Poor Clinical Outcome Research Articles

RET inhibition overcomes resistance to combined CDK4/6 inhibitor and endocrine therapy in ER+ breast cancer

BackgroundCombined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improve the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored.MethodsTo identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy. The functional role of RET was assessed by siRNA-mediated RET silencing and targeted inhibition with the FDA/EMA-approved RET-selective inhibitor selpercatinib in resistant breast cancer cells and patient-derived organoids (PDOs). RET silencing was evaluated mechanistically using global gene expression and pathway analysis. The clinical relevance of RET expression in ER+ breast cancer was investigated by gene array analysis of primary tumors treated with endocrine therapy and by immunohistochemical scoring of metastatic lesions from patients who received combined CDK4/6i and endocrine therapy.ResultsWe show that RET is upregulated in ER+ breast cancer cell lines resistant to combined CDK4/6i and fulvestrant compared to isogenic cells resistant to fulvestrant alone. siRNA-mediated silence of RET in high RET-expressing, combined CDK4/6i- and fulvestrant-resistant cells reduced their growth partially by affecting cell cycle regulators of the G2-M phase and E2F targets. Notably, targeting RET with selpercatinib in combination with CDK4/6i inhibited the growth of CDK4/6i-resistant cell lines and resensitized ER+ breast cancer patient-derived organoids resistant to CDK4/6i. Finally, analysis of RET expression in ER+ breast cancer patients treated with endocrine therapy showed that high RET expression correlated with poor clinical outcomes. We further observed a shorter median survival to combined CDK4/6i and endocrine therapy in patients with RET-positive compared to RET-negative tumors, but this difference did not reach statistical significance.ConclusionsOur findings show that RET is overexpressed in ER+ metastatic breast cancer resistant to combined CDK4/6i and endocrine therapy, rendering RET inhibition a promising therapeutic approach for patients who experience disease progression on combined CDK4/6i and endocrine therapy.

Anatomical Predictors of Access-Related Vascular Complications Following Transfemoral Transcatheter Aortic Valve Replacement.

Access-related vascular complications (VCs) after percutaneous transfemoral transcatheter aortic valve replacement (TAVR) are associated with poor clinical outcomes and remain a significant challenge despite technological advances. The aim of this study was to identify anatomic predictors of access-related VCs after TAVR on preprocedural contrast-enhanced multidetector computed tomography (MDCT). The aim of this study was to identify anatomical predictors of access-related VCs after TAVR on preprocedural contrast-enhanced MDCT. A total of 348 consecutive patients with symptomatic severe AS who underwent transfemoral TAVR were included retrospectively. The primary endpoint of the study was the composite of minor and major access site complications as defined by the Valve Academic Research Consortium-3 (VARC-3) criteria. The study population was divided into two groups according to the VC including VC (+) and VC (-). A total of 101 patients (29%) developed VC (8.7% major, 20.3% minor) following TAVR. Regression analysis identified severe CFA calcification (p = 0.004), CFA depth (p < 0.001), minimum CFA diameter (p < 0.001), CFA depth-to-diameter ratio ≥ 5.6 (p < 0.001), and sheath-to-femoral artery ratio (SFAR) (p < 0.001) as significant predictors of VC. ROC curves generated for the occurrence of VC, the AUC for the femoral artery depth-to-diameter ratio (0.720) was higher than the AUC for the SFAR and the depth of the femoral artery (0.636, 0.630). Complications related to vascular access sites continue to be a significant concern for patients undergoing TF-TAVR. The CFA depth-to-diameter ratio has demonstrated superior predictive performance for VC compared to SFAR as expressed in the literature. Utilizing this criterion may enhance risk stratification for VC in high-risk patients, potentially reducing associated morbidity and mortality.

Identification of key regulators in pancreatic ductal adenocarcinoma using network theoretical approach.

Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease with poor clinical outcomes, which is mainly because of delayed disease detection, resistance to chemotherapy, and lack of specific targeted therapies. The disease's development involves complex interactions among immunological, genetic, and environmental factors, yet its molecular mechanism remains elusive. A major challenge in understanding PDAC etiology lies in unraveling the genetic profiling that governs the PDAC network. To address this, we examined the gene expression profile of PDAC and compared it with that of healthy controls, identifying differentially expressed genes (DEGs). These DEGs formed the basis for constructing the PDAC protein interaction network, and their network topological properties were calculated. It was found that the PDAC network self-organizes into a scale-free fractal state with weakly hierarchical organization. Newman and Girvan's algorithm (leading eigenvector (LEV) method) of community detection enumerated four communities leading to at least one motif defined by G (3,3). Our analysis revealed 33 key regulators were predominantly enriched in neuroactive ligand-receptor interaction, Cell adhesion molecules, Leukocyte transendothelial migration pathways; positive regulation of cell proliferation, positive regulation of protein kinase B signaling biological functions; G-protein beta-subunit binding, receptor binding molecular functions etc. Transcription Factor and mi-RNA of the key regulators were obtained. Recognizing the therapeutic potential and biomarker significance of PDAC Key regulators, we also identified approved drugs for specific genes. However, it is imperative to subject Key regulators to experimental validation to establish their efficacy in the context of PDAC.

