BMC Infect Dis
· 2026 Jul · PMID 42399789
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BACKGROUND: Hepatitis B virus (HBV) infection is a globally prevalent disease and remains a significant public health burden. In Ethiopia, where HBV is endemic, it is a major contributor to chronic liver disease and live...BACKGROUND: Hepatitis B virus (HBV) infection is a globally prevalent disease and remains a significant public health burden. In Ethiopia, where HBV is endemic, it is a major contributor to chronic liver disease and liver-related mortality. Timely disclosure of serostatus is crucial for preventing intra-family transmission, facilitating contact tracing and vaccination, promoting adherence to follow-up and antiviral therapy, and improving the physical and psychosocial well-being of affected individuals. Therefore, this study aimed to assess the prevalence of HBV serostatus disclosure and identify factors associated with disclosure among adults receiving care at the Gastroenterology clinic of Hawassa University Comprehensive Specialized Hospital. METHODS: An institution-based analytical cross-sectional study was conducted from July 20 to September 30, 2025, to enroll all eligible participants. Data were collected via interviewer-administered, semi-structured questionnaires supplemented by a data abstraction sheet, and analyzed using STATA version 16.1. Poisson regression with robust variance estimation identified factors associated with HBV serostatus disclosure; results were presented as adjusted prevalence ratios (aPR) with 95% confidence intervals (CI), and statistical significance was set at P < 0.05. RESULTS: Of the 245 participants, 171 (69.8%) were male, and the median age was 34 years (interquartile range: 26-45 years). Overall, 46.5% of participants (95% CI: 40.3-52.8%) disclosed their HBV serostatus to at least one contact. Factors independently associated with HBV serostatus disclosure included being female (aPR = 1.46; 95% CI: 1.07-2.00), being ever married (aPR = 1.80; 95% CI: 1.21-2.68), living with chronic HBV for more than five years (aPR = 1.25; 95% CI: 1.11-1.96), having no comorbidities (aPR = 3.24; 95% CI: 1.43-5.39), having normal liver status (aPR = 1.31; 95% CI: 1.00-1.72), and having a higher HBV knowledge score (aPR = 1.07; 95% CI: 1.03-1.12). CONCLUSIONS: The findings indicated that HBV serostatus disclosure was low when compared to other African settings. Disclosure was driven by female gender, being ever married, longer duration of HBV diagnosis, absence of comorbidities, normal liver status and higher HBV knowledge. While the study provided valuable insights into the dynamics of disclosure, its cross-sectional design meant that definitive causal relationships could not be established. CLINICAL TRIAL NUMBER: Not applicable.
BMC Gastroenterol
· 2026 Jul · PMID 42399788
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BACKGROUND: While the care of the stoma poses a problem for individuals, the presence of complications, lack of stoma adjustment, and impaired quality of life can be more exhausting for patients, as well. METHODS: This t...BACKGROUND: While the care of the stoma poses a problem for individuals, the presence of complications, lack of stoma adjustment, and impaired quality of life can be more exhausting for patients, as well. METHODS: This thesis study was designed and conducted as a multicenter, randomised controlled intervention study with repetitive measurements in a pretest-posttest order. Patients, who underwent intestinal stoma in 5 hospitals, (one of which was private), in a city in the south-eastern Turkey between 20 March and December 31, 2021, participated in the study. Seventy-four patients, who were regarded eligible, were randomised and divided into experimental and control groups. A patient information form, the Stoma Complications Evaluation Form, the Stoma-Related Problems Form, the Ostomy Adjustment Inventory-23, and the Stoma Quality of Life Scale were used to collect data. RESULTS: Results of the study revealed a significant difference between the groups based on quality of life and stoma adjustment. CONCLUSIONS: The nurse navigation programme not only increases the quality of life and stoma adjustment in patients with stoma but also reduces stoma complications. TRIAL REGISTRATION: ClinicalTrials.gov NCT05809661 (Registered: 30/03/2023). Retrospectively registered.
