Analysis of clinical characteristics of mismatch repair status in colorectal cancer: a multicenter retrospective study.

BACKGROUND: Microsatellite instability (MSI) caused by DNA mismatch repair (MMR) deficiency is of great significance in the occurrence, diagnosis and treatment of colorectal cancer (CRC). AIM: This study aimed to analyze the relationship between mismatch repair status and clinical characteristics of CRC. METHODS: The histopathological results and clinical characteristics of 2029 patients who suffered from CRC and underwent surgery at two centers from 2018 to 2020 were determined. After screening the importance of clinical characteristics through machine learning algorithms, the patients were divided into deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) groups based on the immunohistochemistry results and the clinical feature data between the two groups were observed by statistical methods. RESULTS: The dMMR and pMMR groups had significant differences in histologic type, TNM stage, maximum tumor diameter, lymph node metastasis, differentiation grade, gross appearance, and vascular invasion. There were significant differences between the MLH1 groups in age, histologic type, TNM stage, lymph node metastasis, tumor location, and depth of invasion. The MSH2 groups were significantly different in age. The MSH6 groups had significant differences in age, histologic type, and TNM stage. There were significant differences between the PMS2 groups in lymph node metastasis and tumor location. CRC was dominated by MLH1 and PMS2 combined expression loss (41.77%). There was a positive correlation between MLH1 and MSH2 and between MSH6 and PMS2 as well. CONCLUSIONS: The proportion of mucinous adenocarcinoma, protruding type, and poor differentiation is relatively high in dMMR CRCs, but lymph node metastasis is rare. It is worth noting that the expression of MMR protein has different prognostic significance in different stages of CRC disease.

Proteomic profiling of laser capture microdissection kidneys from diabetic nephropathy patients.

Diabetic nephropathy (DN) remains the primary cause of end-stage renal disease (ESRD), warranting equal attention and separate analysis of glomerular, tubular, and interstitial lesions in its diagnosis and intervention. This study aims to identify the specific proteomics characteristics of DN, and assess changes in the biological processes associated with DN. 5 patients with DN and 5 healthy kidney transplant donor control individuals were selected for analysis. The proteomic characteristics of glomeruli, renal tubules, and renal interstitial tissue obtained through laser capture microscopy (LCM) were studied using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Significantly, the expression of multiple heat shock proteins (HSPs), tubulins, and heterogeneous nuclear ribonucleoproteins (hnRNPs) in glomeruli and tubules was significantly reduced. Differentially expressed proteins (DEPs) in the glomerulus showed significant enrichment in pathways related to cell junctions and cell movement, including the regulation of actin cytoskeleton and tight junction. DEPs in renal tubules were significantly enriched in glucose metabolism-related pathways, such as glucose metabolism, glycolysis/gluconeogenesis, and the citric acid cycle. Moreover, the glycolysis/gluconeogenesis pathway was a co-enrichment pathway in both DN glomeruli and tubules. Notably, ACTB emerged as the most crucial protein in the protein-protein interaction (PPI) analysis of DEPs in both glomeruli and renal tubules. In this study, we delve into the unique proteomic characteristics of each sub-region of renal tissue. This enhances our understanding of the potential pathophysiological changes in DN, particularly the potential involvement of glycolysis metabolic disorder, glomerular cytoskeleton and cell junctions. These insights are crucial for further research into the identification of disease biomarkers and the pathogenesis of DN.

Intercage Polymerization of Postfunctionalized Phosphine Organic Prisms into Cage-Based Assemblies with Tunable Morphologies.

Great effort has been dedicated to the engineering of porous organic cages (POCs) in geometry and topology. Yet, harnessing these cage-like entities as premade building units to construct infinite cage-based superstructures remains elusive. In this study, we design a type of vertex-modified phosphine organic prism by a postfunctionalized approach and use it as a ditopic cage monomer to achieve an intercage supramolecular polymerization via the synergy of metal coordination and π-π dimerization. The resulting cage-by-cage polymers can further hierarchically organize into superstructures of diverse morphologies and dimensionalities, including 1D fibers, 2D lamellae, and 3D vesicles. Control over the cosolvents is capable of well regulating their structural hierarchies and self-assembled shapes. This would pave a way for the creation of cage-based supramolecular assemblies and nanomaterials.

Click method preserves but EDC method compromises the therapeutic activities of the peptide-activated hydrogels for critical ischemic vessel regeneration.