Synergistic inhibition of colorectal cancer progression by silencing Aurora A and the targeting protein for Xklp2.

Unraveling the pathogenesis of colorectal cancer (CRC) can aid in developing prevention and treatment strategies. Aurora kinase A (AURKA) is a key participant in mitotic control and interacts with its co-activator, the targeting protein for Xklp2 (TPX2) microtubule nucleation factor. AURKA is associated with poor clinical outcomes and high risks of CRC recurrence. AURKA/TPX2 co-overexpression in cancer may contribute to tumorigenesis. Despite its pivotal role in CRC development and progression, the action mechanism of AURKA remains unclear. Further research is needed to explore the complex interplay between AURKA and TPX2 and to develop effective targeted treatments for patients with CRC. To compare effects of AURKA and TPX2 and their combined knockdown on CRC cells. We evaluated three CRC gene datasets about CRC (GSE32323, GSE25071, and GSE21510). Potential hub genes associated with CRC onset were identified using the Venn, search tool for the retrieval of interacting genes, and KOBAS platforms, with AURKA and TPX2 emerging as significant factors. Subsequently, cell models with knockdown of AURKA, TPX2, or both were constructed using SW480 and LOVO cells. Quantitative real-time polymerase chain reaction, western blotting, cell counting kit-8, cell cloning assays, flow cytometry, and Transwell assays were used. Forty-three highly expressed genes and 39 poorly expressed genes overlapped in cancer tissues compared to controls from three datasets. In the protein-protein interaction network of highly expressed genes, AURKA was one of key genes. Its combined score with TPX2 was 0.999, and their co-expression score was 0.846. In CRC cells, knockdown of AURKA, TPX2, or both reduced cell viability and colony number, while blocking G0/G1 phase and enhancing cell apoptosis. Additionally, they were weakened cell proliferation and migration abilities. Furthermore, the expression levels of B-cell lymphoma-2-Associated X, caspase 3, and tumor protein P53, and E-cadherin increased with a decrease in B-cell lymphoma-2, N-cadherin, and vimentin proteins. These effects were amplified when both AURKA and TPX2 were concurrently downregulated. Combined knockdown of AURKA and TPX2 was effective in suppressing the malignant phenotype in CRC. Co-inhibition of gene expression is a potential developmental direction for CRC treatment.

Abstract P015: Targeting SPP1 to enhance CAR T cell therapy in glioblastoma: Implications for integrating radiation therapy in resistant solid tumors

Abstract In the evolving landscape of glioblastoma (GBM) treatment, clinical trials exploring chimeric antigen receptor (CAR) T cell therapies have shown promise; however, their therapeutic efficacy remains constrained, particularly due to the immunosuppressive tumor microenvironment (TME). Emerging evidence highlights that the TME, especially myeloid-driven suppressive networks, plays a central role in resistance to CAR T cell therapy. Despite progress in elucidating these mechanisms, significant ambiguities endure, particularly regarding patient-specific TME heterogeneity and its impact on therapeutic outcomes. Radiation therapy remains a cornerstone in GBM management, known not only for its direct cytotoxic effects but also for its ability to modulate the TME and potentially enhance immune responses. However, the combination of radiation with CAR T cell therapy has not been fully explored, particularly in the context of targeting suppressive myeloid subsets. Recent studies suggest that radiation may induce immunogenic changes within the TME, potentially enhancing CAR T cell infiltration and activity. Our study seeks to investigate how targeting key suppressive mediators, such as SPP1-expressing macrophages, can reshape the TME, setting the stage for combinatorial approaches that leverage the immunomodulatory effects of radiation therapy In this study, we utilized single-cell RNA sequencing to analyze tumors from 41 glioma patients undergoing IL13Rα2-targeted CAR T cell therapy. Our findings revealed heightened suppressive extracellular matrix (ECM) remodeling and immunosuppressive signatures driven by SPP1-expressing myeloid cells, predominantly in non-responsive tumors. Elevated SPP1 expression and increased infiltration of SPP1+ myeloid cells were associated with poor clinical outcomes. Functional transcriptomic analyses demonstrated that SPP1-high macrophages exhibited reduced antigen presentation, impaired phagocytosis, and enhanced ECM biogenesis, coupled with elevated lipid metabolism and non-glycolytic ATP production. These metabolic adaptations were linked to a suppressive immunophenotype that hindered CAR T cell efficacy. To explore therapeutic strategies, we assessed the impact of SPP1 blockade in preclinical syngeneic glioma models. Pre-treatment with anti-SPP1 antibodies prior to CAR T cell infusion significantly reprogrammed the TME, enhancing CAR T cell efficacy and reversing resistance in previously non-responsive models. These results highlight the potential of targeting SPP1 to disrupt suppressive macrophage networks, thereby augmenting CAR T cell responses. Our findings underscore SPP1 as a promising target to overcome resistance in CAR T cell therapies for GBM. This study lays the groundwork for future integration of targeted therapies, such as SPP1 inhibition, with radiation therapy to potentially improve therapeutic outcomes in resistant gliomas, offering new avenues for combinatorial therapeutic innovation. Citation Format: Sharareh Gholamin, Heini Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya CominAnduix, Supraja Saravanakumar, Christian Masia, Robyn Wong, Lance Peter, Mei-i Chung, Evan D. Mee, Brenda Aguilar, Davis Y. Torrejon, Anusha Kalbasi, Darya Alizadeh, Xiwei Wu, Antoni Ribas, Stephen Forman, Behnam Badie, Terence M. Williams, Nicholas E. Banovich, Christine E. Brown.Targeting SPP1 to enhance CAR T cell therapy in glioblastoma: Implications for integrating radiation therapy in resistant solid tumors.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P015