Ueda T, Miyagawa K, Shibata M
… +10 more, Mori Y, Oe S, Kajitani K, Uchihara D, Shinohara N, Ogino N, Kumei S, Honma Y, Watanabe T, Harada M
BMC Gastroenterol
· 2026 Jul · PMID 42399778
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BACKGROUND: Second-line chemotherapy (2L) is recommended after gemcitabine plus nab-paclitaxel (GnP) first-line chemotherapy (1L) for unresectable pancreatic cancer (UR-PC). However, in routine clinical practice, not all...BACKGROUND: Second-line chemotherapy (2L) is recommended after gemcitabine plus nab-paclitaxel (GnP) first-line chemotherapy (1L) for unresectable pancreatic cancer (UR-PC). However, in routine clinical practice, not all patients proceed to 2L. This retrospective study aimed to identify baseline clinical and biological factors associated with 2L eligibility. METHODS: We retrospectively reviewed the data of 124 consecutive patients with UR-PC who received 1L GnP between 2016 and 2024 at a single center, excluding those with postoperative recurrence. Patients were grouped by 2L receipt [2L( +), n = 63] or non-receipt [2L( -), n = 61]. Ascites was assessed based on baseline imaging findings and additionally classified as none, mild, or moderate-to-severe. Overall survival (OS) was assessed from completion or discontinuation of 1L GnP, and progression-free survival (PFS) was assessed from 1L GnP initiation, using Kaplan-Meier and Cox regression analyses. Cox regression analysis for OS included only baseline variables. RESULTS: The 2L( +) group less frequently had baseline ascites and better Eastern Cooperative Oncology Group performance status. The distribution of ascites severity also differed significantly between the groups. Median OS was 7.1 vs. 1.9 months (p < 0.001) and median PFS was 5.9 vs. 3.0 months (p = 0.004) for 2L( +) vs. 2L( -). Multivariate Cox analysis identified the absence of ascites as an independent factor associated with longer OS (hazard ratio [HR] 0.595, 95% confidence interval 0.367-0.963; p = 0.035). Multivariate logistic regression revealed that the absence of ascites independently predicted 2L eligibility (adjusted odds ratio 4.435, 95% CI 1.583 - 12.423, p = 0.005). CONCLUSIONS: Baseline ascites was independently associated with reduced eligibility for 2L after 1L GnP in patients with UR-PC. Nevertheless, patients who received 2L had longer survival than those who did not, including among those with baseline ascites. However, this association should be interpreted cautiously because of the retrospective design and potential treatment-selection bias. These findings may support individualized reassessment and proactive supportive care to maximize opportunities for sequential chemotherapy.
BMC Gastroenterol
· 2026 Jul · PMID 42399771
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BACKGROUND: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents the most prevalent chronic liver disease worldwide. The absence of approved pharmacotherapies is largely attributed to their profoun...BACKGROUND: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents the most prevalent chronic liver disease worldwide. The absence of approved pharmacotherapies is largely attributed to their profound molecular heterogeneity. The identification of novel hub genes in MASLD is therefore critical for unraveling the complex molecular mechanisms driving disease pathogenesis and progression. METHODS: We employed an integrative systems-biology approach utilizing Weighted Gene Co-expression Network Analysis (WGCNA) followed by multi-algorithm machine learning (LASSO, Random Forest, SVM-RFE) across GEO datasets (GSE89632, GSE63067) to identify hub genes. Key hub genes were validated in vitro with FFA-treated HepG2 cells and in vivo with an HFD-fed mouse model. RESULTS: Bioinformatic analyses revealed two distinct pathological networks. First, a lipogenesis-associated cluster revealed FMO1 and C10orf140 as upregulated, alongside JUNB downregulation. In vitro, the expression of these genes was significantly associated with the activation of the SREBP-1c/FASN lipogenic pathway. Second, WGCNA revealed a co-expression module that exhibited high correlation with inflammation (R = 0.59, p = 4e-05), from which 11 hub genes relating to inflammation (such as MAP3K8, PFKFB3) were identified. In vivo, HFD mice developed severe steatosis and demonstrated a key pathological paradox: high-level activation of both the pro-lipogenic p-AKT and the inhibitory p-AMPK pathways. CONCLUSION: Our study identified the hub genes FMO1, C10orf140, and JUNB as novel regulators of MASLD lipogenesis through the SREBP-1c pathway. Additionally, we showed that co-activated p-AKT and p-AMPK in steatotic livers indicates "AMPK Resistance". Ultimately, we describe a mechanism of pro-lipogenic signaling that is not curtailed and is accompanied by the inability to compensate for the inhibitory path. All findings reveal potential therapeutic targets for MASLD.
