Citations

Abstract Advancements in understanding H3 K27-altered diffuse midline glioma (DMG) biology have not yet translated into effective therapies for these tumors likely due to delivery challenges across the blood-brain barrier (BBB) and variable tumor genetics. This study systematically probes convective-enhanced delivery (CED) as a means to administer small molecule drugs directly to DMG tumors, circumventing constraints imposed by the BBB. Our findings emphasize the necessity of strategic drug selection and pharmacokinetic analysis in refining CED approaches, advocating for precision medicine techniques specialized for DMG. We demonstrate that while most small molecule drugs are rapidly cleared from the brain following CED, their retention and effectiveness are substantially improved by co-administration of systemic efflux transporter (ET) inhibitors such as everolimus. The synergistic potential of combining everolimus with topotecan or ponatinib offers a novel therapeutic pathway, advocating for further investigation into this DMG management strategy.

Abstract This study reports the first pig-to-human lung xenotransplantation using a six gene-edited pig lung. A left lung from a gene-edited Chinese Bama Xiang pig was transplanted into a 39-year-old brain-dead human recipient. The xenograft maintained viability and functionality for 216 hours without signs of hyperacute rejection. Postoperatively, severe edema resembling primary graft dysfunction (PGD) was observed, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9 under the current immunosuppressive regimen. This pioneering study suggests that genetically modified pig lungs could potentially be used for future clinical applications in xenotransplantation.

ABSTRACT Background The sterol regulatory element‐binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B‐cell lymphoma remains unclear. Methods We examined SREBP protein expression in human B‐cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B‐cell lymphoma cells. Results Our analysis revealed high levels of SREBP2 protein expression in human B‐cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG‐CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B‐cell lymphoma cell proliferation. However, B‐cell lymphoma cells responded to statin treatment by activating the mTORC1‐pS6 pathway, suggesting a compensatory mechanism to overcome statin‐induced cell cycle arrest. Combining low‐dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B‐cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B‐cell lymphoma.

Abstract 3D printing, also known as additive manufacturing, holds immense potential for rapid prototyping and customized production of functional health‐related devices. With advancements in polymer chemistry and biomedical engineering, polymeric biomaterials have become integral to 3D‐printed biomedical applications. However, there still exists a bottleneck in the compatibility of polymeric biomaterials with different 3D printing methods, as well as intrinsic challenges such as limited printing resolution and rates. Therefore, this review aims to introduce the current state‐of‐the‐art in 3D‐printed functional polymeric health‐related devices. It begins with an overview of the landscape of 3D printing techniques, followed by an examination of commonly used polymeric biomaterials. Subsequently, examples of 3D‐printed biomedical devices are provided and classified into categories such as biosensors, bioactuators, soft robotics, energy storage systems, self‐powered devices, and data science in bioplotting. The emphasis is on exploring the current capabilities of 3D printing in manufacturing polymeric biomaterials into desired geometries that facilitate device functionality and studying the reasons for material choice. Finally, an outlook with challenges and possible improvements in the near future is presented, projecting the contribution of general 3D printing and polymeric biomaterials in the field of healthcare.