Abstract P011: STN1 (OBFC1) promotes DNA double-strand break repair in a potentially CTC1-STN1-TEN1 (CST) complex-independent role in pancreatic cancer

Abstract Purpose: Pancreatic cancer (PC) is an aggressive lethal tumor with an unmet need for novel therapeutic approaches. KRAS activating mutations occur in 90-95% of PC and contribute to tumor progression and resistance to therapy, including radiation. The mechanisms by which oncogenic KRAS promotes radiation resistance are critical to understand in order to identify novel therapies. Methods: We first analyzed the expression levels of DNA damage response and repair genes using Affymetrix RNA expression microarray in isogenic HCT116 and SW48 cells with KRAS wide-type and KRASG13D activating mutations to identify novel targets by which KRAS mutations may confer radiation resistance. We analyzed the expression of STN1 in pancreas normal and cancer tissues and assessed the correlation with PC clinical outcomes using TCGA dataset. Human tumor xenografts were generated to explore the role of STN1 on tumor growth in vivo. Radiation response was assessed through clonogenicity and gH2AX foci assays. Homologous recombination (HR) and non-homologous end joining (NHEJ) repair reporter assays, chromatin spreading assay, cell cycle analysis, mitotic catastrophe, Annexin-V assays were performed to investigate the mechanisms of radiation-induced cell death. Mass spectrometry analysis was performed to identify STN1 interacting proteins important in DNA damage response and further validated by immunoprecipitation and immunoblotting. Results: We find that KRAS activation increases STN1 expression to enhance DNA double strand break repair capacity in PC. STN1 is a component of the CST complex normally important for telomere duplication and maintenance. We find that STN1 is significantly upregulated in PC, especially in aggressive subtypes of PC, associates with KRAS oncogenic mutations, and correlates with poor patient clinical outcomes. Genetic silencing or pharmacologic inhibition of KRAS signaling decreases STN1 expression in PC cells, suggesting KRAS signaling positively regulates STN1 expression. Interestingly, STN1 depletion reduces tumor growth in a heterotopic model of KRAS mutant PC. Mechanistically, depletion of STN1 potentiates DNA damage, replication stress, and sensitizes PC cells to ionizing radiation independent of CTC1 and TEN1. In support of this finding, STN1 silencing reduces both HR and NHEJ repair of DSBs. Furthermore, knockdown of STN1 impairs cell cycle arrest at the G2/M phase in response to ionizing radiation, which is accompanied with increased mitotic catastrophe, radiation-induced apoptosis. Proteomic analysis reveals that STN1 physically interacts with many proteins important for DNA repair, replication and cell cycle progression, including ATM, DICER1, CEP164, and CEP250. Conclusion: Our findings have revealed a novel, potentially CST complex-independent role of STN1 in DSB repair after radiation. STN1 may function at one of the apical nodes in the DNA damage response pathway by interacting with ATM. Our findings suggest STN1 may be a promising target for improving genotoxic therapies in KRAS mutant cancers, including PC. Citation Format: Tiantian Cui, Changxian Shen, Linlin Yang, Ling Gui, Sergio Corrales-Guerrero, Sindhu Nair, Joanna M. Karasinska, James T. Topham, Xiaoli Ping, Jeremy M. Stark, Terence M. Williams.STN1 (OBFC1) promotes DNA double-strand break repair in a potentially CTC1-STN1-TEN1 (CST) complex-independent role in pancreatic cancer.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P011

Anti-PTK7 Monoclonal Antibodies Suppresses Oncogenic Phenotypes in Cellular and Xenograft Models of Triple-Negative Breast Cancer

