Precision therapy for intrahepatic cholangiocarcinoma: A case report on adjuvant treatment in a recurrent patient after surgery and literature review.

A 37-year-old female patient was diagnosed with intrahepatic cholangiocarcinoma (ICC), with the lesion located in the right lobe of the liver. Despite radical resection, postoperative adjuvant chemotherapy and a combination of adjuvant chemotherapy and immunotherapy, the patient continued to experience multiple instances of intrahepatic tumor metastases. Furthermore, the patient exhibited significant adverse reactions to systemic chemotherapy and had poor treatment tolerance. Guidance from paraffin section fluorescence in situ hybridization gene sequencing was used to select a combination of immunotherapy and targeted therapy treatments with programmed cell death 1 (PD-1)/PD-1 ligand 1 antibody durvalumab and the targeted drug pemigatinib. The patient tolerated the treatment and has continued to survive for 28 months. According to imaging evaluations, the lesions continued to decrease, with some disappearing completely. The tumor marker carbohydrate antigen 19-9 remained normal for >9 weeks during the treatment. This report described the patient's treatment process in detail and briefly reviewed relevant literature on the treatment progress of postoperative patients with ICC.

The association between higher cardiac troponin levels and the development of left ventricular diastolic dysfunction in septic patients with diabetes mellitus.

This study was designed to retrospectively analyze the relationship between the levels of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) and the development of left ventricular diastolic dysfunction (LVDD) in septic patients with diabetes mellitus. Furthermore, the predictive value of cTnT and cTnI in the LVDD development in those patients was investigated. The clinical information of 159 septic patients with diabetes mellitus treated in the intensive care unit of Affiliated Hospital of Chengde Medical University from June 2016 to January 2023 were retrospectively analyzed. These patients were separated into LVDD group (LVFP > 15 mmHg) and non-LVDD group (LVFP ≤ 15 mmHg) based on left ventricular filling pressure (LVFP). The differences in clinical data, echocardiographic parameters, as well as cTnT and cTnI levels between the LVDD and non-LVDD groups were compared. The relationship between the cTnT and cTnI levels and the echocardiographic parameters was studied using Pearson correlation analysis. Logistic regression analysis was conducted to explore the factors that influenced the LVDD development in septic patients with diabetes. Receiver operator characteristic (ROC) curves were created to evaluate the predictive value of cTnT and cTnI levels for the LVDD development in septic patients with diabetes. Totally 159 septic patients with diabetes were included in this study, with 97 patients in the LVDD group and 62 in the non-LVDD group. Compared with the non-LVDD group, patients in the LVDD group had much lower left ventricular (LV) early diastolic peak inflow velocity (E), LV advanced diastolic peak inflow velocity (A), E/A, and early diastolic mitral annular velocity (Em) while significantly higher E/Em. The LVDD group showed much higher levels of cTnI and cTnT than the non-LVDD group (P < 0.05). Significant positive correlation between log10cTnI level and E/Em ratio (r = 0.425, P < 0.001) was revealed by the Pearson correlation analysis. Multivariate analysis showed that E/A, E/Em, cTnI and cTnT were independent risk factors for the LVDD development in septic patients with diabetes (P < 0.05). As for ROC curve results, the area under the curve (AUC) of cTnT to predict the development of LVDD in septic patients with diabetes was 0.849 (95% CI 0.788-0.910, P < 0.001); the AUC of cTnI was 0.742 (95% CI 0.666-0.817, P < 0.001). Both cTnT and cTnI are independent risk factors and have predictive value for the LVDD development in septic patients with diabetes mellitus.

Study on physicochemical properties and anti-aging mechanism of wheat starch by anionic polysaccharides.

The anti-aging effects of two anionic polysaccharides AG (sodium alginate)/SSPS (soluble soybean polysaccharide) and WS (wheat starch) were evaluated, and their different mechanisms were explored. The rheological properties, gelatinization properties and aging properties were characterized. The addition of AG and SSPS changed the gelatinization parameters of WS, decreased the peak viscosity, breakdown viscosity and setback viscosity, and enhanced the fluidity of the gel system. Additionally, the starch molecular orderliness experiment showed that the relative crystallinity of starch gels decreased with the increase in AG and SSPS concentrations, indicating that the rearrangement of amylopectin was disturbed, which inhibited the cross-linking of starch molecules. The water state analysis showed that the hydrophilicity of AG and SSPS and their interactions with starch molecules influenced the relaxation behavior of water protons in the gel system in a concentration-dependent manner. In conclusion, the addition of AG and SSPS could significantly inhibit the aging of WS gels, probably due to the competition effect of AG and SSPS on water and the interaction with starch molecules. The present study results would provide new theoretical insights into WS-based food research.

