Drug therapies are the cornerstone of systemic treatment for pancreatic cancer patients. However, the relative outcome of drug evaluation is often hampered by the complex microenvironment of pancreatic cancer due to the lack of reasonable tumor models. Here, we proposed a novel platform that integrated pancreatic adenocarcinoma cells encapsulated into hydrogel microcapsules for three-dimensional (3D) tumor cultivation and antitumor agent evaluation. These hydrogel microcapsules contain alginate/poly (N-isopropyl acrylamide) (alginate/PNIPAM) shells and carboxymethyl cellulose cores, which are generated through the microfluidic electrospray technique. The microcapsules have the feature of rapid response to temperature, by which they can regulate the internal pressure environment. Besides, benefiting from good monodispersity, precise size control, and biocompatibility of these microcapsules, these wrapped tumor cells have the capacity for proliferating spontaneously and forming 3D tumors pheroids with good cell viability. We have demonstrated that pancreatic adenocarcinoma cells encapsulated in the composite microcapsules with different PNIPAM concentrations showed different drug sensitivity, which could be ascribed to the influence of external pressures environment. These results indicate that the tumor spheroids coated in these responsive microcapsules have great potential in the analysis of antitumor drug sensitivity.
Artificial intelligence has shown immense potential in cancer prediction, but existing models cannot estimate prediction uncertainty by themselves. Here, we developed a Bayesian neural network (BNN) model, BNN-CRC15, for colorectal cancer (CRC) prediction while assessing its reliability. The model was trained on routine laboratory data obtained from 27,911 participants and provided quantified prediction uncertainty, allowing identification of a subset of participants in which the model was confident, mimicking the diagnostic process of human practitioners. Our model exhibited superior performance (area under the curve = 0.918) in the confident participant group, which accounted for 46.4% of the patients, indicating that routine laboratory data alone are sufficient for accurate predictions in this subset. For the non-confident group, further advanced tests, such as colonoscopy, could be recommended to achieve more accurate predictions. In addition, our model demonstrated superior overall accuracy(0.848) in all patients, outperforming other five traditional algorithms (extreme gradient boosting, support vector machine, logistic regression, random forest, and artificial neural network) and fecal immunochemical test in distinguishing CRC from non-CRC. These findings suggest that our BNN-CRC15 model could serve as a valuable tool for improving CRC diagnosis and prevention.
Malfunction of neutrophil apoptosis and elevated serum lactate levels are the key cellular mechanism of immune suppressive status in septic patients. However, whether increased lactate affects apoptosis of neutrophils and aggravates sepsis development, and the molecular mechanism remain unknown. In this study, first, we analyzed the transcriptional profiles of blood cells in sepsis patients(n = 39) and healthy volunteers (n = 40) to reveal that there is close correlation between the lactate-related gene expression changes associated with lactate production and immune function in leukocytes, especially in neutrophils. Further, we explored the close relationship between lactate and delayed neutrophil apoptosis in human neutrophils. Programmed cell death 1 leg and (PD-L1) was highly expressed in septic patients compared with healthy volunteers. Then, we indicated that elevated levels of lactate in human neutrophils decreased neutrophil apoptosis (P < .001) by up regulating PD-L1 expression. Inhibition of monocarboxylate transporter 1 (MCT1) significantly attenuated neutrophil apoptosis caused by lactate (P < .001). We further performed in vivo experiments in sepsis mice model and determined that increased lactate decreased neutrophil apoptosis (P < .05) and reduces mice survival rate (P < .001), which could also be rescued by MCT1 inhibitor (P < .05). This study revealed that elevated level of lactate in sepsis upregulates PD-L1 expression to decrease apoptosis throughMCT1 in neutrophils, which provides new insight into sepsis treatment strategy by reducing lactate accumulation.
It is widely recognized that platinum-based chemotherapy, particularly cisplatin therapy, can cause ototoxicity. At present, there are no Food and Drug Administration-approved drugs to prevent or alleviate ototoxicity. Ototoxicity is generally believed to be caused by excessive reactive oxygen species production in the inner ear. Accordingly, a variety of antioxidants have been developed to protect against ototoxicity. To improve the efficiency of drug delivery to the cochlea, here, we synthesized simple and easy-to-obtain glutathione carbon dots (GSH CDs) with ultra-small dimensions. The experimental results revealed that the GSH CDs have strong free-radical scavenging activity and can restore mitochondrial function, maintain hair cell stability, and protect hair cells from cisplatin-induced oxidative stress. Thus, GSH CDs may serve as a new therapeutic agent for preventing cisplatin-induced ototoxicity.