Peptide-functionalized hydrogel is one of commonly used biomaterials to introduce hydrogel-induced vessel regeneration. Despite many reports about the discoveries of high-active peptides (or ligands) for regeneration, the study on the conjugating methods for the hydrogel functionalization with peptides is limited. Here, we compared the vasculogenic efficacy of the peptide-functionalized hydrogels prepared by two commonly used conjugating methods, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) and Click methods, through cell models, organ-on-chips models, animal models, and RNA sequencing analysis. Two vascular-related cell types, the human umbilical vein endothelial cells (HUVECs) and the adipose-derived stem cells (ADSCs), have been cultured on the hydrogel surfaces prepared by EDC/Click methods. It showed that the hydrogels prepared by Click method supported the higher vasculogenic activities while the ones made by EDC method compromised the peptide activities on hydrogels. The vasculogenesis assays further revealed that hydrogels prepared by Click method promoted a better vascular network formation. In a critical ischemic hindlimb model, only the peptide-functionalized hydrogels prepared by Click method successfully salvaged the ischemic limb, significantly improved blood perfusion, and enhanced the functional recoveries (through gait analysis and animal behavior studies). RNA sequencing studies revealed that the hydrogels prepared by Click method significantly promoted the PI3K-AKT pathway activation compared to the hydrogels prepared by EDC method. All the results suggested that EDC method compromised the functions of the peptides, while Click method preserved the vascular regenerating capacities of the peptides on the hydrogels, illustrating the importance of the conjugating method during the preparation of the peptide-functionalized hydrogels.

Cage-by-cage supramolecular polymerization via panel-decorated triphenylphosphine organic cage.

Significant efforts have been dedicated to designing porous organic cage compounds with geometric complexity and topological diversity. However, the use of these cage molecules as premade building units for constructing infinite cage-based superstructures remains unexplored. Here, we report the use of a panel-decorated phosphine organic cage as a special monomer to achieve supramolecular polymerization, resulting in cage-by-cage noncovalent polymers through the synergy of metal-coordination and intercageπ-πdimerization. At a monomer concentration of 122 mM, the average degree of polymerization reaches 17, corresponding to a molecular weight of 26 kDa. The obtained cage-based supramolecular polymers can further hierarchically self-assemble into vesicular morphologies or one-dimensional nanofiber architectures. Selective control over the cosolvents can regulate their structural hierarchy and assembled morphology. This approach paves a new way for the construction of cage-based hierarchical assemblies and materials.

Active surveillance of hepatitis E: a 10-year epidemiological analysis in a city in eastern China.

Hepatitis E virus (HEV) is an important cause of acute hepatitis, however, is highly neglected and largely underreported. This study aimed to describe the detailed epidemiology of hepatitis E (HE) through a 10-year surveillance. A community-based active hepatitis surveillance was conducted between November 2007 and October 2017 in 11 townships of Dongtai City in China, involving 355,673 residents. Serum samples were obtained from patients presenting with hepatitis symptoms for more than 3 days. Serum alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (ULN) were considered acute hepatitis. Samples were subsequently tested for IgG and IgM anti-HEV antibodies, HEV RNA, and hepatitis B surface antigen (HBsAg). The data indicated the incidence of HE fluctuated downward from 2007 to 2017, with an average annual age-standardized incidence of 17.50 per 100,000, exceeding the 10.26 per 100,000 in the National Notifiable Disease Report System (NNDRS). The incidence was notably higher among males (20.95 per 100,000) and individuals aged 50-69 years (37.47 per 100,000). Genotype 4 (HEV-4) was the predominantly circulating genotype during the study period. Furthermore, the study revealed the incidence of hepatitis with HEV and hepatitis B virus (HBV) co-infection was 4.99 per 100,000. The active surveillance system identified a higher incidence of HE compared to NNDRS, with a decreased prevalence over a 10-year period. While efforts are still needed to prevent HE in high-risk populations, including individuals with hepatitis B and the elderly.

Isobavachalcone: A redox antifungal agent impairs the mitochondria protein of Cryptococcus neoformans.

Isobavachalcone (IBC) is a natural small molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration was 0.5-1 µg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate production, and an increase in hydrogen peroxide (H2O2) caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and minimum inhibitory concentration detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of adenosine triphosphate, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.

Gas-Responsive and Gas-Releasing Polymer Assemblies.

In order to explore the unique physiological roles of gas signaling molecules and gasotransmitters in vivo, chemists have engineered a variety of gas-responsive polymers that can monitor their changes in cellular milieu, and gas-releasing polymers that can orchestrate the release of gases. These have advanced their potential applications in the field of bio-imaging, nanodelivery, and theranostics. Since these polymers are of different chain structures and properties, the morphology of their assemblies will manifest distinct transitions after responding to gas or releasing gas. In this review, we summarize the fundamental design rationale of gas-responsive and gas-releasing polymers in structure and their controlled transition in self-assembled morphology and function, as well as present some perspectives in this prosperous field. Emerging challenges faced for the future research are also discussed.

