Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

KIAA1429 regulates lung adenocarcinoma proliferation and metastasis through the PI3K/AKT pathway by modulating ARHGAP30 expression.

BACKGROUND: Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6-methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. METHODS: This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP-seq), as well as RNA stability tests to ascertain the half-life and stability of the target genes. RESULTS: The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP-seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. CONCLUSION: This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular-based interventions for LUAD.

Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1.

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy.

Construction of poly (ionic liquid)-derived gold/silver alloy@nitrogen-doped carbon shell and its application for ratiometric electrochemical detection of nitric oxide.

A nitrogen-doped carbon shell loaded with a gold and silver alloy (Au/Ag@NCS) was constructed for highly sensitive electrochemical detection of NO. The Au/Ag@NCS material was prepared by use of SiO2 particles as a template to polymerize imidazolium-based ionic liquids loaded with gold and silver salts, and subsequent carbonization treatment and template removal. The hollow structure of the carbon material acted as a carrier for electrochemical sensing, offering high specific surface area, large pore capacity, robust electron conductivity, and excellent mechanical stability. The inclusion of gold in the composite enhanced its catalytic and sensing capabilities, while silver oxidation was employed as a reference signal for accurate detection. By utilization of the Au/Ag@NCS-modified electrode, a wide detection range from 0.5 nM to 1.05 µM with a low detection limit of 0.32 nM was achieved for NO detection. The electrochemical sensor also exhibited high selectivity and excellent stability. The fabricated sensor was further utilized to explore the release of NO from breast cancer cells, revealing that the electrochemical platform could be regarded as an important method to study the daily tests of NO in clinical application.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Progress in approved drugs from natural product resources.

Natural products (NPs) have consistently played a pivotal role in pharmaceutical research, exerting profound impacts on the treatment of human diseases. A significant proportion of approved molecular entity drugs are either directly derived from NPs or indirectly through modifications of NPs. This review presents an overview of NP drugs recently approved in China, the United States, and other countries, spanning various disease categories, including cancers, cardiovascular and cerebrovascular diseases, central nervous system disorders, and infectious diseases. The article provides a succinct introduction to the origin, activity, development process, approval details, and mechanism of action of these NP drugs.

Insight into the Storage Mechanism of Sandwich-Like Molybdenum Disulphide/Carbon Nanofibers Composite in Aluminum-Ion Batteries.

Aluminum-ion batteries (AIBs) have become a research hotspot in the field of energy storage due to their high energy density, safety, environmental friendliness, and low cost. However, the actual capacity of AIBs is much lower than the theoretical specific capacity, and their cycling stability is poor. The exploration of energy storage mechanisms may help in the design of stable electrode materials, thereby contributing to improving performance. In this work, molybdenum disulfide (MoS2) was selected as the host material for AIBs, and carbon nanofibers (CNFs) were used as the substrate to prepare a molybdenum disulfide/carbon nanofibers (MoS2/CNFs) electrode, exhibiting a residual reversible capacity of 53 mAh g-1 at 100 mA g-1 after 260 cycles. The energy storage mechanism was understood through a combination of electrochemical characterization and first-principles calculations. The purpose of this study is to investigate the diffusion behavior of ions in different channels in the host material and its potential energy storage mechanism. The computational analysis and experimental results indicate that the electrochemical behavior of the battery is determined by the ion transport mechanism between MoS2 layers. The insertion of ions leads to lattice distortion in the host material, significantly impacting its initial stability. CNFs, serving as a support material, not only reduce the agglomeration of MoS2 grown on its surface, but also effectively alleviate the volume expansion caused by the host material during charging and discharging cycles.

Enhanced Fe(ii)/Fe(iii) cycle by boron enabled efficient Cr(vi) removal with microscale zero-valent iron.