Abstract Background Alpha fetoprotein (AFP) is a circulating tumor marker utilized clinically to detect liver cirrhosis, liver cancer and testicular seminomas. AFP molecule contains one single N-glycosylation site, with highly variable glycan structures, resulting in diverse AFP glycoforms in circulating blood. The core fucosylation of AFP (AFP-L3) is a clinical biomarker to monitor and predict risks of liver cancer progression and recurrence. Clinical testing for AFP-L3 utilizes lectin-binding and gel-shift electrophoresis. We developed a novel method to measure AFP glycoforms, based on immune-enrichment and liquid chromatography with high resolution mass spectrometry (LC-HRMS). Methods Immune enrichment of AFP was achieved by anti-AFP antibody, immobilized to magnetic beads. After binding and enrichment, the magnetic beads were washed, AFP was eluted, and the samples were analyzed by LC-HRMS (Exploris 480 MS and Vanquish UHPLC, Thermo Fisher Scientific), using full scan, positive polarity acquisition mode. Chromatographic separation was performed on PLRP column (Agilent); flow rate 200 µL/min. The HRMS data were processed and deconvoluted with intact mass analysis workflow in Biopharma Finder 5.1 (Thermo Fisher Scientific) to derive the intact AFP masses. The method’s sensitivity and imprecision were assessed by replicate analysis of serial diluted patient serum samples. AFP and its associated glycoforms were matched and identified with an in-house developed bioinformatics workflow. The deconvoluted intact masses and the sum intensity of detected charged species for each AFP glycoform were used to quantify relative abundance of AFP glycoforms. Results The method specificity for AFP was confirmed by bottom-up analysis after immune-enrichment with observed peptide sequence coverage over 35%. The recovery of the immune enrichment was shown to be independent of the AFP glycoform compositions. The identified AFP glycoforms and their relative abundance were consistent among replicates between AFP concentration 100 ng/mL and 5000 ng/mL. Analysis of authentic serum specimens from patients with different chronic liver diseases and liver cancer (n=102), revealed multiple complex biantennary branched AFP glycan modifications, with different numbers of terminal sialic acid and core fucose. Four AFP glycoforms were identified in over 60% patient samples with elevated AFP concentrations. Although occurring consistently, relative abundance of these AFP glycoforms varied significantly among patients. Assessment of the AFP fucosylation and sialylation features suggested that the two are orthogonal processes. Clinical correlations suggested that fewer terminal sialic acids were associated with impaired liver functions, while the fucosylation was linked to inflammatory responses and presence of liver malignancy. Strong linear correlation (Spearman’s rs=0.952, N=35) was observed between AFP-L3% quantitated by the LC-HRMS method, and AFP-L3% determined by the lectin-binding based isotachophoresis assay (Wako Diagnostics). Discrepancies between the two methods were observed in specimens containing < 400 ng/mL of AFP, in which the LC-HRMS method detected only a single predominant glycoform. Conclusions We developed and evaluated the LC-HRMS method for profiling circulating AFP glycoforms in patients with chronic liver diseases and liver cancer. The detected AFP glycoforms and their relative abundance were used to establish glycan features, which can be further linked to cancer development, impaired liver function, and inflammation.

Background and Aims: This investigation examined the association of pancreatitis and pancreatitis-related pain with serum levels of two endocannabinoid molecules such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two paracannabinoid molecules such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Methods: A case–control study was conducted within the Prospective Evaluation of Chronic Pancreatitis for Epidemiological and Translational Studies, including participants with no pancreas disease ( N = 56), chronic abdominal pain of suspected pancreatic origin or indeterminate chronic pancreatitis (CP) ( N = 22), acute pancreatitis ( N = 33), recurrent acute pancreatitis ( N = 57), and definite CP ( N = 63). Results: Circulating AEA concentrations were higher in women than in men ( p = 0.0499), and PEA concentrations were higher in obese participants than those who were underweight/normal or overweight ( p = 0.003). Asymptomatic controls with no pancreatic disease had significantly ( p = 0.03) lower concentrations of AEA compared with all disease groups combined. The highest concentrations of AEA were observed in participants with acute pancreatitis, followed by those with recurrent acute pancreatitis, chronic abdominal pain/indeterminant CP, and definite CP. Participants with pancreatitis reporting abdominal pain in the past year had significantly ( p = 0.04) higher concentrations of AEA compared with asymptomatic controls. Levels of 2-AG were significantly lower ( p = 0.02) among participants reporting abdominal pain in the past week, and pain intensity was inversely associated with concentrations of 2-AG and OEA. Conclusions: Endocannabinoid levels may be associated with stage of pancreatitis, perhaps through activation of the CB1 receptor. Validation of our findings would support the investigation of novel therapeutics, including cannabinoid receptor-1 antagonists, in this patient population.