Nakamura M, Suzuki K, Yoshida E
… +4 more, Miyamoto Y, Nomoto T, Dohi K, Wada G
Int J Emerg Med
· 2026 Jul · PMID 42399761
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BACKGROUND: Spontaneous pneumomediastinum (SPM) is a rare condition with a generally favorable prognosis, although severe complications, including respiratory arrest or tension emphysema, are reported; swallowing may be...BACKGROUND: Spontaneous pneumomediastinum (SPM) is a rare condition with a generally favorable prognosis, although severe complications, including respiratory arrest or tension emphysema, are reported; swallowing may be an under-recognized precipitating factor. CASE PRESENTATION: A man in his 20s swallowed one‑third of a 10‑cm steamed meat bun without chewing. He developed throat tightness and chest pain without cough and presented to our emergency department. Chest computed tomography (CT) findings revealed extensive mediastinal emphysema; swallowing‑triggered spontaneous pneumomediastinum was diagnosed, and intravenous piperacillin/tazobactam was initiated. Esophagography on day 2 and endoscopy on day 3 showed no leakage or perforation. A CT scan on day 8 revealed near resolution, and he was discharged on day 9 without recurrence. We speculated that the large, unchewed bolus caused transient airway obstruction, leading to a sudden increase in intratracheal pressure and resulting in tracheal or alveolar microinjury. CONCLUSIONS: This case highlights swallowing of a large, unchewed food bolus as a potential trigger of pneumomediastinum. Considering swallowing‑triggered spontaneous pneumomediastinum in patients presenting with chest pain after eating may facilitate early diagnosis and help avoid unnecessary invasive investigations.
Since February 2022, the war in Ukraine has led to large-scale displacement, including people living with HIV (PLWH). Early reports described predominantly virologically suppressed individuals with preserved immune funct...Since February 2022, the war in Ukraine has led to large-scale displacement, including people living with HIV (PLWH). Early reports described predominantly virologically suppressed individuals with preserved immune function. Data on refugees with HIV presenting during later phases of the war are limited. We conducted a retrospective single-center study including adult refugees with HIV from Ukraine presenting to a tertiary care center in Germany. Paticipants were grouped by time of presentation: Cohort 1 (March-December 2022) and Cohort 2 (January 2023-February 2024). Clinical, immunological, and virological parameters were compared between cohorts. A total of 86 individuals were included (Cohort 1: n = 46; Cohort 2: n = 40). Participants in cohort 2 more frequently received their first HIV diagnosis after presentation in Germany, with no previously documented HIV diagnosis in Ukraine or elsewhere, compared with cohort 1 (67% vs. 5%; p < 0.0001). Participants in Cohort 2 more often presented with detectable HIV RNA (65% vs. 29%; p < 0.0001) and advanced immunodeficiency (CD4 < 200/µL: 28% vs. 9%; p < 0.05). Among individuals with prior HIV diagnosis, virological failure was more common in Cohort 2 (50% vs. 14%; p = 0.006). AIDS-defining illnesses occurred more frequently in Cohort 2 (p = 0.005). Serological evidence of HBV and HCV infection was high in both cohorts. Refugees with HIV from Ukraine presenting during later phases of the war exhibit more advanced disease and poorer virological control compared with earlier arrivals. These findings suggest increasing disruption of HIV care over time and highlight the need for low-threshold access to testing, comprehensive screening, and rapid initiation of antiretroviral therapy in this population.
