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176 papers

Tumor response and tolerability under fractionated x-ray irradiation in a mouse xenograft model.

Choi K et al. · Jun 25, 2026

Objective. Modern self-contained x-ray irradiators offer a safer alternative to radionuclide sources for preclinical radiation research and can deliver conformal, clinically relevant dose distributions. However, concerns persist regarding their performance and biological toxicity as direct replacements in radiobiological studies. We assessed two preclinical x-ray platforms, a collimated cabinet X-Rad320 and an image-guided small animal radiation research platform (SARRP), for induced tumor response, tolerability, and dosimetric accuracy in a subcutaneous xenograft prostate tumor model under 2 Gy daily fractionated radiotherapy. Approach. Male athymic mice bearing 22Rv1 xenografts were randomized into cohorts receiving total doses of 10, 16, or 20 Gy (5, 8, or 10 2-Gy fractions) on either platform. Unirradiated controls were included. Tumor burden was quantified by the area under the tumor growth curve (AUC). Machine dose delivery accuracy was verified quarterly with alanine pellet dosimetry. Main results. Across regimens, no animals met humane body condition or weight endpoints or exhibited overt clinical toxicity. All irradiated groups had lower tumor normalized AUCs than controls, but the dose response was not clearly monotonic, and not all differences remained statistically significant after correcting for multiple comparisons. At 14 d post-treatment, SARRP at 16 Gy provided the greatest tumor suppression, with no significant additional benefit observed with 20 Gy. Histological γ -H2AX staining provided complementary evidence of a radiation-induced dose response. Significance. Focused x-ray platforms can reproducibly deliver conventional fractionated radiotherapy regimens in mice, inducing tumor response without overt clinical toxicity. However, platform-specific dose deviations highlight the need for rigorous dosimetric calibration and quality assurance to ensure they can effectively replace cesium-137 for in vivo research with comparable tumor control outcomes.

Medicine

Design of an artificial intelligence model to screen spontaneous speech to detect Alzheimer's Disease.

Madden KM et al. · Jun 25, 2026

There is a shortage of physicians trained in the specialized care of Alzheimer's disease (AD). One possible solution is to use machine learning (ML)/artificial intelligence (AI) techniques to screen for the effects of AD on speech patterns, a technique that has the potential for automation. Our objective was to evaluate the ability of various language processing/artificial intelligence (AI) techniques to classify subjects into AD and controls. Our study used the Pitt dataset (n = 549), from DementiaBank, a shared dataset of audio files of spontaneous speech using the standardized Cookie Theft Picture Description task. The dataset was divided into training (n = 337), development (n = 115) and test (n = 97) datasets. A series of language processing techniques were tested on their ability to classify subjects into AD and controls, including classical (Tfidf, Term Frequency-Inverse Document Frequency), hybrid (Tfidf + text embeddings), neural classification and large language models. The hybrid model (Tfidf + text embeddings) was the best performing one, with accuracy and recall of 0.92 and 0.93 respectively on the test dataset. However, when tested on an independently collected validation dataset it only achieved 0.70 accuracy and 0.44 recall, performing well in identifying controls but missing some true AD cases. The model also demonstrated similar performance in identifying controls in a dataset that included a high proportion of diverse cognitive conditions, similar to referrals to a specialized memory clinic. AI techniques have demonstrated some utility for the classification of spontaneous speech audio files into those with AD and controls although these techniques could benefit from having enlarged datasets.

Medicine

Vaccination against tumour endothelial marker Robo4 inhibits tumour growth.

Escobar-Riquelme F et al. · Jun 25, 2026

Introduction Targeting tumour antigens is a major challenge in cancer-immunotherapy. We use active vaccination to induce antibodies targeting self-antigen Robo4, which is selectively expressed on tumour vascular endothelium, and supports vascular development. Our previous work showed that a conjugate of Robo4 with a foreign carrier protein induced autoantibodies specific to Robo4, which inhibited angiogenesis and tumour growth. Methods To translate the vaccine protocol to exploit a carrier protein used in routine human vaccination schedules, the well-characterized, non-toxic fragment C of tetanus toxin (TTc) was selected as the carrier protein. Recombinant protein Robo4-TTc (R4-TTc) was produced by Robo4 genetically linked to TTc. Results Priming with the carrier TTc followed by boost with Robo4-TTc (R4-TTc) efficiently induces strong antibody responses to Robo4 and inhibits tumour growth in LLC1 and 4T1 tumour models. The growth inhibition was correlated with anti-Robo4 IgG1 titres. Furthermore, decreased vessel formation and increased immune cell infiltration in tumours from R4-TTc vaccinated mice in the absence of detectable adverse effects on health. Conclusion The data indicate that this vaccination strategy remodels tumour vessels and probably promotes immunogenic pathway activation, therefore repressing tumour growth.