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is frequently upregulated in various cancers, including triple-negative breast cancer (TNBC), and is associated with poor clinical outcomes. Analysis of The Cancer Genome Atlas (TCGA) data confirmed that PTK7 mRNA expression is significantly higher in TNBC tumor tissues compared with adjacent normal tissues and non-TNBC breast cancer subtypes. Kaplan–Meier survival analysis demonstrated a strong correlation between high PTK7 expression and worse relapse-free survival in TNBC patients (HR = 1.46, p = 0.015). In vitro, anti-PTK7 monoclonal antibodies (mAbs) significantly reduced proliferation, wound healing, migration, and invasion in TNBC MDA-MB-231 cells. Ki-67 immunofluorescence assays revealed substantial decreases in cell proliferation following treatment with PTK7 mAbs (32-m, 43-m, 50-m, and 52-m). Moreover, actin polymerization, a critical process in cell migration and invasion, was markedly impaired upon PTK7 mAb treatment. In vivo, PTK7 mAbs significantly reduced tumor volume and weight in a TNBC xenograft mouse model compared with controls. Treated tumors exhibited decreased expression of Ki-67 and vimentin, indicating reduced proliferation and epithelial-to-mesenchymal transition. These findings highlight PTK7 as a promising therapeutic target in TNBC and demonstrate the potent anti-cancer effects of PTK7-neutralizing mAbs both in vitro and in vivo. Further exploration of PTK7-targeted therapies, including humanized mAbs and antibody-drug conjugates, is warranted to advance treatment strategies for PTK7-positive TNBC.

Neurological deterioration after acute ischemic stroke: A common phenomenon with important implications.

Background：Neurological deterioration following acute ischemic stroke (AIS) is a common clinical phenomenon associated with poor clinical outcomes. However, neurological deterioration can be attributed to diverse mechanisms in different clinical contexts. Further, there is still a lack of standard and well-recognized definitions of neurological deterioration, which compounds the complexities and challenges of its early identification and management of neurological deterioration. As AIS becomes increasingly common, the need to address neurological deterioration after AIS in clinical practice and further improve functional outcomes is becoming more urgent. Summary: To facilitate earlier recognition and more precise interventions, in this review, we comprehensively outline the evolution of the definition of neurological deterioration, its incidence in various patient groups, and the potential underlying causes rooted in multiple pathophysiological mechanisms. We further highlight the diverse risk factors associated with neurological deterioration and provide an overview of the scientific basis and practical applications of preventative and therapeutic strategies. Key messages: Early identification and management of neurological deterioration in AIS patients is crucial but challenging due to lack of unified assessment criteria and diverse mechanisms. Standardizing definitions and developing targeted strategies based on pathological mechanisms and pharmacological profiles are needed to improve outcomes.

Dandelion extract suppresses the stem-like properties of triple-negative breast cancer cells by regulating CUEDC2/β-catenin/OCT4 signaling axis.

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, featuring a high proportion of cancer stem cells (CSCs) and the poorest clinical outcomes. Taraxacum mongolicum Hand. -Mazz., widely recognized as dandelion, is a traditional medicinal herb that has demonstrated promising anti-TNBC potential. However, the efficacy of dandelion in anti-TNBC stem-like properties remains to be elucidated. The aim was to examine the impact of dandelion extract on the stemness properties of TNBC and to delineate the underlying mechanisms. UHPLC-Q-Orbitrap HRMS was employed to characterize the components present in dandelion extract. Network pharmacology was utilized to explore the impact of dandelion-derived compounds on the molecular pathways associated with TNBC. The assessment of TNBC stem-like properties was conducted through mammosphere formation assays and flow cytometry analysis. Western blotting, qRT-PCR, and immunofluorescence were employed to investigate the mechanisms of dandelion extract. 4T1-luc xenograft tumor model was used to assess the anti-tumor effect of dandelion extract in vivo. IVIS imaging technology was used to monitor lung metastasis. In this study, pharmacological network analysis revealed the potential regulatory effects of dandelion extract on TNBC stemness. Dandelion extract disrupts the stem-like properties in MDA-MB-231 and MDA-MB-468 cell lines via reducing ALDH+ cells proportion, impeding mammosphere formation, and downregulating CSC-related markers, including SOX2, SOX9, NANOG, and FOXM1. Furthermore, CUE domain containing protein 2 (CUEDC2) promotes the maintenance of TNBC stemness and contributes to the anti-stemness effects of dandelion extract. Mechanistically, dandelion extract inhibits CUEDC2-mediated nuclear translocation of β-catenin, thereby reducing the transcriptional activity of OCT4. In vivo, dandelion extract suppresses tumor growth, lung metastasis, and decreases the expression of CSC-related markers. These findings suggest that dandelion extract inhibits TNBC stem-like properties via modulating the CUEDC2/β-catenin/OCT4 signaling axis, highlighting its potential as a therapeutic option for TNBC.

