Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment.

In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.

Development and Optimization of a Bladder Cancer Algorithm Using SEER-Medicare Claims Data.

PURPOSE: Categorizing patients with cancer by their disease stage can be an important tool when conducting administrative claims-based studies. As claims databases frequently do not capture this information, algorithms are increasingly used to define disease stage. To our knowledge, to date, no study has used an algorithm to categorize patients with bladder cancer (BC) by disease stage (non-muscle-invasive BC [NMIBC], muscle-invasive BC [MIBC], or locally advanced/metastatic urothelial carcinoma [la/mUC]) in a US-based health care claims database. METHODS: A claims-based algorithm was developed to categorize patients by disease stage on the basis of the administrative claims portion of the SEER-Medicare linked data. The algorithm was validated against a reference SEER registry, and the algorithm's parameters were iteratively modified to improve its performance. Patients were included if they had an initial diagnosis of BC between January 2016 and December 2017 recorded in SEER registry data. Medicare claims data were available for these patients until December 31, 2019. The algorithm was evaluated by assessing percentage agreement, Cohen's kappa (κ), specificity, positive predictive value (PPV), and negative predictive value (NPV) against the SEER categorization. RESULTS: A total of 15,484 patients with SEER-confirmed BC were included: 10,991 (71.0%) with NMIBC, 3,645 (23.5%) with MIBC, and 848 (5.5%) with la/mUC. After multiple rounds of algorithm optimization, the final algorithm had an agreement of 82.5% with SEER, with a κ of 0.58, a PPV of 87.0% for NMIBC, and 76.8% for MIBC and a high NPV for la/mUC of 98.0%. CONCLUSION: This claims-based algorithm could be a useful approach for researchers conducting claims-based studies categorizing patients with BC at diagnosis.

Leidenfrost Effect-Induced Chaotic Vortex Flow for Efficient Mixing of Highly Viscous Droplets.

Efficiently mixing highly viscous liquids in microfluidic systems is appealing for green chemistry such as chemical synthesis and catalysis, but it is a long-standing challenge owing to the unfavorable diffusion kinetics. In this work, a new strategy is explored for mixing viscous droplets by harnessing a peculiar Leidenfrost state, where the substrate temperature is above the boiling point of the liquid without apparent liquid evaporation. Compared to the control experiment where the droplet stays at a similar temperature but in the contact boiling regime, the mixing time can be reduced significantly. Moreover, it is demonstrated that the liquid mixing originates from the chaotic convection flow in the Leidenfrost droplet, characterized by the internal vortex motion evidenced by the microscale visualization. A correlation between mixing time and droplet volume is also proposed, showing a good agreement with experimental results. It is further shown that Leidenfrost droplets can be used to synthesize nanoparticles of the desired morphology, and it is anticipated that this simple and scalable fabrication approach will find applications in the biological, pharmaceutical, and chemical industries.

Deep learning segmentation of mandible with lower dentition from cone beam CT.

OBJECTIVES: This study aimed to train a 3D U-Net convolutional neural network (CNN) for mandible and lower dentition segmentation from cone-beam computed tomography (CBCT) scans. METHODS: In an ambispective cross-sectional design, CBCT scans from two hospitals (2009-2019 and 2021-2022) constituted an internal dataset and external validation set, respectively. Manual segmentation informed CNN training, and evaluations employed Dice similarity coefficient (DSC) for volumetric accuracy. A blinded oral maxillofacial surgeon performed qualitative grading of CBCT scans and object meshes. Statistical analyses included independent t-tests and ANOVA tests to compare DSC across patient subgroups of gender, race, body mass index (BMI), test dataset used, age, and degree of metal artifact. Tests were powered for a minimum detectable difference in DSC of 0.025, with alpha of 0.05 and power level of 0.8. RESULTS: 648 CBCT scans from 490 patients were included in the study. The CNN achieved high accuracy (average DSC: 0.945 internal, 0.940 external). No DSC differences were observed between test set used, gender, BMI, and race. Significant differences in DSC were identified based on age group and the degree of metal artifact. The majority (80%) of object meshes produced by both manual and automatic segmentation were rated as acceptable or higher quality. CONCLUSION: We developed a model for automatic mandible and lower dentition segmentation from CBCT scans in a demographically diverse cohort including a high degree of metal artifacts. The model demonstrated good accuracy on internal and external test sets, with majority acceptable quality from a clinical grader.

Ultrastable piezoelectric biomaterial nanofibers and fabrics as an implantable and conformal electromechanical sensor patch.