Medicine

Development and validation of an interpretable ultrasound radiomics model for benign and malignant classification of breast lesions: a multicenter large-sample study.

Zhang D et al. · Jun 25, 2026

Objectives To develop and validate a combined ultrasound-based radiomics-clinical model for differentiating benign and malignant breast lesions. Materials and methods A total of 3142 patients from eight hospitals between February 2012 and September 2024 were included in this multicenter retrospective development and validation study, with an additional single-center prospective test cohort. Lesions were manually segmented, and radiomics features were automatically extracted to construct five machine learning models. The best-performing radiomics model was combined with clinical features to build a combined model. Model performance and its impact on Breast Imaging Reporting and Data System (BI-RADS)-based biopsy decisions were evaluated. Results Logistic regression (LR) showed the best radiomics performance, with area under the curves (AUCs) of 0.83, 0.82, 0.81, and 0.82 across the training, internal test, external test, and prospective test sets. The clinical model achieved AUCs of 0.87, 0.85, 0.87, and 0.86, whereas the combined model achieved AUCs of 0.92, 0.90, 0.92, and 0.93, significantly outperforming both single-modality models (all p Conclusion The interpretable ultrasound-based radiomics model enables reliable, noninvasive breast lesion diagnosis and may reduce unnecessary biopsies. Critical relevance statement This work developed an interpretable radiomics-clinical combined model in a multicenter retrospective development and validation study, with additional testing in a single-center prospective cohort, and may support breast lesion risk stratification and biopsy decision-making after further prospective clinical utility evaluation. Key points Conventional ultrasound diagnosis of breast cancer shows limited specificity. A multicenter radiomics-clinical combined model showed improved diagnostic performance, with additional validation in a prospective test cohort.

Medicine

The Challenge of Determining the Etiology of Encephalopathy in an Elderly Patient.

Ionescu VA et al. · Jun 25, 2026

Encephalopathy is a heterogeneous clinical syndrome with numerous neurological and systemic etiologies. We report the case of a 67-year-old man, a chronic ethanol consumer, admitted with a one-week history of confusional syndrome. Initial laboratory tests revealed severe hypercalcemia, acute kidney injury, mild anemia, and hyperproteinemia. Serum ammonia levels were within normal limits, reducing the likelihood of hepatic encephalopathy despite the patient's chronic ethanol use. Cerebral imaging excluded acute cerebrovascular events, while abdominal ultrasound demonstrated splenomegaly and normal-sized kidneys. Serum protein electrophoresis and immunofixation identified a monoclonal IgG-kappa component, strongly suggestive of multiple myeloma. The patient's neurocognitive symptoms improved rapidly following systemic corticosteroid therapy and fluid-electrolyte rebalancing, confirming hypercalcemia as the primary mechanism of encephalopathy. Hypercalcemic encephalopathy as an initial manifestation of multiple myeloma is exceedingly rare. This case highlights the diagnostic complexity in elderly patients with multiple potential contributors to altered mental status, including chronic ethanol exposure and renal dysfunction. The presence of normal renal dimensions, unexplained hypercalcemia, and a monoclonal component should prompt evaluation for plasma cell malignancy. Early recognition of hypercalcemia-induced encephalopathy and prompt investigation for underlying hematologic malignancy are essential to prevent irreversible organ damage and to ensure timely initiation of specific therapy.

Medicine

Virtual Reality Simulation in Postgraduate Pediatric Critical Care Training Based on Trainee Perceptions in London: Exploratory Mixed Methods Study.