DNA templated Click Chemistry via 5-vinyl-2'-deoxyuridine and an acridine-tetrazine conjugate induces DNA damage and apoptosis in cancer cells.

AIMS: Click Chemistry is providing valuable tools to biomedical research, but its direct use in therapies remains nearly unexplored. For cancer treatment, nucleoside analogues (NA) such as 5-vinyl-2'-deoxyuridine (VdU) can be metabolically incorporated into cancer cell DNA and subsequently "clicked" to form a toxic product. The inverse electron-demand Diels-Alder (IEDDA) reaction between VdU and an acridine-tetrazine conjugate (PINK) has previously been used to label cell nuclei of cultured cells. Here, we report tandem usage of VdU and PINK to induce cytotoxicity. MAIN METHODS: Cell lines were subsequently treated with VdU and PINK, and cell viability was measured via well confluency and 3D tumor spheroid assays. DNA damage and apoptosis were evaluated using Western Blotting and cell cycle analysis by flow cytometry. Double stranded DNA break (DSB) formation was measured using the comet assay. Apoptosis was assessed by fluorescent detection of externalized phosphatidylserine residues. KEY FINDINGS: We report that the combination of VdU and PINK synergistically induces cytotoxicity in cultured human cells. The combination of VdU and PINK strongly reduced cell viability in 2D and 3D cultured cancer cells. Mechanistically, the compounds induced DNA damage through DSB formation, which leads to S-phase accumulation and apoptosis. SIGNIFICANCE: The combination of VdU and PINK represents a novel and promising DNA-templated "click" approach for cancer treatment via selective induction of DNA damage.

Interpretation of the effects of hydroxypropyl starch and hydroxypropyl distarch phosphate on frozen raw noodles quality during frozen storage: Studies on water state and starch-gluten network properties.

The impacts of both structural variations induced by low temperature and physiochemical changes induced by modified starch on the qualities of frozen raw noodles (FRNs) were investigated during long-term freezing storage. The addition of modified starch was a potentially effective method to delay the loss of FRNs qualities during storage. In this study, hydroxypropyl starch (HPS) and hydroxypropyl distarch phosphate (HPDSP) were added to improve the cooking and textural characteristics of FRNs. The cooking loss rate of FRNs with the addition of 12%HPS was consistent with that of the control (4.39 % and 4.37 %, respectively), while after 8 weeks of storage showed the significant decrease effect (5.01 % and 5.78 %, respectively). In addition, adding HPS or HPDSP could change the colour and lustre of FRNs to that preferred by consumers. When 6 % HPS or HPDSP were added, the FRNs showed the lowest of freezable water content during storage. The test results of FTIR showed the secondary structure of FRNs was maintained with the introduction of HPS or HPDSP during refrigeration, and the microstructure was improved during the frozen storage period. Consequently, the results provided a theoretical basis and new insight for the production and transportation of FRNs.

Fluid nanoporous microinterface enables multiscale-enhanced affinity interaction for tumor-derived extracellular vesicle detection.

Tumor-derived extracellular vesicles (T-EVs) represent valuable markers for tumor diagnosis and treatment guidance. However, nanoscale sizes and the low abundance of marker proteins of T-EVs restrict interfacial affinity reaction, leading to low isolation efficiency and detection sensitivity. Here, we engineer a fluid nanoporous microinterface (FluidporeFace) in a microfluidic chip by decorating supported lipid bilayers (SLBs) on nanoporous herringbone microstructures with a multiscale-enhanced affinity reaction for efficient isolation of T-EVs. At the microscale level, the herringbone micropattern promotes the mass transfer of T-EVs to the surface. At the nanoscale level, nanoporousity can overcome boundary effects for close contact between T-EVs and the interface. At the molecular level, fluid SLBs afford clustering of recognition molecules at the binding site, enabling multivalent binding with an ∼83-fold increase of affinity compared with the nonfluid interface. With the synergetic enhanced mass transfer, interface contact, and binding affinity, FluidporeFace affords ultrasensitive detection of T-EVs with a limit of detection of 10 T-EVs µL-1, whose PD-L1 expression levels successfully distinguish cancer patients from healthy donors. We expect this multiscale enhanced interfacial reaction strategy will inspire the biosensor design and expand liquid biopsy applications, especially for low-abundant targets in clinical samples.