Poly(l-lactic acid) (PLLA) is a widely used U.S. Food and Drug Administration-approved implantable biomaterial that also possesses strong piezoelectricity. However, the intrinsically low stability of its high-energy piezoelectric ß phase and random domain orientations associated with current synthesis approaches remain a critical roadblock to practical applications. Here, we report an interfacial anchoring strategy for fabricating core/shell PLLA/glycine (Gly) nanofibers (NFs) by electrospinning, which show a high ratio of piezoelectric ß phase and excellent orientation alignment. The self-assembled core/shell structure offers strong intermolecular interactions between the -OH groups on Gly and C=O groups on PLLA, which promotes the crystallization of oriented PLLA polymer chains and stabilizes the ß phase structure. As-received core/shell NFs exhibit substantially enhanced piezoelectric performance and excellent stability. An all NF-based nonwoven fabric is fabricated and assembled as a flexible nanogenerator. The device offers excellent conformality to heavily wrinkled surfaces and thus can precisely detect complex physiological motions often found from biological organs.

How liquids charge the superhydrophobic surfaces.

Liquid-solid contact electrification (CE) is essential to diverse applications. Exploiting its full implementation requires an in-depth understanding and fine-grained control of charge carriers (electrons and/or ions) during CE. Here, we decouple the electrons and ions during liquid-solid CE by designing binary superhydrophobic surfaces that eliminate liquid and ion residues on the surfaces and simultaneously enable us to regulate surface properties, namely work function, to control electron transfers. We find the existence of a linear relationship between the work function of superhydrophobic surfaces and the as-generated charges in liquids, implying that liquid-solid CE arises from electron transfer due to the work function difference between two contacting surfaces. We also rule out the possibility of ion transfer during CE occurring on superhydrophobic surfaces by proving the absence of ions on superhydrophobic surfaces after contact with ion-enriched acidic, alkaline, and salt liquids. Our findings stand in contrast to existing liquid-solid CE studies, and the new insights learned offer the potential to explore more applications.

Turning the tide in aggressive lymphoma: liquid biopsy for risk-adapted treatment strategies.

Diffuse large B cell lymphoma (DLBCL) exhibits significant biological and clinical heterogeneity that presents challenges for risk stratification and disease surveillance. Existing tools for risk stratification, including the international prognostic index (IPI), tissue molecular analyses, and imaging, have limited accuracy in predicting outcomes. The therapeutic landscape for aggressive lymphoma is rapidly evolving, and there is a pressing need to identify patients at risk of refractory or relapsed (R/R) disease in the context of personalized therapy. Liquid biopsy, a minimally invasive method for cancer signal detection, has been explored to address these challenges. We review advances in liquid biopsy strategies focusing on circulating nucleic acids in DLBCL patients and highlight their clinical potential. We also provide recommendations for biomarker-guided trials to support risk-adapted treatment modalities.

Ophthalmic drug effects on the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment.

Drugs that can treat one disease may either be detrimental or beneficial toward another due to possible cross-interactions. Therefore, care in choosing a suitable drug for patients with multiple diseases is crucial in successful patient management. This study explores several currently available ophthalmic drugs used to treat common ocular diseases to understand how they can affect the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment found in abundance in the corneal protein aggregation deposits of lattice corneal dystrophy (LCD) patients. Results from this study provided supporting evidence that some drugs intended to treat other diseases can enhance or inhibit fibrillar aggregation of TGFBIp peptide, which may have potential implication of affecting the disease progression of LCD by either worsening or ameliorating it. Comparisons of the different properties of ophthalmic compounds explored in this study may also provide some guidance for future design of drugs geared toward the treatment of LCD.

Surface Nanostructures Promote Droplet Splash on Hot Substrates.

Splash, one of the most visually apparent droplet dynamics, can manifest on any surface above a certain impact velocity, regardless of surface wettability. Previous studies demonstrate that elevating the substrate temperature can suppress droplet splash, which is unfavorable for many practical applications, such as spray cooling and combustion. Here, we report that the suppression effect of substrate temperature on splash is nullified by utilizing surfaces with nanostructures. By manipulating air evacuation time through surface nanostructures, we have identified a pathway for precise control over the splash threshold and the ability to tailor the dependence of the splash onset on surface temperature. We further propose a theoretical criterion to determine different splash regimes by considering the competition between air evacuation and the development of flow instabilities. Our findings underscore the crucial role of nanostructures in splash dynamics, offering valuable insights for the control of splash in various industrial scenarios.

Pathways for macrophage uptake of cell-free circular RNAs.

Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.

Recent advances in shape memory polymeric nanocomposites for biomedical applications and beyond.

Shape memory polymers (SMPs), which initiate shape transformation in response to environmental stimuli, have attracted significant attention in both academic research and technological innovation. The combination of functional nanomaterials and SMPs has led to the emergence of a variety of shape memory polymeric nanocomposites (SMPNs) with multifunctional properties. This has injected new vitality and vigor into fields such as tissue engineering, biomedicine, optical sensing, aerospace and mechanical engineering. In this review article, we present a brief introduction to the fundamentals of SMPs and SMPNs, followed by a discussion of the recent advances in their multifunctional applications in biomedical manufacturing, drug delivery devices, mechanical sensing, micro-engines, etc. The opportunities and challenges in the future development of SMPs are also discussed.