Berlin AC et al. · Jun 25, 2026

Background Simulation-based training has established itself as integral to clinical education, particularly for high-stakes, low-frequency pediatric emergencies. Innovations incorporating virtual reality (VR) are rapidly gaining traction for offering scalable, repeatable, and immersive opportunities for scenario-based learning. Understanding its role and applicability in postgraduate pediatric training, however, remains limited, with further exploration required into how pediatric trainees perceive, conceptualize, and anticipate VR-based simulation within real-world training contexts. Objective This study explored London-based pediatric trainees' perceptions of VR simulation as an adjunct for developing skills in recognizing and managing critically ill children. Methods An exploratory mixed methods study was conducted among pediatric trainees across all training levels within the London School of Paediatrics between April 2024 and July 2024. Data were collected using a 35-item online questionnaire containing Likert-scale, categorical, and open-ended questions, alongside virtual semistructured interviews. The questionnaire explored current training practices; confidence and preparedness in managing critically ill children; familiarity and experience with VR; and perceived benefits, limitations, barriers, and facilitators to adoption. Quantitative data were analyzed descriptively, with exploratory Mann-Whitney U tests and Spearman correlations where appropriate. Internal consistency of key domains was assessed using Cronbach α. Qualitative data from open-ended responses and interviews were analyzed thematically using the Braun and Clarke reflexive approach. Quantitative and qualitative strands were integrated at the interpretation stage to contextualize survey patterns with illustrative qualitative insights. Results Thirty trainees participated in the survey (30/450, 6.7%; female: 16/30, 53%), with participants spanning all 8 training years. Two senior trainees participated in interviews. Clinical exposure or experience and simulation training were identified as central to developing skills in managing pediatric emergencies. Trainees also described limited exposure to high-acuity scenarios; variable access to high-fidelity simulation; and constraints related to workload, supervision, and feedback. Most participants (21/30) had no prior VR exposure in a medical setting, while 17% (5/30) had used VR training, and all reported positive experiences. Despite limited exposure, 93% (28/30) of participants were willing to try VR simulation for exposure to rare scenarios, structured decision-making, and confidence-building. Key perceived barriers included high cost (24/30, 80%), technological literacy (17/30, 57%), infrastructure (15/30, 50%), and limited stakeholder familiarity or support (25/30, 83%). Participants suggested taster sessions, faculty advocacy, leadership engagement, and phased implementation as potential facilitators. Internal consistency of attitudinal survey items was good (Cronbach α=0.80). Conclusions Despite limited exposure, pediatric trainees viewed VR simulation as a valuable adjunct to existing critical care training, particularly for those in earlier stages of training. However, these findings represent anticipatory perceptions rather than evidence of educational effectiveness. The implementation of VR will depend on addressing key infrastructural, organizational, educational, and equity-related barriers. Further multicenter studies are needed to evaluate the educational impact and feasibility, learning outcomes, and cost-effectiveness in postgraduate pediatric critical care training programs.

Medicine

Preclinical evaluation of cysteine protease-inhibitor aloxistatin (E64d) for heart failure therapy.

Jordan M et al. · Jun 25, 2026

Heart failure (HF) affects over 64 million people worldwide causally linked to fibrotic scarring. None of the available cardiac drugs target fibrosis directly, underlining unmet clinical need for novel therapies. This study aimed to explore the therapeutic potential of the cysteine protease inhibitor aloxistatin as a repurposed drug candidate to combat fibrotic progression in predictive HF models. Aloxistatin reduced migratory and proliferative capacities of human cardiac fibroblasts (HCFs) derived from various HF backgrounds. Mechanistically, aloxistatin attenuated TGFβ1-induced pro-fibrotic signaling in cardiomyopathy-derived HCFs by inhibiting extracellular matrix organization-related gene expression and secretion of MMP2 und FN1, partially mediated through CAPN2 inhibition. Transcriptomic analysis of rat ex vivo myocardial slices revealed a pronounced suppression of inflammatory pathways. Anti-inflammatory effects of aloxistatin were further confirmed by reduced NFκB activity in reporter cells and inhibited HLA-DR expression in human iPSC-derived macrophages. Application of diverse preclinical cardiac HF models arguably underlined aloxistatin as a potential drug repurposing strategy by simultaneously counteracting myocardial inflammatory signaling and pro-fibrotic mechanisms. This preclinical study suggests aloxistatin therapy for translational use to attenuate cardiac remodeling and progression of heart failure.

Medicine

A microprotein encoded by FERMT3 modulates endothelial cell protein catabolism and induces cell cycle arrest and senescence.