Synergetic collision and space separation in microfluidic chip for efficient affinity-discriminated molecular selection.

Efficient molecular selection is a prerequisite for generating molecular tools used in diagnosis, pathology, vaccinology, and therapeutics. Selection efficiency is thermodynamically highly dependent on the dissociation equilibrium that can be reached in a single round. Extreme shifting of equilibrium towards dissociation favors the retention of high-affinity ligands over those with lower affinity, thus improving the selection efficiency. We propose to synergize dual effects by deterministic lateral-displacement microfluidics, including the collision-based force effect and the two-dimensional (2D) separation-based concentration effect, to greatly shift the equilibrium. Compared with previous approaches, this system can remove more low- or moderate-affinity ligands and maintain most high-affinity ligands, thereby improving affinity discrimination in selection. This strategy is demonstrated on phage display in both experiment and simulation, and two peptides against tumor markers ephrin type-A receptor 2 (EphA2) and CD71 were obtained with high affinity and specificity within a single round of selection, which offers a promising direction for discovery of robust binding ligands for a wide range of biomedical applications.

Selective, user-friendly, highly porous, efficient, and rapid (SUPER) filter for isolation and analysis of rare tumor cells.

Rapid, efficient, and selective separation of tumor cells from complex body fluids is urgently needed for clinical application of tumor-cell-based liquid biopsy. Herein, a size-selective affinity filtration system, named selective, user-friendly, highly porous, efficient, and rapid filter (SUPER Filter), was developed for high-performance tumor cell isolation and analysis. SUPER Filter enabled selective interaction of tumor cells with size-optimized and antibody-coated micropore walls during filtration, achieving a high efficiency of 91.0 ± 6.1% in buffer and 83.7 ± 6.4% in whole blood. Meanwhile, its larger micropore size than those of traditional filtration devices greatly reduced the nonspecific capture of background cells (55-126 cells per mL blood) with enrichment factors of 1.1 × 104-1.0 × 105 and a purity of 52.7 ± 4.2%. Moreover, its high porosity enabled ultra-fast (<5 s for 1 mL of blood or 10 mL of buffer samples) and user-friendly gravity-driven filtration. Finally, SUPER Filter demonstrated rapid, efficient, and selective separation of tumor cells from blood and large-volume pleural and ascetic fluid samples from cancer patients for morphological and molecular analysis. We expect that this size-selective affinity filtration strategy facilitates the clinical application of tumor-cell-based liquid biopsy.

Single-Cell Digital Microfluidic Mass Spectrometry Platform for Efficient and Multiplex Genotyping of Circulating Tumor Cells.

Gene mutation profiling of heterogeneous circulating tumor cells (CTCs) offers comprehensive and real-time molecular information of tumors for targeted therapy guidance, but the lack of efficient and multiplex genotyping techniques for single-CTC analysis greatly hinders its development and clinical application. This paper reports a single-CTC mass spectrometry analysis method for efficient and multiplex mutation profiling based on digital microfluidics. Digital microfluidics affords integrated single-CTC manipulation, from single-CTC isolation to high-performance whole genome amplification, via nanoliter droplet-based wettability trapping and hydrodynamic adjustment of cell distribution. Coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, multiplex mutation information of individual CTCs can be efficiently and accurately identified by the inherent mass differences of different DNA sequences. This platform achieves Kirsten rat sarcoma viral oncogene mutation profiling of heterogeneous CTCs at the single-cell level from cancer patient samples, offering new avenues for genotype profiling of single CTCs and cancer therapy guidance.

Reversible Immunoaffinity Interface Enables Dynamic Manipulation of Trapping Force for Accumulated Capture and Efficient Release of Circulating Rare Cells.