A Reference Profile of N-Glycosylation for Human Kidney and the Identification of Cell-Cell Interactions between Parietal Epithelial Cells and Capillary Endothelial Cells by Single-Cell Glycosylation-Sequencing.

BACKGROUND: N-glycosylation is one of the most common posttranslational modifications in humans, and these alterations are associated with kidney diseases. METHODS: A novel technological approach, single-cell N-acetyllactosamine sequencing (scLacNAc-seq), was applied to simultaneously detect N-glycosylation expression and the transcriptome at single-cell resolution in three human kidney tissues from zero-time biopsy. Cell clusters, glycation abundance in each cell cluster, functional enrichment analysis, cell-cell crosstalk, and pseudotime analysis were applied. RESULTS: Using scLacNAc-seq, 24,247 cells and 22 cell clusters were identified, and N-glycan abundance in each cell was obtained. Transcriptome analysis revealed a close connection between capillary endothelial cells (CapECs) and parietal epithelial cells (PECs). PECs and CapECs communicate with each other through several pairs of ligand receptors (e.g., TGFB1-EGFR, GRN-EGFR, TIMP1-FGFR2, VEGFB-FLT1, ANGPT2-TEK, and GRN-TNFRSF1A). Finally, a regulatory network of cell-cell crosstalk between PECs and CapECs was constructed, which is involved in cell development. CONCLUSIONS: We here, for the first time, constructed the glycosylation profile of 22 cell clusters in the human kidney from zero-time biopsy. Moreover, cell-cell communication between PECs and CapECs through the ligand-receptor system may play a crucial regulatory role in cell proliferation.

High-fidelity single logical qubit encoding scheme assisted by single-sided quantum dot-cavity systems.

We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.

Safety and efficacy of a programmed cell death 1 inhibitor combined with oxaliplatin plus S-1 in patients with Borrmann large type III and IV gastric cancers.

BACKGROUND: Gastric cancer (GC) is the fifth most common and the fourth most lethal malignant tumour in the world. Most patients are already in the advanced stage when they are diagnosed, which also leads to poor overall survival. The effect of postoperative adjuvant chemotherapy for advanced GC is unsatisfactory with a high rate of distant metastasis and local recurrence. AIM: To investigate the safety and efficacy of a programmed cell death 1 (PD-1) inhibitor combined with oxaliplatin and S-1 (SOX) in the treatment of Borrmann large type III and IV GCs. METHODS: A retrospective analysis (IRB-2022-371) was performed on 89 patients with Borrmann large type III and IV GCs who received neoadjuvant therapy (NAT) from January 2020 to December 2021. According to the different neoadjuvant treatment regimens, the patients were divided into the SOX group (61 patients) and the PD-1 + SOX (P-SOX) group (28 patients). RESULTS: The pathological response (tumor regression grade 0/1) in the P-SOX group was significantly higher than that in the SOX group (42.86% vs 18.03%, P = 0.013). The incidence of ypN0 in the P-SOX group was higher than that in the SOX group (39.29% vs 19.67%, P = 0.05). The use of PD-1 inhibitors was an independent factor affecting tumor regression grade. Meanwhile, the use of PD-1 did not increase postoperative complications or the adverse effects of NAT. CONCLUSION: A PD-1 inhibitor combined with SOX could significantly improve the rate of tumour regression during NAT for patients with Borrmann large type III and IV GCs.