Ready for Discharge, but Are They Ready to Go Home? Examining Neighborhood-Level Disadvantage as a Marker of the Social Exposome and the Swallowing Care Process in a Retrospective Cohort of Inpatients With Dementia.

PURPOSE: Socioeconomically disadvantaged areas are more resource poor, impacting adherence to swallowing care recommendations. Neighborhood-level disadvantage metrics, such as the Area Deprivation Index (ADI), allow for examination of social determinants of health (SDOH) in a precise region. We examined ADI in a cohort of persons living with dementia (PLWD) to determine representation of those residing in areas of socioeconomic disadvantage (high ADI), distribution of swallowing care provided, and frequency of SDOH-related counseling or resource linking prior to discharge. METHOD: A retrospective chart abstraction was performed for all inpatients with a diagnosis of dementia (N = 204) seen by the Swallow Service at a large academic hospital in 2014. State ADI Deciles 1 (least) to 10 (most socioeconomic disadvantage) and decile groups (1-3, 4-7, and 8-10) were compared with the surrounding county. Frequency of videofluoroscopic swallowing evaluations (VFSEs) based on ADI deciles was recorded. To determine whether SDOH-related counseling or resource linking occurred for those in high ADI (8-10) neighborhoods, speech-language pathology notes, and discharge summaries were reviewed. Descriptive statistics, independent samples t tests, and one-way analysis of variance were calculated. RESULTS: ADI was significantly higher in this cohort (M = 3.84, SD = 2.58) than in the surrounding county (M = 2.79, SD = 1.88, p = .000). There was no significant difference in utilization of swallowing services across decile groups (p = .88). Although the majority (85%) in high ADI areas was recommended diet modifications or alternative nutrition likely requiring extra resources, there was no documentation indicating that additional SDOH resource linking or counseling was provided. CONCLUSIONS: These findings raise important questions about the role and responsibility of speech-language pathologists in tailoring swallowing services to challenges posed by the lived environment, particularly in socioeconomically disadvantaged areas. This underscores the need for further research to understand and address gaps in postdischarge support for PLWD in high-ADI regions and advocate for more equitable provision of swallowing care.

Using silver nanoparticle-decorated whey protein isolate amyloid fibrils to modify the electrode surface used for electrochemical detection of para-nitrophenol.

Due to their organized structures, remarkable stiffness, and nice biocompatibility and biodegradability, amyloid fibrils serve as building blocks for versatile sustainable materials. Silver nanoparticles (AgNPs) are commonly used as the nano-catalysts for various electrochemical reactions. Given their large specific surface area and high surface energy, AgNPs exhibit high aggregation propensity, which hampers their electrocatalytic performance. Food protein wastes have been identified to be associated with climate change and environmental impacts, and a surplus of whey proteins in dairy industries causes high biological and chemical demands, and greenhouse gas emissions. This study is aimed at constructing sustainable electrode surface modifiers using AgNP-deposited whey protein amyloid fibrils (AgNP/WPI-AFs). AgNP/WPI-AFs were synthesized and characterized via spectroscopic techniques, electron microscopy, and X-ray diffraction. Next, the electrocatalytic performance of AgNP/WPI-AF modified electrode was assessed via para-nitrophenol (p-NP) reduction combined with various electrochemical analyses. Moreover, the reaction mechanism of p-NP electrocatalysis on the surface of AgNP/WPI-AF modified electrode was investigated. The detection range, limit of detection, sensitivity, and selectivity of the AgNP/WPI-AF modified electrode were evaluated accordingly. This work not only demonstrates an alternative for whey valorization but also highlights the feasibility of using amyloid-based hybrid materials as the electrode surface modifier for electrochemical sensing purposes.

Development of subunit selective proteasome substrates for Schistosoma species.

Schistosomiasis, or bilharzia, is a neglected tropical disease caused by Schistosoma spp. blood flukes that infects over 200 million people worldwide. Just one partially effective drug is available, and new drugs and drug targets would be welcome. The 20S proteasome is a validated drug target for many parasitic infections, including those caused by Plasmodium and Leishmania. We previously showed that anticancer proteasome inhibitors that act through the Schistosoma mansoni 20S proteasome (Sm20S) kill the parasite in vitro. To advance these initial findings, we employed Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to define the substrate cleavage specificities of the three catalytic ß subunits of purified Sm20S. The profiles in turn were used to design and synthesize subunit-specific optimized substrates that performed two to eight fold better than the equivalent substrates used to measure the activity of the constitutive human proteasome (c20S). These specific substrates also eliminated the need to purify Sm20S from parasite extracts - a single step enrichment was sufficient to accurately measure substrate hydrolysis and its inhibition with proteasome inhibitors. Finally, we show that the substrate and inhibition profiles for the 20S proteasome from the three medically important schistosome species are similar, suggesting that data arising from an inhibitor development campaign that focuses on Sm20S can be extrapolated to the other two targets with consequent time and cost savings.