Romani P, Nirchio N, Arboit M
… +20 more, Barbieri V, Tosi A, Michielin F, Shibuya S, Benoist T, Wu D, Hindmarch CCT, Giomo M, Urciuolo A, Giamogante F, Roveri A, Chakravarty P, Montagner M, Calì T, Elvassore N, Archer SL, De Coppi P, Rosato A, Martello G, Dupont S
Bang YH, Kang D, Lee S
… +22 more, Kim S, Jeon I, Park E, Choi J, Song GW, Yoo MW, Song JS, Song IH, Kim YH, Kim HR, Song HJ, Kim DH, Choi KD, Lee JH, Ahn JY, Shim JH, Lee D, Choi J, Kim JE, Kim SY, Bae DJ, Park SR
Neoadjuvant immunotherapy may improve long-term outcomes by activating antitumor immunity before surgery. We evaluated danburstotug (IMC-001), an anti-PD-L1 antibody, in resectable gastric cancer (GC), esophageal squamou...Neoadjuvant immunotherapy may improve long-term outcomes by activating antitumor immunity before surgery. We evaluated danburstotug (IMC-001), an anti-PD-L1 antibody, in resectable gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC). In this phase II trial, patients received two cycles of danburstotug (20 mg/kg every 2 weeks) before surgery. The primary endpoint was major pathologic response (MPR, <10% viable tumor). Key secondary endpoints included safety, radiologic/metabolic response, survival outcomes, and translational immune profiling. Forty-eight patients were evaluable (16 per cohort). The study did not meet its pre-specified primary endpoint, with MPR achieved in 2/48 patients (4.2%)-one ESCC and one HCC (6.3% per cohort). However, pathologic tumor regression to ≤50% viable tumor was observed in 11/48 patients (22.9%; GC 25.0%, ESCC 31.3%, HCC 12.5%). Among evaluable patients, partial responses were observed radiographically in 17.6% and metabolically in 23.3%. Treatment was well tolerated, with grade ≥3 treatment-related adverse events in 6.0% and no grade 4-5 events; two surgical delays were observed, of which one was treatment-related. All patients underwent surgery with R0 resection. Immune profiling revealed cancer type-specific immune-remodeling. Neoadjuvant danburstotug was safe, did not compromise surgical outcomes, and provided exploratory insights into treatment-induced immune microenvironment remodeling. ClinicalTrials.gov ID: NCT04196465, date of registration: August 28, 2019.
Exercise is fundamental to healthy aging, yet how it mitigates age-related molecular changes and how fitness level shapes exercise responses remain unclear. To address these questions, we performed transcriptomics, lipid...Exercise is fundamental to healthy aging, yet how it mitigates age-related molecular changes and how fitness level shapes exercise responses remain unclear. To address these questions, we performed transcriptomics, lipidomics and metabolomics on skeletal muscle of young and older adults with differing physical function, both before and after an acute bout of submaximal exercise. At baseline, older adults exhibited reduced expression of genes associated with cellular respiration and energy metabolism compared to young adults with comparable activity levels. Here we found that 50% of these age-related differences were absent in trained older adults, resulting in profiles resembling those of young adults. Although all participants displayed transcriptional immune and stress responses upon acute exercise, the magnitude of these responses in older adults was positively correlated with their physical fitness. Integrated multiomic analyses further revealed links among mitochondrial respiration, lipid metabolism, stress responses and NAD biology. These findings demonstrate that sustained physical training transforms age-related molecular profiles and provide a molecular atlas for study of fitness-dependent aging mechanisms.
Automated segmentation of PDAC is a prerequisite to realize the promise of precision oncology, yet existing approaches remain insufficiently validated at the cohort scale and acquisition heterogeneity required for clinic...Automated segmentation of PDAC is a prerequisite to realize the promise of precision oncology, yet existing approaches remain insufficiently validated at the cohort scale and acquisition heterogeneity required for clinical deployment. We developed and validated a pancreas-localized three-dimensional convolutional neural network model (Model-BB) using 1859 multi-institutional treatment-naïve, biopsy-confirmed PDAC CT examinations. Model-BB achieved a DSC of 0.76 ± 0.13 on internal testing and 0.76 ± 0.09 on external validation, with stable performance across acquisition site, scanner vendor, slice thickness, and temporal epochs. Upstream localization analysis showed complete tumor enclosure in 224 of 241 test cases (92.9%), with preserved performance (DSC 0.78) among cases with partial peripheral exclusion, indicating that localization error was not the principal source of reduced performance. In a controlled architectural benchmark, Model-BB outperformed Swin UNETR, a 3D vision transformer (DSC, 0.76 ± 0.13 versus 0.68 ± 0.18; p < 0.001). On a difficulty-enriched subset (n = 50), Model-BB achieved DSC 0.71 against a STAPLE-derived consensus, exceeding individual reader-pair agreement (DSC range, 0.57-0.65), with concordance correlation coefficient 0.93 for tumor volume. These findings support anatomically constrained, task-specific segmentation as a reproducible geometric substrate for volumetric tumor-burden quantification, treatment-response assessment, and multimodal outcomes modeling, pending prospective validation in clinical-trial workflows.