Raheja M et al. · Jun 25, 2026

Background Endothelial cells express numerous microproteins (miPs) encoded by small open reading frames (smORFs), yet the biological function of most remains unknown. This study set out to characterize a novel 69 amino acid miP encoded within the FERM domain containing kindlin-3 transcript (miP-FERMT3), which is upregulated under inflammatory conditions. Methods Confocal microscopy was used to determine miP-FERMT3 localization, and its interaction partners were determined by mass spectrometry and immunoblotting. RNA sequencing and quantitative mass spectrometry were performed to assess transcriptional and proteomic alterations. Cell proliferation and cell cycle progression were examined by live cell imaging, EdU incorporation and flow cytometry, while senescence was determined by β-galactosidase staining, live cell imaging and RT-qPCR-based analysis of telomere length. Results In endothelial cells, miP-FERMT3 localized mainly to centriole subdistal appendages, where it colocalized with ninein and CEP170 and induced centrosome amplification. The expression of miP-FERMT3 caused cell cycle arrest and DNA damage, evidenced by γ-H2AX foci and nuclear p53 accumulation. Consistent with this, miP-FERMT3-expressing endothelial cells exhibited downregulation of genes required for cell-cycle progression and upregulation of genes involved in cell cycle inhibition and senescence. However, canonical p53 target genes were not induced and cell cycle arrest occurred independently of p53. Mechanistically, miP-FERMT3 interacted with proteins involved in ubiquitin/proteasome-dependent protein catabolism, including PSMD9, CUL2 and TRIM8, and its expression increased protein ubiquitination, centrosomal neddylation and proteasomal activity. Notably, enhanced proteasomal turnover of p21 in miP-FERMT3-expressing endothelial cells resulted in replication stress, as evidenced by increased CHK1 phosphorylation. These alterations culminated in rapid induction of cellular senescence, characterized by enlarged cell size, β-galactosidase activity, telomere shortening and a paracrine pro-inflammatory activation of naïve endothelial cells. Analyses of independent murine and human transcriptomic and proteomic aging datasets further revealed that FERMT3 expression and protein abundance increase with age. Conclusions miP-FERMT3 is a novel regulator of protein catabolism that promotes p21 degradation, replication stress and p53-independent cell cycle arrest and senescence in endothelial cells. Given the aging-associated upregulation of FERMT3 in mouse and human endothelial cells, increased miP-FERMT3 expression may contribute to the onset of vascular senescence as a hallmark of aging.

Medicine

Real-World Evidence Assessment of the Risk of Nonfatal Stroke in Patients Prescribed SGLT2 Inhibitors.

Ayers AT et al. · Jun 25, 2026

Aims Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in adults with Type 2 diabetes (AwT2D) has recently been associated with decreased stroke risk. In this study, we investigate the impact of SGLT2i on stroke. Materials and methods We conducted a cohort study using an electronic health record (EHR) representing 66 million patients to examine whether AwT2D have a lower incidence of stroke and/or transient ischemic attack (TIA) if treated with SGLT2i. All analyses were completed utilizing high-dimensional propensity score matching to control for confounders. Results AwT2D treated with SGLT2i compared to other antidiabetic medications, assessed after 1 year, starting 2 weeks after the date of prescription of SGLT2i or other antidiabetic drug, had a significantly lower incidence of any stroke (Odds Ratio (OR): 0.84 with 95% Confidence Interval (CI) 0.79-0.91, p p p = 0.005), and TIA (OR: 0.87 with 95% CI 0.80-0.95, p = 0.003). Conclusion Among AwT2D, those treated with SGLT2i had lower incidence of stroke and TIA compared with adults treated with other antidiabetic medications.

Medicine

Lymphatic Embolization for Lymphatic Leakage After Pelvic Lymph Node Dissection: Case Report.

Oshima R et al. · Jun 25, 2026

Introduction Radical cystectomy with pelvic lymph node dissection for muscle-invasive bladder cancer may be complicated by postoperative lymphatic leakage when high-output drainage persists despite conservative management. We describe treatment of diffuse lymphoascites after pelvic lymph node dissection using upstream lymphatic embolization. Case presentation A man in his 70s developed lymphatic leakage with drainage > 1000 mL/day after radical cystectomy and pelvic lymph node dissection. Lymphoscintigraphy showed bilateral iliac leakage with diffuse intraperitoneal spread, making local sclerotherapy unsuitable. Intranodal lymphangiography via bilateral inguinal nodes identified iliac lymphatic duct leaks. Upstream embolization with a N-butyl cyanoacrylate-ethiodized oil mixture through multiple inguinal nodes rapidly reduced drainage, allowing drain removal by day 4 and discharge by day 10 without persistent lymphedema. Conclusion Upstream lymphatic embolization is a minimally invasive option for refractory high-output lymphatic leakage after pelvic lymph node dissection.

Medicine