Forced capillary wetting of viscoelastic fluids.

HYPOTHESIS: Achieving rapid capillary wetting is highly desirable in nature and industries. Previous endeavors have primarily concentrated on passive wetting strategies through surface engineering. However, these approaches are inadequate for high-viscosity fluids due to the significant viscous resistance, especially for non-Newtonian fluids. In contrast, forced wetting emerges as a promising method to address the challenges associated with achieving rapid wetting of non-Newtonian fluids in capillaries. EXPERIMENTS: To investigate the forced wetting behavior of viscoelastic fluids in capillaries, we employ Xanthan Gum (XG) aqueous solutions as target fluids with the storage modulus significantly exceeding the loss modulus. We utilize smooth glass capillaries connected to a syringe pump to achieve high moving speeds of up to 1 m/s. FINDINGS: Our experiments reveal a significant distinction in the power-law exponent that governs the scaling relationship between the dynamic contact angle and velocity for viscoelastic fluids compared to Newtonian fluids. This exponent is considerably smaller and varies based on the concentration of viscoelastic fluids and the diameter of the capillaries. We suggest that the viscosity dominates the wetting dynamics of viscoelastic fluids, manifested by the contact line morphology-dependent behavior. This insight has significant implications for microfluidics and drug injectability.

Laser-Induced Electron Synchronization Excitation for Photochemical Synthesis and Patterning Graphene-Based Electrode.

Micro-supercapacitors (MSCs) represent a pressing requirement for powering the forthcoming generation of micro-electronic devices. The simultaneous realization of high-efficiency synthesis of electrode materials and precision patterning for MSCs in a single step presents an ardent need, yet it poses a formidable challenge. Herein, a unique shaped laser-induced patterned electron synchronization excitation strategy has been put forward to photochemical synthesis RuO2 /reduced graphene oxide (rGO) electrode and simultaneously manufacture the micron-scale high-performance MSCs with ultra-high resolution. Significantly, the technique represents a noteworthy advancement over traditional laser direct writing (LDW) patterning and photoinduced synthetic electrode methods. It not only improves the processing efficiency for MSCs and the controllability of laser-induced electrode material but also enhances electric fields and potentials at the interface for better electrochemical performance. The resultant MSCs exhibit excellent area and volumetric capacitance (516 mF cm-2 and 1720 F cm-3 ), and ultrahigh energy density (0.41 Wh cm-3 ) and well-cycle stability (retaining 95% capacitance after 12000 cycles). This investigation establishes a novel avenue for electrode design and underscores substantial potential in the fabrication of diverse microelectronic devices.

Increased Purinergic Signaling in Human Dental Pulps With Inflammatory Pain is Sex-Dependent.

An enhanced understanding of neurotransmitter systems contributing to pain transmission aids in drug development, while the identification of biological variables like age and sex helps in the development of personalized pain management and effective clinical trial design. This study identified enhanced expression of purinergic signaling components specifically in painful inflammation, with levels increased more in women as compared to men. Inflammatory dental pain is common and potentially debilitating; as inflammation of the dental pulp can occur with or without pain, it provides a powerful model to examine distinct pain pathways in humans. In control tissues, P2X3 and P2X2 receptors colocalized with PGP9.5-positive nerves. Expression of the ecto-nucleotidase NTPDase1 (CD39) increased with exposure to extracellular adenosine triphosphate (ATP), implying CD39 acted as a marker for sustained elevation of extracellular ATP. Both immunohistochemistry and immunoblots showed P2X2, P2X3, and CD39 increased in symptomatic pulpitis, suggesting receptors and the ATP agonist were elevated in patients with increased pain. The increased expression of P2X3 and CD39 was more frequently observed in women than men. In summary, this study identifies CD39 as a marker for chronic elevation of extracellular ATP in fixed human tissue. It supports a role for increased purinergic signaling in humans with inflammatory dental pain and suggests the contribution of purines shows sexual dimorphism. This highlights the potential for P2X antagonists to treat pain in humans and stresses the need to consider sex in clinical trials that target pain and purinergic pathways. PERSPECTIVE: This article demonstrates an elevation of ATP-marker CD39 and of ATP receptors P2X2 and P2X3 with inflammatory pain and suggests the rise is greater in women. This highlights the potential for P2X antagonists to treat pain and stresses the consideration of sexual dimorphism in studies of purines and pain.