relationship with cancer incidence has not been studied yet. Our objective was to assess how alcohol consumption patterns, with particular emphasis on the MADP, relate to the incidence of the seven alcohol-related cancers. This information is needed to support cancer prevention recommendations that may go beyond the amount of alcohol consumed to also include the drinking pattern. Methods: We prospectively followed 19,541 participants in the SUN ("Seguimiento Universidad de Navarra") cohort for a median of 13.8 years. We classified participants into four groups, namely, abstainers and three further groups according to their adherence to the MADP score (low, moderate and high). Results: A substantial reduction in the risk of alcohol-related cancer incidence was observed only in men for high versus low adherence to the MADP, with an adjusted hazard ratio (HR) of 0.44 (95% confidence intervals (CIs) (0.21-0.92)). The category of moderate adherence to the MADP showed a lower risk of cancer incidence with a tendency towards statistical significance (HR = 0.56, 95% CI, 0.30-1.06). For women, no result reached statistical significance. Conclusions: Based on the available evidence, separate messages by sex should be delivered. In men, the association between alcohol and cancer goes beyond the amount of alcohol consumed, and a Mediterranean drinking pattern may be beneficial even for alcohol-related cancers. Men should, therefore, receive an additional message: among alcohol consumers, greater adherence to the MADP may help lower their risk of developing alcohol-related cancers. No benefit is supported for the MADP against alcohol-related cancers in women.

Background/Objectives: Ambulatory status at hospital discharge contributes to subsequent functional recovery in older adults following hip fracture. This study aimed to identify independent predictors of ambulatory status at hospital discharge following surgery for fragility hip fractures in a tertiary care setting in Southern Thailand. Methods: A retrospective study was conducted among patients aged 50 years and older who underwent surgery for low-energy hip fractures between 1 October 2018, and 30 September 2023. Data on preoperative, intraoperative, postoperative, and process of care factors were collected from electronic medical records. Student's t-tests and chi-square tests compared candidate variables between groups. Univariable and multivariable risk analyses were performed to identify independent predictors of ambulation at discharge. Results: Among 532 patients (72.7% women; mean age 76.8 ± 9.7 years), 314 (59.0%) were ambulatory at hospital discharge. Multivariable analysis demonstrated that achieving rehabilitation at the ambulation training level (mRR = 24.10; 95% CI: 9.14-63.60; p < 0.001) and undergoing hip arthroplasty (mRR = 1.17; 95% CI: 1.07-1.29; p < 0.001) were significant positive predictors of ambulation. Conversely, a history of cerebrovascular disease with hemiplegic sequelae (mRR = 0.70; 95% CI: 0.53-0.91; p < 0.01) and delayed initiation of rehabilitation more than 72 h postoperatively ((mRR = 0.84; 95% CI: 0.73-0.97; p < 0.05) were associated with reduced likelihood of ambulation. Conclusions: Ambulatory status at hospital discharge was strongly associated with early, ambulation-level rehabilitation and hip arthroplasty, whereas history of stroke and delayed rehabilitation reduced mobility. These findings emphasize the importance of timely, targeted rehabilitation to optimize functional recovery after hip fracture surgery.

Background: The aim of this study is to assess the safety of sodium channel blocker (SCB) therapy in patients with atrial fibrillation (AF). Methods: The REGUEIFA registry is a prospective, observational, multicenter registry from a Community Health Area in Spain that recruited patients with AF, whom it followed for 2 years. Results: From the 997 patients, 632 were assigned to a rhythm control strategy and analyzed. Patients exposed to SCBs demonstrated a risk ratio (RR) of 0.38 (95% CI: 0.18-0.79; p = 0.007) for worsening heart failure (HF), and 0.40 (95% CI: 0.21-0.78; p = 0.005) for the composite endpoint (death, ischemic stroke, or worsening HF), with no significant differences in all-cause mortality, cardiovascular (CV) mortality, ischemic stroke, or bleeding compared with patients not exposed to SCBs. In the subgroup of patients with structural heart disease, no differences were observed between those exposed and those not exposed to SCBs across all the clinical outcomes analyzed (all-cause mortality, CV mortality, ischemic stroke, bleeding and composite event). However, a lower event trend was observed across all these variables. The rate of sinus rhythm at 2 years follow-up was significantly higher in the SCB group (81.8% vs. 63.9%; p < 0.001). During Cox regression analysis for all-cause mortality, SCB exposure was not identified as an independent factor (HR: 0.82; 95% CI 0.17-3.87; p = 0.802). Age (HR: 1.10; 95% CI: 1.04-1.17; p < 0.001) and HF (HR: 4.23; 95% CI: 1.63-11.00; p = 0.003) were the only predictors of mortality. Conclusions: SCB therapy appears to be safe and effective, both in the overall cohort and in the patient subgroup with AF and structural heart disease. These agents may play a role in AF management in patients with revascularized coronary heart disease, left ventricular hypertrophy, and HF with preserved left ventricular ejection fraction.