Salmonella enterica remains a leading foodborne zoonotic pathogen worldwide, with poultry serving as a major reservoir and vehicle for antimicrobial resistance dissemination to humans. This study investigated the genotyp...Salmonella enterica remains a leading foodborne zoonotic pathogen worldwide, with poultry serving as a major reservoir and vehicle for antimicrobial resistance dissemination to humans. This study investigated the genotypic basis and distribution of multidrug resistance (MDR) among 29 S. enterica isolates from broiler farms in Egypt, emphasizing the role of mobile genetic elements as integrons and the assessment of genetic relatedness using ERIC-PCR. Molecular screening revealed high prevalence of resistance determinants, including floR (93.1%), tetA (86.2%), aphA1 (82.8%), cmlA (75.9%), ereA (75.9%), sulI (62.1%), aadA1 (51.7%), dfrA1 (48.3%), aac(3)-IV (44.8%), tetB (41.4%), sulII (31.0%), aac(6')-Ib-cr (24.1%), catA1 (20.7%), fosA3 (20.7%), and qnrA (10.3%). High-risk serovars, including S. Jerusalem, S. Colorado, and S. Kentucky, harbored multiple resistance genes and exhibited pronounced XDR profiles. Notably, this study reports the detection of aphA1 and fosA3 in Salmonella isolates derived from broiler chickens, which may represent an early or uncommon finding in Egypt. Many resistance genes were associated with horizontally transferable class 1 integron, underscoring its key role in the dissemination of multidrug resistance (MDR) within poultry systems and along the food chain. ERIC-PCR genotyping segregated isolates into two major genetic groups with seven sub-clusters, reflecting clustering patterns and genetic diversity among the isolates, alongside notable heterogeneity in resistance, virulence, and biofilm-associated genes.Overall, poultry in Egypt represents a significant reservoir of genetically diverse and potentially transmissible MDR S. enterica, highlighting the need for enhanced antimicrobial stewardship and genomic surveillance to mitigate public health risks.
Hiroki S, Fukasawa T, Honda M
… +1 more, Kawakami K
Pharmacoepidemiol Drug Saf
· 2026 Jul · PMID 42399205
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PURPOSE: Observational studies have repeatedly reported lower cancer incidence among metformin users than nonusers, but findings are inconsistent and often affected by issues such as immortal time, unclear comparators, a...PURPOSE: Observational studies have repeatedly reported lower cancer incidence among metformin users than nonusers, but findings are inconsistent and often affected by issues such as immortal time, unclear comparators, and use of total cancer as a composite outcome, which precludes adequate adjustment for site-specific confounding. These limitations can be mitigated by explicitly emulating a target trial with a suitable active comparator. METHODS: We emulated a target trial using a Japanese claims database (April 2014-March 2024) to assess whether metformin reduces colorectal cancer (CRC) risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with type 2 diabetes. DPP-4is served as an active comparator because they are widely used as first-line alternatives in Japan and have no clear evidence of affecting CRC risk. We estimated the observational analogue of the per-protocol effect using pooled logistic regression with inverse probability weighting to adjust for baseline and time-varying confounders. RESULTS: Among 26 273 metformin users and 108 299 DPP-4i users, the 5-year risk of CRC was 1.55% (95% confidence interval, 1.16 to 2.04) versus 1.26% (1.13 to 1.41), yielding a risk difference of 0.29% (-0.12 to 0.79) and a risk ratio of 1.23 (0.91 to 1.66). CONCLUSIONS: Metformin use did not reduce the 5-year risk of CRC compared with DPP-4is. This finding is consistent with meta-analyses of randomized trials and contrasts with earlier observational reports of substantial benefit, which were likely inflated by methodological flaws. Explicitly emulating a target trial minimized design-related biases and provided estimates that support causal interpretation.