Incidence and outcomes of dysnatremia in crush injury patients admitted to Türkiye’s largest hospital following the Kahramanmaraş earthquake

ObjectivesDysnatremia is a critical electrolyte disturbance that can significantly impact the prognosis of trauma patients by influencing fluid balance, neurological function, and hemodynamics. Although sodium disorder is common in hospitalized patients, few studies have specifically examined the incidence of dysnatremia in patients presenting to the emergency department for post-earthquake trauma. The aim of this study is to evaluate the incidence of dysnatremia and the prognosis of patients with dysnatremia in trauma patients admitted to our center after the Kahramanmaraş earthquake.Materials and methodsBetween February 6th, 2023 and February 20th, 2023, a total of 422 patients with earthquake-related crush injuries after the Kahramanmaras earthquake were retrospectively analyzed. Patients were divided into two groups: the survivor group and the exitus group. Then, patients with dysnatremia were evaluated. Age, gender, the city where patients came from, type of presentation, injured organ systems and extremities, laboratory findings, ward admission, intensive care admission, GCS, MESS, ISS, RTS, TRISS, and hemodialysis sessions were analyzed.ResultsA total of 422 earthquake victims with crush injuries were included in the study. Dysnatremia was present in 28% of the patients, and these patients had a longer hospital stay. GCS was lower, MESS and ISS values were higher, and survival rates according to TRISS were lower. Multiple extremity trauma, crush syndrome, and dialysis rates were more common in the dysnatremia group. Additionally, fasciotomy, amputation and mortality rates were higher in the dysnatremia group.ConclusionDysnatremia is a common finding in patients with crush injuries and is associated with more severe trauma and poorer clinical outcomes. This study highlights the need for close monitoring and management of sodium disturbances in trauma patients, not only in the context of earthquakes but across various disaster scenarios. Recognizing and addressing dysnatremia can contribute to improved patient outcomes in disaster and emergency settings.

P1309 Is there any association between genetic polymorphisms and response to Anti-TNFs in patients with inflammatory bowel disease ? Experience of a Tunisian IBD center

Abstract Background Although highly effective, primary failure and loss of response to anti tumor necrosis factors (anti-TNF) alpha in inflammatory bowel disease (IBD) are common and associated with poor clinical outcomes. Multiple factors, including genetics, have been involved in the response to anti TNF alpha therapy. Thus, the purpose of our study was to evaluate the impact of the polymorphism of the SNPs rs1799724 (TNF alpha), rs767455 (TNFRSF1A), and rs1061622 (TNFRSF1B) in the response to anti-TNF alpha treatment in Tunisian IBD patients. Methods We conducted a prospective study including patients followed for IBD and treated with anti-TNF alpha. We classified these patients into two groups: responders and non-responders to anti-TNF alpha. Genomic DNA was purified from peripheral blood leucocytes using the salting-out method. Subjects were genotyped for polymorphisms TNF (rs 1799724), TNFRSF1A (rs767455) and TNFRSF1B (rs1061622) using a variant of allele-specific PCR, Mutagenically Separated PCR (MS-PCR). Genotypic and allelic frequencies were compared between the two groups of patients. Results We included 61 IBD patients with a mean age of 38,9 years [18-64 years]. Forty six patients (75.4%) had CD and 15 (24.6%) had UC. In the CD group, 35 (76.1%) patients were treated with infliximab and 11(23.9%) with Adalimumab. Nineteen were responders to treatment (41,3%) and 27 (58.7%) experienced treatment failure: primary failure in 4 and loss of response in 23. Genetic analysis did not show any association between the response to anti TNF alpha treatment and SNPs rs1799724 (TNF alpha) (P= 0,12 ; OR = 1,9) and rs1061622 (TNFRSF1B) (P= 0,9; OR= 1,06). Although, the CT genotype of rs767455 (TNFRSF1A) was associated with non-response (OR= 3.5 with a 95% CI [0.98-12.4], p=0.049). In the UC group, 14 patients were treated with Infliximab and only one patient treated with Adalimumab. Seven patients responded to anti-TNF therapy (46.7%) and 8 were non-responders (53.3%) with 5 cases of primary failure and 3 cases of loss of response. We didn’t find any association between the SNPs rs1799724 (TNF alpha), rs767455 (TNFRSF1A), and rs1061622 (TNFRSF1B) and response to anti TNF alpha in the UC patients. Conclusion Among the three SNPs studied, only the rs767455 (TNFRSF1A) was shown to be associated with non-response to anti-TNF in chrohn’s disease patients. However, our results need to be validated in a larger sample of patients.

P0432 CMV infection in IBD patients with disease flare in the era of advanced therapies and outpatient setting