Cinnamaldehyde: An effective component of Cinnamomum cassia inhibiting Helicobacter pylori.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Cinnamomum cassia) is a common traditional Chinese medicine, which can promote the secretion and digestion of gastric juice, improve the function of gastrointestinal tract. Cinnamaldehyde (CA) is a synthetic food flavoring in the Chinese Pharmacopoeia. AIM OF THE STUDY: This study aimed to search for the active ingredient (CA) of inhibiting H. pylori from Cinnamomum cassia, and elucidate mechanism of action, so as to provide the experimental basis for the treatment of H. pylori infection with Cinnamomum cassia. MATERIALS AND METHODS: It's in vitro and in vivo pharmacological properties were evaluated based on minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and an acute gastric inflammation model in mice infected with H. pylori. Drug safety was evaluated using the CCK8 method and high-dose administration in mice. The advantageous characteristics of CA in inhibiting H. pylori were confirmed using acidic conditions and in combination with the antibiotics. The mechanism underlying the action of CA on H. pylori was explored using scanning electron microscopy (SEM), adhesion experiments, biofilm inhibition tests, ATP and ROS release experiments, and drug affinity responsive target stability (DARTS) screening of target proteins. The protein function and target genes were verified by molecular docking and Real-Time quantitative reverse transcription PCR (qRT-PCR). RESULTS: The results demonstrated that CA was found to be the main active ingredient against H. pylori in Cinnamomum cassia in-vitro tests, with a MIC of 8-16 µg/mL. Moreover, CA effectively inhibited both sensitive and resistant H. pylori strains. The dual therapy of PPI + CA exhibited remarkable in vivo efficacy in the acute gastritis mouse model, superior to the standard triple therapy. DARTS, molecular docking, and qRT-PCR results suggested that the target sites of action were closely associated with GyrA, GyrB, AtpA, and TopA, which made DNA replication and transcription impossible, then leading to inhibition of bacterial adhesion and colonization, suppression of biofilm formation, and inhibition ATP and enhancing ROS. CONCLUSIONS: This study demonstrated the suitability of CA as a promising lead drug against H. pylori, The main mechanisms can target GyrA ect, leading to reduce ATP and produce ROS, which induces the apoptosis of bacterial.

Accumulation of docosapentaenoic acid (n-3 DPA) in a novel isolate of the marine ichthyosporean Sphaeroforma arctica.

OBJECTIVE: Currently, there is lack of a consistent and highly enriched source for docosapentaenoic acid (n-3 DPA, C22:5), and this work report the isolation of microorganism that naturally produces n-3 DPA. RESULTS: In this work, we screened microorganisms in our culture collections with the goal to isolate a strain with high levels of n-3 DPA. We isolated a strain of Sphaeroforma arctica that produces up to 11% n-3 DPA in total fatty acid and has a high n-3 DPA to DHA/EPA ratio. The cell growth of the isolated strain was characterized using microscopy imaging and flow cytometer technologies to confirm the coenocytic pattern of cell divisions previously described in S. arctica. Our novel isolate of S. arctica grew more robustly and produced significantly more n-3 DPA compared to previously isolated and described strains indicating the uniqueness of the discovered strain. CONCLUSION: Overall, this work reports a first isolate n-3 DPA producing microorganism and establishes the foundation for future strain improvement and elucidation of the physiological function of this LC-PUFA for human nutrition and health.

Clinical Effect of Vitamin E Combined with Recombinant Human Epidermal Growth Factor on the Recurrent Oral Ulcer and Effects of Serum Superoxide Dismutase, IL-10, and TNF-α.

Objective: To examine the therapeutic effects of vitamin E combined with recombinant human epidermal growth factor on recurrent oral ulcers as well as on the levels of serum superoxide dismutase (SOD), interleukin-10 (IL-10), and tumor necrosis factor- (TNF-α), to provide evidence to facilitate medical management. Method: From June 2021 to May 2022, 84 patients with recurrent oral ulcers assessed and treated in our hospital were assigned to the control group and observation group with 42 cases in each group. Vitamin E was administered to the control group, while recombinant human epidermal growth factor and vitamin E were administered to the observation group. The clinical efficacy, serum SOD level, inflammatory factor level (IL-10, TNF-α), immune function index, clinical symptom improvement, pain disappearance time, healing time of ulcer surface, and adverse reactions were examined. Results: Clinical efficacy of the observation group (92.86%) was considerably greater than the control group (73.81%), (P < .05). Following treatment, the observation group had comparatively higher levels of serum SOD and significantly decreased TNF-α and IL-10 concentrations compared to the control group (P < .05). Similarly, post-treatment, the observation group had substantially higher CD3+, CD4+, and CD4+/CD8+ concentrations and lower CD8+ concentrations compared to the normal control (P < .05). In contrast to the control group, the observation group's pain degree score, ulcer diameter, duration for pain relief, and ulcer surface healing time duration were reduced substantially (P < .05). Notably, the incidence of adverse reactions was fairly similar in both groups (P > .05). Conclusion: Vitamin E combined with recombinant human epidermal growth factor has a significant clinical effect on recurrent oral ulcers, can achieve rapid improvement of symptoms in patients, and is relatively safe to be used as a clinical therapy.

Access to N-Aryl (Iso)quinolones via Aryne-Induced Three-Component Coupling Reaction.

N-Aryl (iso)quinolones are of increasing interest in material and medicinal chemistry, although general routes for their provision remain underexplored, especially when compared with its N-alkyl counterparts. Herein, we report a modular and transition-metal-free, aryne-induced three-component coupling protocol that allows the facile synthesis of structurally diverse N-aryl (iso)quinolones from readily accessible halo-(iso)quinolines in the presence of water. Preliminary results highlight the applicability of our method through scale-up synthesis, downstream derivatization, and flexible synthesis involving other types of aryne precursors.