Ohashi Y, Maruta A, Koizumi T
… +12 more, Iwata S, Uemura S, Tezuka R, Iwasa Y, Okuno M, Iwata K, Mukai T, Ichikawa H, Mita N, Yoshida K, Iwashita T, Shimizu M
Pancreatology
· 2026 Jun · PMID 42399187
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BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is a well-recognized precursor of pancreatic cancer; however, the optimal surveillance strategy for IPMN remains controversial. This study aimed to evaluate the...BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is a well-recognized precursor of pancreatic cancer; however, the optimal surveillance strategy for IPMN remains controversial. This study aimed to evaluate the clinical impact of semiannual surveillance using endoscopic ultrasonography (EUS) and magnetic resonance imaging (MRI) for the detection of malignant transformation, including IPMN-derived and concomitant carcinoma. METHODS: This multicenter prospective observational study included 360 patients with branch-duct or mixed-type IPMN enrolled between April 2018 and December 2025. Patients underwent surveillance every 6 months with blood tests and EUS or MRI. The primary endpoint was the curative resection rate among patients diagnosed with IPMN-derived or concomitant carcinoma. Secondary endpoints included the incidence of newly developed worrisome features (WF) and high-risk stigmata (HRS), as well as the cumulative incidence of malignancy. RESULTS: During a median follow-up period of 69 months, newly developed WF and HRS were observed in 30.3% and 2.5% of patients, respectively. Malignant transformation was confirmed in 12 patients (3.3%), including nine with IPMN-concomitant carcinoma and three with IPMN-derived carcinoma. Curative resection was performed in 9 of these patients, resulting in a surgical transition rate of 75.0%. All malignant pancreatic lesions were detected at a resectable or borderline-resectable stage at diagnosis. CONCLUSIONS: Semiannual surveillance using EUS and MRI facilitated the detection of malignant pancreatic lesions at a surgically treatable stage in patients with IPMN. This surveillance strategy may be clinically valuable for identifying IPMN-derived and concomitant carcinoma at stages amenable to surgical treatment in high-risk populations.
OBJECTIVES: The primary focus of this study was to compare the diagnostic accuracy of temporal muscle (TM) B-mode ultrasound and shear wave elastography (SWE) parameters in the assessment of pediatric and to establish pr...OBJECTIVES: The primary focus of this study was to compare the diagnostic accuracy of temporal muscle (TM) B-mode ultrasound and shear wave elastography (SWE) parameters in the assessment of pediatric and to establish practical cutoff values for clinical use. METHODS: This prospective observational study included a total of 89 children aged 5-18 years, consisting of 35 primary malnourished patients and 54 healthy controls. TM thickness, total tissue thickness (muscle and subcutaneous fat), tissue stiffness, and shear wave speed were measured in the temporal fossae using a high-frequency linear transducer. For SWE quality standardization, Motion Stability (M-STB) and Reliability (RLB) indices were actively utilized. The obtained data were modeled using multivariate logistic regression, Decision Curve Analysis (DCA), and receiver operating characteristic (ROC) curves. RESULTS: All investigated ultrasonographic and biomechanical values were significantly lower in the malnutrition group compared to controls (p < 0.001). In the multivariate logistic regression analysis, which was adjusted to resolve multicollinearity (VIF > 20) among the SWE parameters, TM thickness emerged as the strongest independent predictor of malnutrition (OR = 0.428, p < 0.001). ROC analyses demonstrated that TM thickness yielded the highest diagnostic accuracy (AUC = 0.887). A cut-off value of approximately 11.15 mm for this parameter provided a sensitivity of 82.9% and specificity of 90.7%. The DeLong test results confirmed that the discriminatory power of TM thickness was statistically superior to that of the elastography data. CONCLUSIONS: TM thickness measurement via B-mode ultrasound is a practical, reproducible, and promising adjunctive point-of-care parameter for detecting malnutrition-induced muscle atrophy in pediatric patients, demonstrating superiority over SWE parameters; however, external multicenter validation is warranted before routine clinical implementation.