Abstract Background The infection with cytomegalovirus (CMV) has typically been reported to be associated with poor clinical outcomes in inflammatory bowel disease patients with severe, steroid-refractory ulcerative colitis.Data on prevalence, clinical picture and evolution of CMV infection in IBD outpatient setting, including patients with Crohn’s disease colitis are limited. Methods All IBD patients who underwent colonoscopy or flexible recto/sigmoidoscopy for clinical suspicion of disease flare were identified in the electronic medical record system of two IBD referral centra.Patients with histopathological hallmarks of CMV infections and/or positivity of immunohistochemical staining for CMV were identified and further analyzed. Basic demographics,laboratory findings,medications and CMV infection treatment were noted. Results In total, 226 endoscopic and histologic findings were reviewed, of which, eight were tested positive for CMV infections. Seven out of these eight patients had typical histopathological morphology with inclusion bodies and teste positive for CMV immunohistochemistry, one patient had only CMV immunohistochemical staining positive. There were four patients with colonic Crohn’s disease and four with ulcerative colitis, median age 42 years (range 25-72 years); median duration of the disease was 10 years (range 1-20 years). All patients had symptoms of colonic disease activity, two patients had fever. Median CRP was 27,5 mg/L (range 3-240), all patients had normal leucocytes and thrombocytes count and no liver tests abnormalities.None of the patients had systemic corticosteroids at the time of CMV diagnosis, one patient was using topical budesonide and one budesonide-MMX; three patients were treated with infliximab for several years; two had vedolizumab; one ustekinumab and two patients had no treatment and were about to start their first line biologic.All patients were treated with virostatic treatment with valganciclovir or ganciclovir.All patients had their biologic treatment interrupted for the time of antivirotic treatment. One of the patients who needed i.v. treatment had no improvement upon antivirotic treatment with persistent CMV viremia and underwent colectomy with rapid resolution of symptoms afterwards. The remaining seven patients achieved clinical response with antivirotic treatment and subsequent biologic therapy. Conclusion CMV infection in IBD patients with active colonic disease is rare but when present, it can lead to systemic manifestation of the infection. In contrast to the thus far reported typical picture of infection complicating severe ulcerative colitis, it can occurs in both, Crohn’s disease and ulcerative colitis patients with moderate disease activity and without extensive immune suppressive treatment. References Maresca, R et al. Cytomegalovirus Infection: An Underrated Target in Inflammatory Bowel Disease Treatment. J. Clin. Med. 2024, 13, 136

P0675 Ultrasonographic assessment of response in hospitalized patients with acute severe ulcerative colitis

Abstract Background Patients admitted with acute severe ulcerative colitis (ASUC) respond to medical therapy in upto two-third cases but monitoring and early detection of non-response is of prime importance to prevent colectomy or mortality, through use of rescue medical therapy. This study evaluates the utility of ultrasonography (USG) in prognostication and decision-making for ASUC patients undergoing standardized treatment protocols. USG offers a non-invasive approach to assess bowel wall thickening and vascularity, pivotal indicators of disease activity. Methods In this prospective study, 45 ASUC patients undergoing intravenous steroid therapy were enrolled, with additional randomization to receive tofacitinib or placebo. USG evaluations of bowel wall thickness (defined as ≥3 mm) and vascularity were conducted at baseline and on day 5, with data available for 41 patients. Clinical responses were assessed using the Lichtiger index. Correlations between USG findings, clinical outcomes, and biochemical markers such as CRP and albumin were analyzed. Results Baseline USG revealed bowel wall thickening in the sigmoid colon in 82.9% (34/41) of patients and in the descending colon in 70% (28/41). (Figure 1) Responders showed a significant reduction in bowel wall thickness in the sigmoid and descending colon (p &amp;lt; 0.05), whereas non-responders exhibited no changes. (Figure 2) There was a moderate correlation between bowel wall thickening across different segments (Spearman’s rho = 0.3–0.5, p &amp;lt; 0.05), but no significant correlation with CRP, albumin, or endoscopic severity. Doppler findings indicated similar rates of increased vascularity (Limberg grade ≥3) in both responders and non-responders at baseline and follow-up. Ancillary findings, such as pericolic fat thickening and free fluid, were associated with poor clinical outcomes, highlighting their prognostic value. Notably, baseline USG identified skip lesions in two patients, later confirmed to have Crohn’s colitis instead of ASUC. The sample size was limited as the trial is ongoing, and the treatment groups (tofacitinib vs. placebo) remain blinded. Conclusion Serial ultrasonography of the left colon provides valuable, non-invasive insights into treatment response in ASUC, correlating well with reductions in clinical activity and bowel wall thickness among responder. Presence of pericolic fat thickening and ascites correlates with poor outcomes, while doppler assessment does not contribute to the assessment. Importantly, baseline USG may aid in differentiating ASUC from Crohn’s colitis in patients with index presentation as acute severe colitis.