Background: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development.

Methods: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications.

Results: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF-cenegermin and recombinant CNTF-Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance.

Conclusions: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance.

Background: Seronegative rheumatoid arthritis (SNRA), defined by the absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), represents 20-30% of rheumatoid arthritis cases. Once considered a milder phenotype, SNRA is now recognised as a heterogeneous entity in which a substantial subset of patients develops structural progression comparable to seropositive RA. The binary RF/ACPA-based definition is increasingly viewed as insufficient, as the broader anti-modified protein antibody (AMPA) family-including antibodies against carbamylated, acetylated and malondialdehyde-acetaldehyde-modified proteins-indicates that many "seronegative" patients may harbour unconventional humoral autoimmunity undetected by standard assays. Objectives: To synthesise contemporary insights into the epidemiology, immunopathology, diagnostic challenges and therapeutic management of SNRA, with emphasis on erosive versus non-erosive phenotypes and the implications of the AMPA paradigm. Methods: A comprehensive literature search of PubMed, Cochrane Library and Google Scholar identified randomised trials, observational cohorts and systematic reviews, with focus on studies published within the past decade. Results: SNRA displays partially distinct immune features, including lower formation of tertiary lymphoid structures and variable activation of innate inflammatory circuits. However, the traditional adaptive-versus-innate dichotomy is overly reductionist. Growing evidence suggests that unconventional humoral responses directed against non-classical post-translational modifications may be present in a proportion of RF/ACPA-negative patients. Additional qualitative dimensions-such as IgA isotypes and fine-specificity profiles-represent further heterogeneity with potential prognostic significance. Although ACPA remains the strongest predictor of erosive progression, up to one-third of seronegative patients develop erosions within five years. The 2010 ACR/EULAR criteria may delay diagnosis in SNRA. Cytokine inhibitors and JAK inhibitors show largely serostatus-independent efficacy, whereas B-cell and T-cell-targeted therapies demonstrate attenuated responses in SNRA. Conclusions: SNRA is clinically and immunologically diverse. Integrating the AMPA framework is essential for refining classification and prognostication. Distinguishing erosive from non-erosive forms may guide treatment, while future work should prioritise biomarkers predicting progression and therapeutic response.

Background/Objectives: Continuous trauma-system monitoring is limited by the lack of scalable, low-cost tools. The Pavia Trauma Management Epidemiology (PaTraME) project uses routinely collected ICD-9-CM discharge data (SDO) and the Trauma Mortality Probability Model (TMPM) to derive Injury Severity Score (XISS) and probability of death (TMPM-POD), creating a cost-free surveillance framework for regional trauma networks. Methods: We conducted a retrospective study of all major-trauma admissions (XISS > 15) in Pavia Province from 2014 to 2021. Anonymized SDO records were linked with emergency department flows and mortality registries. XISS and TMPM-POD were computed for each case. Case volumes, severity distributions, hub-centralization, and mortality (in-hospital, 30-day, and 180-day) were analyzed using trend and regression models (p < 0.05). Conclusions: We identified 1959 major-trauma admissions. Volumes increased up to 2019, dropped during the COVID-19 pandemic, and partially recovered in 2021 (p < 0.001). Overall, 61.5% of patients were admitted to hub centers, with an upward trend (p < 0.001). Hubs treated more severe trauma (median XISS 17 vs. 16; TMPM-POD 0.06 vs. 0.05, both p < 0.001). In-hospital mortality remained stable (8.2-11.4%, p = 0.828). TMPM-POD showed strong agreement with observed in-hospital mortality (Lin's concordance correlation coefficient 0.81), though calibration worsened at higher risk levels. PaTraME confirms TMPM-POD as a valid mortality predictor and demonstrates a reproducible administrative-data framework for trauma surveillance. Rising hub admissions and stable mortality despite increasing complexity suggest improved system performance. Stratification of XISS and TMPM-POD between hub and spoke centers highlights peripheral hospitals managing disproportionately severe cases, informing targeted resource allocation and supporting quality improvement via automated dashboards.