DNA programming, which is based on the principle of base complementary pairing and Boolean operations, exhibits organizational structures and algorithms similar to those observed in machine language. Consequently, the practical implementation of DNA logic programming can be achieved through the utilization of programming techniques, enabling the discrimination and output generation. In recent years, DNA programming has witnessed a convergence with disciplines, such as life sciences, medicine, and other interdisciplinary areas, thereby giving rise to an advanced research system that yields valuable insights. This development has paved the way for multidisciplinary cutting-edge research. Furthermore, the successful transition from conceptualization to the practical implementation of DNA programming has been accomplished. This review summarizes the recent advances in DNA logic programming within the biomedical fields, specifically emphasizing the conceptualization and execution of DNA logic programming constructs. The benefits and obstacles associated with the adoption of DNA programming in cutting-edge research areas are also highlighted.
Atomic force microscopy (AFM) is an analytical technique that is increasingly utilized to determine interaction forces on the colloidal and cellular level. Fluidic force microscopy, also called FluidFM, became a vital tool for biomedical applications. FluidFM combines AFM and nanofluidics by means of a microchanneled cantilever that bears an aperture instead of a tip at its end. Thereby, single colloids or cells can be aspirated and immobilized to the cantilever, for example, to determine adhesion forces. To allow for quantitative measurements, the socalled (inverse) optical lever sensitivity (OLS and InvOLS, respectively) must be determined, which is typically done in a separate set of measurements on a hard, non-deformable substrate. Here, we present a different approach that is entirely based on hydrodynamic principles and does make use of the internal microfluidic channel of a FluidFM-cantilever and an external pressure control. Thereby, a contact-free calibration of the (inverse) optical lever sensitivity (InvOLS) becomes possible in under a minute. A quantitative model based on the thrust equation, which is well-known in avionics, and finite element simulations, is provided to describe the deflection of the cantilever as a function of the externally applied pressure. A comparison between the classical and the here-presented hydrodynamic method demonstrates equal accuracy.
Surface-enhanced Raman spectroscopy (SERS) has become an essential biodetection technique. Due to its high sensitivity, good signal specificity, and resistance to photobleaching, SERS has been widely used in biomedical research fields such as molecular imaging, tumor diagnosis, and drug monitoring. This review focuses on the progress of SERS in biomedical applications.We first introduce the basic principle of SERS and the progress of substrate research. Then, we summarize the latest research progress on SERS in drugmonitoring, cell and exosome detection, tumor imaging, and detection platforms combining microfluidic and lateral flow technologies. Subsequently, the applied research of SERS in early diagnosis of pancreatic cancer and drug efficacy monitoring is described. Finally, the future development direction and possible challenges of SERS in tumor diagnosis and treatment are proposed.
Transcription factor 21 (TCF21) and estrogen receptor beta (ERβ, encoded by ESR2) are highly expressed in endometriotic stromal cells (ESCs) and contribute to the pathogenesis of endometriosis. However, the exploration of TCF21 and ERβ expression regulation at the molecular level remains limited. Here, by using bioinformatics analysis and experimental verification, we identified PES1, also known as Pescadillo, as a negative regulator in the development of endometriosis that downregulates TCF21 and ERβ expression in ESCs. PES1 overexpression regulated critical biological processes involved in endometriosis development, such as invasion and apoptosis. A coimmunoprecipitation assay showed that PES1 could form a complex with Forkhead box M1 (FOXM1). Further analyses elucidated that siPES1 in ectopic lesions decreased the stability of FOXM1 protein and reduced the binding activities of FOXM1 to TCF21 and ESR2 promoters, thus weakening the transcriptional inhibition of TCF21 and ERβ by FOXM1. Moreover, in an endometriosis mousemodel, overexpressing PES1 effectively reduced the growth of ectopic lesions and suppressed TCF21 and ERβ expression, which suggests a promising therapeutic strategy for endometriosis. Collectively, our results indicate that the loss of PES1 in ectopic lesions contributes to endometriosis progression by upregulating ERβ and TCF21 expression through heterodimer formation with FOXM1. Moreover, targeting PES1 could serve as a treatment method for endometriosis.
Colorectal cancer (CRC) is a complex malignancy, influenced not only by cancer cells but also by the tumor microenvironment (TME). Within the TME, emerging evidence highlights the presence and functional roles of diverse microbial entities, referred to as intratumoral microbiota. The distribution of these microbiota exhibits significant heterogeneity and engages in dynamic interactionswith tumor cells, forming a unique ecosystem. Certain bacterial strains distinctly influence the TME of CRC, affecting the characteristics and progression of the tumor. This review summarizes the intricate roles of intratumoral microbiota within CRC’s TME, emphasizing their importance in the disease’s development and progression, and discuss the opportunities and challenges in the field.