Efficacy of Inhaled Treprostinil in a Patient with Systemic Sclerosis-Associated Pulmonary Hypertension and Interstitial Lung Diseases Refractory to Conventional Intravenous Epoprostenol

Background: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is widely recognized as the most severe subtype of connective tissue disease-associated pulmonary hypertension (CTD-PH), particularly in patients with complicating factors such as interstitial lung disease (ILD) and biventricular failure. This condition is associated with the poorest clinical outcomes among PH subtypes, presenting significant challenges in both management and prognosis. Despite the use of conventional therapies, including intravenous administration of epoprostenol, a promising prostacyclin analogue, treatment outcomes for SSc-PH remain suboptimal. While epoprostenol has demonstrated efficacy in reducing pulmonary arterial pressures, its clinical application is often constrained by the risk of ventilation–perfusion (V-Q) mismatch, particularly at higher doses. Case presentation: We report the case of a 73-year-old woman with SSc-PH complicated by ILD, who experienced progressive hemodynamic deterioration despite receiving optimized therapy with intravenous epoprostenol. Efforts to escalate the dose of epoprostenol were limited by the development of severe V-Q mismatch, precluding further dose increases. In light of these challenges, inhaled treprostinil was introduced as an adjunctive therapy. There were significant improvements in her pulmonary hypertension and hemodynamic parameters, ultimately allowing the discontinuation of intravenous dobutamine and stabilization of her hemodynamics, as well as her respiratory function, exercise capacity, and quality of life. Conclusions: This case highlights the potential clinical utility of combining inhaled treprostinil with intravenous epoprostenol for the treatment of SSc-PH in patients with concurrent ILD. By addressing the limitations associated with high-dose intravenous prostacyclin therapy, this combination approach may represent a promising therapeutic strategy for improving outcomes in this difficult-to-treat patient population. Further investigation is warranted to establish the efficacy and feasibility of this combination therapy in larger cohorts of patients with SSc-PH and associated ILD.

A Snapshot of United States Sarcoidosis Patients and their Perceived Disease Impact: Results of the Sarcoidosis Research Institute Survey

PurposeThe priorities and concerns of sarcoidosis patients in the United States (US) have not been well-described.MethodsA survey constructed by sarcoidosis patients and doctors was administered to US sarcoidosis patients. The survey queried patients concerning their demographics, disease state, disease impact on health and well-being, health care priorities and impressions of sarcoidosis care. Respondents were solicited via social media and networking with sarcoidosis clinicians.Results1018 US sarcoidosis patients completed this survey. 65% were female, 63% White, 34% Black, and 87% > 45 years old. The most common organs involved were the lungs 87%, skin 30%, heart 25%, and eyes 25%. Household income was < $50 K in 31% and > $150 K in 14% of patients. There was a fairly even split between those living in urban (29%), suburban (42%), and rural (29%) environments. The patients’greatest concerns were fear of worsening disease, fear of sarcoidosis developing in more organs, and fear of sarcoidosis not improving. These were closely followed by concerns about poor health-related quality of life (HRQoL), inability to enjoy everyday activities, lack of medical research, disability from sarcoidosis, and pulmonary function status. Lack of physician knowledge and poor physician communication were ranked of lowest concern. Concerns about ineffective medications and cost of medical care were also ranked relatively low. Patients overwhelmingly considered information from their doctor as very useful.ConclusionIn this survey of over 1000 US sarcoidosis patients, their greatest concerns were fear of poor clinical outcomes. The patients were relatively less concerned about their doctors’ knowledge about sarcoidosis and poor physician communication. Although patients expressed significant concerns about poor HRQoL, not all domains of HRQoL were equally affected. US sarcoidosis patients rank concerns about disease progression higher than disease impact on HRQoL.

C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance.

Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pediatric Predictive Artificial Intelligence Implemented in Clinical Practice from 2010-2021: A Systematic Review.

To review pediatric artificial intelligence (AI) implementation studies from 2010-2021 and analyze reported performance measures. We searched PubMed/Medline, Embase CINHAL, Cochrane Library CENTRAL, IEEE and Web of Science with controlled vocabulary. AI intervention in a pediatric clinical setting that learns from data (i.e., data-driven, as opposed to rule-based) and takes actions to make patient-specific recommendations; published between 01/2010 to 10/2021; must have agency (AI must provide guidance that affects clinical care, not merely running in background). We extracted study characteristics, target users, implementation setting, time span, and performance measures. Of 126 articles reviewed as full text, 17 met inclusion criteria. Eight studies (47%) reported both clinical outcomes and process measures, six (35%) reported only process measures, and two (12%) reported only clinical outcomes. Five studies (30%) reported no difference in clinical outcomes with AI, four (24%) reported improvement in clinical outcomes compared to controls, two (12%) reported positive effects on clinical outcomes with use of AI but had no formal comparison or controls, and one (6%) reported poor clinical outcomes with AI. Twelve studies (71%) reported improvement in process measures, while two (12%) reported no improvement. Five (30%) studies reported on at least 1 human performance measure. While there are many published pediatric AI models, the number of AI implementations is minimal with no standardized reporting of outcomes, care processes, or human performance measures. More comprehensive evaluations will help elucidate mechanisms of impact.