Engineering Dual CO2- and Photothermal-Responsive Membranes for Switchable Double Emulsion Separation.

Stimulus-responsive membranes demonstrate promising applications in switchable oil/water emulsion separations. However, they are unsuitable for the treatment of double emulsions like oil-in-water-in-oil (O/W/O) and water-in-oil-in-water (W/O/W) emulsions. For efficient separation of these complicated emulsions, fine control over the wettability, response time, and aperture structure of the membrane is required. Herein, dual-coated fibers consisting of primary photothermal-responsive and secondary CO2-responsive coatings are prepared by two steps. Automated weaving of these fibers produces membranes with photothermal- and CO2-responsive characteristics and narrow pore size distributions. These membranes exhibit fast switching wettability between superhydrophilicity (under CO2 stimulation) and high hydrophobicity (under near-infrared stimulation), achieving on-demand separation of various O/W/O and W/O/W emulsions with separation efficiencies exceeding 99.6%. Two-dimensional low-field nuclear magnetic resonance and correlated spectra technique are used to clarify the underlying mechanism of switchable double emulsion separation. The approach can effectively address the challenges associated with the use of stimulus-responsive membranes for double emulsion separation and facilitate the industrial application of these membranes.

Influence of the brain­gut axis on neuroinflammation in cerebral ischemia­reperfusion injury (Review).

Stroke, a debilitating cerebrovascular ailment, poses significant threats to human life and health. The intricate interplay between the gut­brain­microbiota axis (GBMA) and cerebral ischemia­reperfusion has increasingly become a focal point of scientific exploration, emerging as a pivotal research avenue in stroke pathophysiology. In the present review, the authors delved into the nexus between the GBMA and neuroinflammation observed post­stroke. The analysis underscored the pivotal roles of histone deacetylase 3 and neutrophil extracellular traps subsequent to stroke incidents. The influence of gut microbial compositions and their metabolites, notably short­chain fatty acids and trimethylamine N­oxide, on neuroinflammatory processes, was further elucidated. The involvement of immune cells, especially regulatory T­cells, and the intricate signaling cascades including cyclic GMP­AMP synthase/stimulator of interferon genes/Toll­like receptor, further emphasized the complex regulatory mechanisms of GBMA in cerebral ischemia/reperfusion injury (CI/RI). Collectively, the present review offered a comprehensive perspective on the metabolic, immune and inflammatory modulations orchestrated by GBMA, augmenting the understanding of its role in neuroinflammation following CI/RI.

Establishment and Validation of a Transdermal Drug Delivery System for the Anti-Depressant Drug Citalopram Hydrobromide.

To enhance the bioavailability and antihypertensive effect of the anti-depressant drug citalopram hydrobromide (CTH) we developed a sustained-release transdermal delivery system containing CTH. A transdermal diffusion meter was first used to determine the optimal formulation of the CTH transdermal drug delivery system (TDDS). Then, based on the determined formulation, a sustained-release patch was prepared; its physical characteristics, including quality, stickiness, and appearance, were evaluated, and its pharmacokinetics and irritation to the skin were evaluated by applying it to rabbits and rats. The optimal formulation of the CTH TDDS was 49.2% hydroxypropyl methyl cellulose K100M, 32.8% polyvinylpyrrolidone K30, 16% oleic acid-azone, and 2% polyacrylic acid resin II. The system continuously released an effective dose of CTH for 24 h and significantly enhanced its bioavailability, with a higher area under the curve, good stability, and no skin irritation. The developed CTH TDDS possessed a sustained-release effect and good characteristics and pharmacokinetics; therefore, it has the potential for clinical application as an antidepressant.

Digital PCR for Single-Cell Analysis.

Single-cell analysis provides an overwhelming strategy for revealing cellular heterogeneity and new perspectives for understanding the biological function and disease mechanism. Moreover, it promotes the basic and clinical research in many fields at a single-cell resolution. A digital polymerase chain reaction (dPCR) is an absolute quantitative analysis technology with high sensitivity and precision for DNA/RNA or protein. With the development of microfluidic technology, digital PCR has been used to achieve absolute quantification of single-cell gene expression and single-cell proteins. For single-cell specific-gene or -protein detection, digital PCR has shown great advantages. So, this review will introduce the significance and process of single-cell analysis, including single-cell isolation, single-cell lysis, and single-cell detection methods, mainly focusing on the microfluidic single-cell digital PCR technology and its biological application at a single-cell level. The challenges and opportunities for the development of single-cell digital PCR are also discussed.