Background: Type 2 diabetes mellitus (T2DM) is often associated with hyperuricemia, both conditions worsening kidney function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control and kidney function; however, data on their long-term antihyperuricemic effects in real-world clinical settings remain limited. Therefore, we aimed to compare the effects of SGLT2 inhibitors versus allopurinol on serum uric acid (sUA), kidney function, and clinical outcomes. Methods: This retrospective cohort study evaluated patients with T2DM and hyperuricemia initiated on 10 mg empagliflozin (n = 70), 10 mg dapagliflozin (n = 78), or 100 mg allopurinol (n = 66) between 1 January 2017, and 1 January 2020. Drug dosages were kept constant throughout the study. Baseline and follow-up data (3, 6, 12, 24, and 36 months) were collected. Results: Over 36 months, empagliflozin and dapagliflozin significantly reduced sUA (from 452 (95) to 399 (69) µmol/L and from 450 (81) to 364 (71) µmol/L, respectively) and stabilized eGFR without a significant decline. Allopurinol also reduced sUA (from 430 (89) to 345 (69) µmol/L) but was associated with a progressive eGFR decline (from 70 (35) to 57 (32) mL/min/1.73 m²). Mortality was the highest in the allopurinol group; however, therapy discontinuation was the lowest with this treatment. Conclusions: SGLT2 inhibitors achieved comparable sUA reduction to allopurinol by 36 months while preserving eGFR. Allopurinol was associated with higher mortality and hospitalization rates; SGLT2 inhibitor therapy was associated with favorable multidomain outcomes, but strategies to address adverse effects are needed to enhance adherence.

Background: Periprosthetic joint infections (PJIs) of the hip and knee are one of the most severe complications in arthroplasty, often requiring prolonged antibiotic therapy and multiple revision surgeries. The increasing prevalence of multidrug-resistant organisms and biofilm-associated PJIs has renewed interest in bacteriophage therapy as a targeted, adjunctive treatment option in refractory cases. This investigation systematically reviews and discusses the current evidence regarding the application, outcomes, and safety profile of bacteriophage therapy in the management of PJIs. Methods: This systematic review was conducted in accordance with the 2020 PRISMA statement. PubMed, Google Scholar, EMBASE, and Web of Science were accessed in August 2025. No time constraints were used for the search. All clinical studies investigating bacteriophage therapy for bacterial PJIs were considered for eligibility. Results: A total of 18 clinical studies, comprising 53 patients treated with bacteriophage therapy for PJI, were included. The mean follow-up was approximately 13.6 months. Staphylococcus aureus was the most frequent pathogen (18 cases); phage cocktails were used in 33 patients and monophage preparations in 9, all combined with suppressive antibiotic therapy. Persistent or resistant joint pain was reported in only two patients (3.8%), while signs of ongoing infection despite phage therapy were observed in four patients (7.5%). Adverse events following BT were inconsistently reported. Conclusions: Bacteriophage therapy shows promise as an adjunctive treatment for hip and knee PJIs, especially in refractory or multidrug-resistant cases. Current evidence is limited and methodologically weak, underscoring the need for well-designed clinical trials to clarify efficacy, safety, and optimal integration into existing orthopaedic infection protocols.