Controllable assembly and disassembly of recognition interface are vital for bioanalysis. Herein, a strategy of dynamic manipulation of trapping force by engineering a dynamic and reversible immunoaffinity microinterface (DynarFace) in a herringbone chip (DynarFace-Chip) for liquid biopsy is proposed. The DynarFace is assembled by magnetically attracting immunomagnetic beads (IMBs) on chip substrate, with merits of convenient operation and reversible assembly. The DynarFace allows accumulating attachment of IMBs on circulating rare cell (CRC) surfaces during hydrodynamically enhanced interface collision, where accumulatively enhanced magnetic trapping force improves capture efficiency toward CRCs with medium expression of biomarkers from blood samples by 134.81% compared with traditional non-dynamic interfaces. Moreover, magnet withdrawing-induced disappearance of trapping force affords DynarFace disassembly and CRC release with high efficiency (>98%) and high viability (≈98%), compatible with downstream in vitro culture and gene analysis of CRCs. This DynarFace strategy opens a new avenue to accumulated capture and reversible release of CRCs, holding great potential for liquid biopsy-based precision medicine.

Auto-Panning: a highly integrated and automated biopanning platform for peptide screening.

Biopanning, a common affinity selection approach in phage display, has evolved numerous ligands for diagnosis, imaging, delivery, and therapy applications. However, traditional biopanning has suffered from time-consuming processes, highly-repetitive procedures and labor-intensive manual operation. Herein, a highly integrated and automated biopanning platform (Auto-Panning) is proposed. Based on digital microfluidics (DMF), biopanning processes are integrated on a chip with highly reproducible, precise, automated liquid manipulation. Therefore, 3 rounds of Auto-Panning can be accomplished within 16 h, instead of nearly a week of complicated manual operations. Auto-Panning has been used to evolve a specific peptide against cancer biomarker EphA2 with excellent cellular penetrating ability and significant invasion suppression biofunction, successfully demonstrating the practicality of the platform. Overall, as an automated programmable molecular screening platform, Auto-Panning will further promote the discovery and applications of novel ligands.

Spin-noise spectrum in a pulse-modulated field.

We measure the spin noise spectrum (SNS) of a thermal Rubidium vapor in a pulse-modulated transverse magnetic field and develop a simple theory to describe the main structure of the SNS. Notably, when the pulse area is equal to π, the SNS consists of resonances centered at half-odd-integer multiples of the modulation frequency, while revealing the spin dynamics of the system in a zero field. Our study opens a promising way of studying zero-field spin dynamics by spin noise spectrum free from any low-frequency environmental disturbances.

Spin squeezing of 1011 atoms by prediction and retrodiction measurements.

The measurement sensitivity of quantum probes using N uncorrelated particles is restricted by the standard quantum limit1, which is proportional to [Formula: see text]. This limit, however, can be overcome by exploiting quantum entangled states, such as spin-squeezed states2. Here we report the measurement-based generation of a quantum state that exceeds the standard quantum limit for probing the collective spin of 1011 rubidium atoms contained in a macroscopic vapour cell. The state is prepared and verified by sequences of stroboscopic quantum non-demolition (QND) measurements. We then apply the theory of past quantum states3,4 to obtain spin state information from the outcomes of both earlier and later QND measurements. Rather than establishing a physically squeezed state in the laboratory, the past quantum state represents the combined system information from these prediction and retrodiction measurements. This information is equivalent to a noise reduction of 5.6 decibels and a metrologically relevant squeezing of 4.5 decibels relative to the coherent spin state. The past quantum state yields tighter constraints on the spin component than those obtained by conventional QND measurements. Our measurement uses 1,000 times more atoms than previous squeezing experiments5-10, with a corresponding angular variance of the squeezed collective spin of 4.6 × 10-13 radians squared. Although this work is rooted in the foundational theory of quantum measurements, it may find practical use in quantum metrology and quantum parameter estimation, as we demonstrate by applying our protocol to quantum enhanced atomic magnetometry.

Auto-affitech: an automated ligand binding affinity evaluation platform using digital microfluidics with a bidirectional magnetic separation method.

The dissociation constant (Kd) is a crucial parameter for characterizing binding affinity in molecular recognition, including antigen-antibody, DNA-protein, and receptor-ligand interactions. However, conventional methods for Kd characterization usually involve a multi-step process and time-consuming operations for incubation, washing, and detection, thus causing problems, such as time delays, microbead loss, degradation of sensitive molecules, and personal errors. Here we demonstrate an automated ligand binding affinity evaluation platform (Auto-affitech) using digital microfluidics (DMF), with individual droplets at the microliter level, programmed to rapidly perform the incubation and separation of target-beads and binding ligands. Because the loss of the beads influences the detection results, we propose a new strategy for magnetic bead separation using DMF, termed the bidirectional separation method. By splitting one droplet into two asymmetric droplets, high bead retention efficiency (89.57% ± 0.05%) and high washing efficiency (99.59% ± 0.17%, with four washings) were obtained. We demonstrate the determination of Kd of an aptamer-protein system (EpCAM and its corresponding aptamer SYL3C) and an antigen-antibody system (H5N1 antigen and antibody), proving the capability and universality of Auto-affitech in various receptor-ligand systems. Integrating all the sample processing procedures, the Auto-affitech not only saves manual labor and minimizes personal errors, but also conserves samples and shortens analysis time. Overall, this platform successfully demonstrates to be an automated approach for dissociation constant evaluation and exhibits great potential for highly efficient screening of ligands.