BackgroundVariable flip angle (VFA) and modified Look–Locker inversion recovery (MOLLI) are frequently used for noninvasive evaluation of renal interstitial fibrosis (IF) in chronic kidney disease (CKD). However, controversy remains over which method is preferred.PurposeTo compare the diagnostic efficacy of VFA and MOLLI for T1 mapping in evaluating renal IF.Study TypeProspective.SubjectsFifty‐one participants with CKD (CKD stage 1–5, 35 males) and 18 healthy volunteers (eight males).Field Strength/Sequence3.0 T, three‐dimensional gradient echo sequence for B1+ VFA, and two‐dimensional gradient echo sequence for MOLLI.AssessmentImage quality was assessed on a five‐point scale. Cortex and medulla T1 values (cT1 and mT1), corticomedullary T1 value difference (ΔT1, medulla − cortex), and corticomedullary T1 value ratio (ratio T1, cortex:medulla) were compared between VFA and MOLLI as well as between IF grade (0–4) based on biopsy.Statistical TestsIntraclass correlation coefficient, Bland–Altman analysis, analysis of variance, Kruskal–Wallis test, correlation analysis, and receiver operating characteristics analysis with the area under the curve (AUC). P‐value <0.05 was considered significant.ResultsMOLLI provided significantly better image quality compared to VFA. cT1 and mT1 values significantly differed between VFA and MOLLI (cT1‐VFA: 1771.4 ± 139.4 msec vs. cT1‐MOLLI: 1729.9 ± 132.1 msec; mT1‐VFA: 2076.0 [interquartile range (IQR): 2045.9–2129.9] msec vs. mT1‐MOLLI: 2039.2 [IQR: 1997.8–2071.6] msec). ΔT1 and ratio T1 values were not different between VFA and MOLLI (ΔT1: 300.8 ± 71.4 vs. 306.0 ± 78.4, respectively, P = 0.33 and ratio T1: 0.85 ± 0.038 vs. 0.85 ± 0.041, respectively, P = 0.064). No difference was observed between T1 variables and T1 mapping methods in diagnosing IF.Data ConclusionΔT1 and ratio T1 were not different between VFA and MOLLI. Both VFA and MOLLI are effective for noninvasive assessment of renal IF.Level of Evidence2Technical EfficacyStage 2

Abstract Background The CDC reported a 35% increase in hospital-onset (HO) carbapenem-resistant Enterobacterales (CRE) infections during the COVID-19 pandemic. We evaluated patient outcomes following HO and community-onset (CO) CRE bloodstream infections (BSI). Methods Patients prospectively enrolled in CRACKLE-2 from 56 hospitals in 10 countries between 30 April 2016 and 30 November 2019 with a CRE BSI were eligible. Infections were defined as CO or HO by CDC guidelines, and clinical characteristics and outcomes were compared. The primary outcome was desirability of outcome ranking (DOOR) 30 days after index culture. Difference in 30-day mortality was calculated with 95% CI. Results Among 891 patients with CRE BSI, 65% were HO (582/891). Compared to those with CO CRE, patients with HO CRE were younger [median 60 (Q1 42, Q3 70) years versus 65 (52, 74); P &lt; 0.001], had fewer comorbidities [median Charlson comorbidity index 2 (1, 4) versus 3 (1, 5); P = 0.002] and were more acutely ill (Pitt bacteraemia score ≥4: 47% versus 32%; P &lt; 0.001). The probability of a better DOOR outcome in a randomly selected patient with CO BSI compared to a patient with HO BSI was 60.6% (95% CI: 56.8%–64.3%). Mortality at 30-days was 12% higher in HO BSI (192/582; 33%) than CO BSI [66/309 (21%); P &lt; 0.001]. Conclusion We found a disproportionately greater impact on patient outcomes with HO compared to CO CRE BSIs; thus, the recently reported increases in HO CRE infections by CDC requires rigorous surveillance and infection prevention methods to prevent added mortality.