UAE pharmacists’ perceptions of the causes of unwanted or unused medications, their practices, and barriers to promoting safe medication disposal by the public

BackgroundThe improper disposal of unwanted or unused medications is a pressing issue that can lead to drug misuse and environmental contamination. Pharmacists play a crucial role in promoting safe drug disposal by the public. This study explores pharmacists’ perceptions of the causes of unwanted and unused medications, their practices, and the barriers to promoting safe medication disposal among the public in the United Arab Emirates.MethodsThis cross-sectional study included pharmacists working in the UAE’s community and hospital settings with direct patient contact. A convenience sampling approach was used, where pharmacists who were available during the data collection period were invited to participate. Printed copies or a survey link to the questionnaire were provided to pharmacists to complete independently during in-person visits. Participants were categorised into three levels: extensive, adequate, or minimal involvement, based on their engagement in activities such as reviewing patients’ medications, educating them on proper storage and disposal, and participating in drug take-back programmes. Chi-square test was used to assesses the association between categorical variables and pharmacists practice levels. The data was analysed using the Statistical Package for the Social Sciences (SPSS) software version 29.ResultsA total of 370 pharmacists participated in this survey, most of whom were between 18 and 34 years old (69.2%). The top three perceived causes of unwanted or unused medications include changes in prescriptions due to patients’ poor clinical outcomes (83.8%), inappropriate storage conditions (79.7%), and expiration of medications (78.6%). Moreover, factors such as pharmacist age, type of pharmacy, country of education, pharmacy location, employment status, and years of experience were significantly associated with pharmacists’ level of involvement in promoting safe medication disposal practices. The most cited barriers were a lack of public awareness about the risks of improper medication disposal (88.9%), lack of time due to workload (82.4%), and lack of training and education (78.1%). Most pharmacists believed in collaborating with public health agencies to promote medication disposal awareness (97.6%) and developing national guidelines (97.6%).ConclusionThis study’s findings have significant implications for public health, highlighting the necessity of essential groundwork for developing targeted interventions and policies to enhance public awareness and identify specific areas where pharmacists can actively encourage safe medication disposal practices in the UAE.

Takotsubo Cardiomyopathy After Subarachnoid Hemorrhage: Who Is At Risk?

Takotsubo Cardiomyopathy (TCM) is a rare but well recognized complication of subarachnoid hemorrhage associated with increased morbidity and poor clinical outcomes. There is a scarcity of literature describing the prevalence and risk factors associated with this complication. The aim of this study was to identify patients who are at risk of developing TCM in non-traumatic subarachnoid hemorrhage. The 2016 to 2021 National Inpatient Sample (NIS) was used to identify adult inpatients with a primary diagnosis of non-traumatic subarachnoid hemorrhage. Univariate and multivariable analyses adjusting for patient demographics, comorbidity status, and hemorrhage etiology were used to characterize statistical associations with disease-related complications. Patients with TCM were further divided into those with "good" or "poor" functional outcomes and compared. A total of 42 141 patients were identified as having a subarachnoid hemorrhage from 2016 to 2021. Of these patients 486 patients (1.2%) were found to have TCM. TCM was associated with increased length of stay (19.15 ± 17.8 days vs 11.72 ± 14.4, P < .001), increased total costs ($451 502.59 ± 443 777.9 vs $242 327.92 ± 338 862.3, P < .001), increased number of days from admission to first procedure (1.74 ± 4.5 vs 1.94 ± 5.0, P < .001), and increased mortality (31.7% vs 22.8%, P < .001). After controlling for confounding factors, independent risk factors for TCM in patients with non-traumatic subarachnoid hemorrhage included: Female (Odds Ratio [OR]: 3.11, 95% Confidence Interval [CI]: 2.50-3.89, P < .001), Congestive Heart Failure (OR:4.60, CI:3.70-5.71, P < .001), and Fluid and Electrolyte Disorders (OR: 2.52, CI: 2.05-3.11, P < .001). Patients with good functional outcomes were found to have younger age (54.85 years ± 14.0 vs 58.14 ± 14.7, P < .001), decreased length of stay (17.11 ± 16.9 vs 19.83 ± 18.1, P < .001), decreased total charge ($370 245.94 ± 517 702.8 vs $477 366.55 ± 417 122.4, P < .001), and decreased mortality (P < .001) compared to those with poor functional outcomes. TCM after subarachnoid hemorrhage is associated with increased mortality, length of stay, total cost, number of procedures in patients, and number of days to first procedure. Neurosurgeons and Neurocritical care medical professionals should be aware of the comorbidities and factors associated with increased TCM after subarachnoid hemorrhage in order to improve patient outcomes.

CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions

The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we perform a high-throughput screening and identify Casein kinase II (CK2) as an uncharacterized upstream regulator of YAP1 turnover in cancer cells of ovarian cancer and several other cancer types. Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo. Moreover, we reveal that DUB3 as a bona fide deubiquitinase of YAP1, which functionally links CK2 and YAP1 stability in a variety of human cancers. Mechanistically, CK2α directly phosphorylates DUB3 at Thr495, thereby facilitating DUB3-mediated deubiquitination process of YAP1. On the contrary, the loss of Thr495 phosphorylation by the phosphorylation-defective mutant DUB3 T495A, the cancer-related mutant DUB3 D496H and CK2 inhibition failed to deubiquitinate and stabilize YAP1 effectively. Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1.