A Highly Stretchable Self-Healing Poly(dimethylsiloxane) Elastomer with Reprocessability and Degradability.

It is a challenge to synthesize materials that possess the properties of high stretchability and self-healability. Herein a new poly(dimethylsiloxane) elastomer with high stretchability, room-temperature self-healability, repeatable reprocessability, and controlled degradability is reported by incorporating an aromatic disulfide bond and imine bond. The as-prepared elastomer can be stretched to over 2200% of its original length. Without external stimuli, a damaged sheet can completely heal in 4 h. In addition, the elastomer can be reprocessed multiple times without obvious performance degradation and degraded controllably by three ways. All these properties of the elastomer can be ascribed to the unique dual-dynamic-covalent sacrificial system.

An Allosteric-Probe for Detection of Alkaline Phosphatase Activity and Its Application in Immunoassay.

A fluorescence strategy for alkaline phosphatase (ALP) assay in complicated samples with high sensitivity and strong stability is developed based on an allosteric probe (AP). This probe consists of two DNA strands, a streptavidin (SA) aptamer labeled by fluorophore and its totally complementary DNA (cDNA) with a phosphate group on the 5' end. Upon ALP introduction, the phosphate group on the cDNA is hydrolyzed, leaving the unhydrolyzed cDNA sequence for lambda exonuclease (λ exo) digestion and releasing SA aptamer for binding to SA beads, which results in fluorescence enhancement of SA beads that can be detected by flow cytometry or microscopy. We have achieved a detection limit of 0.012 U/mL with a detection range of 0.02~0.15 U/mL in buffer and human serum. These figures of merit are better than or comparable to those of other methods. Because the fluorescence signal is localized on the beads, they can be separated to remove fluorescence background from complicated biological systems. Notably, the new strategy not only applies to ALP detection with simple design, easy operation, high sensitivity, and good compatibility in complex solution, but also can be utilized in ALP-linked immunosorbent assays for the detection of a wide range of targets.

Nitrogen removal via nitrite in domestic wastewater treatment using combined salt inhibition and on-line process control.

Nitrogen removal through the nitrite pathway has been successfully achieved using on-line aeration length control. However, it takes a long time period to get steady performance when using on-line control as the sole strategy. On the other hand, salt inhibition has also been used to achieve the nitrite pathway, with potentially adverse effects on the overall microbial community at high salt concentrations. The objective of this study is to develop a control strategy based on the combination of low salt inhibition levels and on-line control to accelerate the achievement of nitrite pathway in a sequencing batch reactor (SBR) treating domestic wastewater. Salt concentrations and on-line control parameters were chosen in batch tests. The recovery of the nitrite-oxidizing bacteria (NOB) activity was examined after stopping on-line control and salt dosing. The findings clearly show that combining salt inhibition at low salinity (5 g/L) with on-line pH control is an efficient strategy to achieve nitrogen removal via nitrite quickly and steadily.

[Effects of salinity concentration on N2O production during nitrification].

The experiment investigated the production and conversion rate of N2O during nitrification using saline sewage and municipal wastewater. Different kinds of sludge were used, domesticated by saline sewage influent (salinity 7.5 g/L) and municipal wastewater (salinity 0.1 g/L), respectively. The results showed that the production of N2O using saline sewage was 2.85 times higher than that using municipal wastewater. The production and conversion rate of N2O during nitrification under different salinities were also investigated. The results showed that the production of N2O was almost the same when salinity decreased from 7.5 g/L to 5.0 g/L, even 2.5 g/L. However, specific ammonia oxidation rate was increased with the decrease of salinity. The sudden increase of salinity, from 7.5 g/L to 10 g/L, resulted in the increase of N2O production and conversion rate but decrease of specific ammonia oxidation rate. Consequently, It is important to avoid the severe fluctuation of salinity resulted in the increase of N2O production and conversion rate.