Alnatsha A, Xu J, Habshi T
… +33 more, Li Q, Rickú K, Allawadhi P, Saka D, Dai R, Xue Y, Nguyen H, Stadler H, Weltermann T, Zhou Q, Schreiner N, Xue Y, Rittinghausen V, Ormanns S, Klauschen F, Zhang D, Böck S, Benoit M, Ben Khaled N, Lahiri S, Imhof A, Klingl A, Jaiswal A, Sahoo GP, Regel I, Mueller S, Öllinger R, Rad R, Belka C, Bange T, Lauber K, Mayerle J, Mahajan UM
BACKGROUND: As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vita...BACKGROUND: As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vital component of the cellular stress response, yet the underlying regulatory mechanisms in cancer remain elusive. Acid sphingomyelinase (SMPD1) facilitates the conversion of SM to CER, functioning as a key enzymatic driver of CER-mediated signalling. OBJECTIVES: Herein, we aim to evaluate the role of SMPD1-driven sphingolipid metabolism in pancreatic carcinogenesis. DESIGN: A targeted quantitative analysis of the plasma metabolome was conducted involving patients with pancreatic ductal adenocarcinoma (PDAC, n=202) and matched control subjects (n=204). Multiplex immunohistochemistry was performed on resected PDAC (n=122) to identify expression of SMPD1 with tumour and immune cell markers. CRISPR/Cas9 driven Smpd1-deleted murine cell lines were generated and subsequently assessed for their carcinogenic potential in vitro. The effects of deletion on tumour formation were evaluated using both syngeneic orthotopic and metastatic murine models. RESULTS: Here, we demonstrate that tumour cell-autonomous expression of SMPD1, in pancreatic ductal adenocarcinoma (PDAC), is associated with poorer patients' outcomes. ablation in murine PDAC cells resulted in reduced proliferation and migration in vitro and decreased metastases and tumour burden in vivo. Integrated transcriptomic, metabolomic and proteomic studies revealed that SMPD1 abrogation impairs Kras oncogenic signalling and, thus, reduces tumour burden. Reduced plasma membrane interaction of Kras was associated with SMPD1-dependent sphingolipid metabolism. Notably, the SMPD1 inhibitor (ARC39) potently synergised with the Kras inhibitor (MRTX1133). CONCLUSION: In summary, SMPD1 regulated plasma membrane sequestration of Kras represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC.
Extraintestinal () infection rarely involves bone and can mimic malignancy. A man in his 70s with chronic kidney disease presented with a longstanding, painless, fluctuant anterior lower leg mass without systemic or gas...Extraintestinal () infection rarely involves bone and can mimic malignancy. A man in his 70s with chronic kidney disease presented with a longstanding, painless, fluctuant anterior lower leg mass without systemic or gastrointestinal symptoms. Imaging showed a proximal tibial lytic lesion and aspiration of a superficial collection grew Symptoms persisted despite 4 weeks of oral amoxicillin-clavulanate (875-125 mg every 12 hours) plus oral metronidazole (500 mg every 8 hours). MRI demonstrated chronic tibial osteomyelitis with cortical disruption and a contiguous intramedullary and soft tissue abscess consistent with a Brodie's abscess. He underwent excisional debridement with dead-space management and local vancomycin, followed by prolonged pathogen-directed antimicrobials. Two deep intraoperative cultures again yielded rare with negative aerobic and blood cultures. He improved without amputation and remained stable at 9-month follow-up.
PURPOSE: To evaluate the impact of socioeconomic factors on survival in patients with HCC undergoing interventional LRT at a tertiary center. MATERIALS AND METHODS: A retrospective cohort of 1,091 HCC patients treated wi...PURPOSE: To evaluate the impact of socioeconomic factors on survival in patients with HCC undergoing interventional LRT at a tertiary center. MATERIALS AND METHODS: A retrospective cohort of 1,091 HCC patients treated with interventional LRT (2000-2022). Clinical and socioeconomic data (gender, insurance, race, education, language, marital status) were collected. Survival analysis utilized Kaplan-Meier and multivariable Cox regression to assess the impact of socioeconomic factors . Among identified patients (median age: 63 [IQR=12.14], 81% male), the majority had Medicare (43%) or private insurance (33%), were White (63%), had a college (42%) or high school (45%) education, and were married (51%). Median AFP was 11 (IQR=76); most were Child-Pugh B (72%), BCLC Stage A (66%) and ECOG 0 (75%). Overall mortality was 62%, and 23% underwent liver transplant. RESULTS: Female gender (HR 1.26, 95% CI 1.03-1.55, p = 0.028), lower education (high school vs. college; HR 1.24, 95% CI 1.04-1.50, p = 0.015), and being divorced (HR 1.43, 95% CI 1.08-1.90, p = 0.012) were independently associated with increased mortality. Asian race predicted improved survival (HR 0.44, 95% CI 0.29-0.67, p < 0.05). CONCLUSION: Asian race, male gender, marriage, and higher education independently predicted better survival in HCC patients receiving interventional LRT.