Recently, researchers have been paying much attention to zero-valent iron (ZVI) in the field of pollution remediation. However, the depressed electron transport from the iron reservoir to the iron oxide shell limited the wide application of ZVI. This study was aimed at promoting the performance of microscale ZVI (mZVI) for hexavalent chromium (Cr(vi)) removal by accelerating iron cycle with the addition of boron powder. It was found that the addition of boron powder enhanced the Cr(vi) removal rate by 2.1 times, and the proportion of Cr(iii) generation after Cr(vi) removal process also increased, suggesting that boron could promote the reduction pathway of Cr(vi) to Cr(iii). By further comparing the Cr(vi) removal percentage of Fe(iii) with or without the boron powder, we found that boron powder could promote the percentage removal of Cr(vi) with Fe(iii) from 10.1% to 33.6%. Moreover, the presence of boron powder could decrease the potential gap values (ΔEp) between Fe(iii) reduction and Fe(ii) oxidation from 0.668 V to 0.556 V, further indicating that the added boron powder could act as an electron sacrificial agent to promote the reduction process of Fe(iii) to Fe(ii), and thus enhancing the reduction of Cr(vi) with Fe(ii). This study shed light on the promoted mechanism of Cr(vi) removal with boron powder and provided an environmentally friendly and efficient approach to enhance the reactivity of the mZVI powder, which would benefit the wide application of mZVI technology in the environmental remediation field.

Microbiomes in pancreatic cancer can be an accomplice or a weapon.

Recently, several investigations have linked the microbiome to pancreatic cancer progression. It is critical to reveal the role of different microbiomes in the occurrence, development, and treatment of pancreatic cancer. The current review summarizes the various microbiota types in pancreatic cancer while updating and supplementing the mechanisms of the representative gut, pancreatic, and oral microbiota, and their metabolites during its pathogenesis and therapeutic intervention. Several novel strategies have been introduced based on the tumor-associated microbiome to optimize the early diagnosis and prognosis of pancreatic cancer. The pros and cons involving different microbiomes in treating pancreatic cancer are discussed. The microbiome-related clinical trials for pancreatic cancer theranostics are outlined. This convergence of cutting-edge knowledge will provide feasible ideas for developing innovative therapies against pancreatic cancer.

Facile electrochemiluminescence sensing platform based on Gd2O3:Eu3+ nanocrystals for organophosphorus pesticides detection in vegetable samples.

In this work, europium ion-doped gadolinium trioxide nanocrystals (Gd2O3:Eu3+ NCs) were successfully synthesized and applied to construct an electrochemiluminescence (ECL) sensor. Compared with pure Gd2O3, the doping of Eu3+ ions caused enhanced ECL intensity and more stable signals. Based on the excellent ECL performance of Gd2O3:Eu3+ NCs, we constructed a new ECL sensing platform for the detection of organophosphorus pesticides (OPs). The ECL sensor showed a good linear relationship in the concentration range of 1 nM to 1 pM, with a limit of detection of 0.12 pM (S/N = 3) for dichlorvos (DDVP). In addition, the constructed ECL sensor was applied for the detection of DDVP in vegetable samples, and good recoveries were obtained. The results indicated that the ECL sensor exhibited fantastic performance properties and had good application prospects in OPs detection.

A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.

Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.

Fully bio-based epoxy resins from lignin and epoxidized soybean oil: Rigid-flexible, tunable properties and high lignin content.

The application of epoxidized soybean oil (ESO) in thermosetting polymers is impeded by its unsatisfactory thermomechanical properties. Here, in order to address the limitation, technical lignin was modified by tung oil anhydride and then used as the hardener to compensate for the inherent flexibility defects of ESO thermosets (TLs). As the lignin content increased, a notable improvement in the activation energy of TLs was observed, attributed to the restraining effect of lignin's rigid structure on segmental relaxation. Concurrently, the tensile strength of TLs increased from 2.8 MPa to 34.0 MPa, concomitant with a decrease in elongation at break from 32.9 % to 8.0 %. Comparative analysis with TL-0 (devoid of lignin) demonstrated substantial enhancements in glass transition temperature, shape fixation ratio, and shape recovery ratio for TL-50 (comprising 50 wt% of lignin), elevating from 16.9 °C, 89.1 %, and 89.5 % to 118.6 °C, 94.0 %, and 99.3 %, respectively. These results unequivocally highlight the favorable dynamic mechanical and shape memory properties conferred upon TLs by lignin addition. While the introduction of lignin adversely affected thermal stability, a notable improvement in char yield (800 °C) was observed. Collectively, these findings underscore the potential of technical lignin as a promising bio-based curing agent for ESO.

Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy.

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e, encoded KWLX-12e, with good inhibitory activity against PARP1 (IC50 = 6.89 nM) and EZH2 (IC50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC50 = 2.84 µM) and BT-549 cells (IC50 = 0.91 µM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.

Plantago asiatica L. polysaccharides: Physiochemical properties, structural characteristics, biological activity and application prospects: A review.

Plantago asiatica L. (PAL), a traditional herb, has been used in East Asia for thousands of years. In recent years, polysaccharides extracted from PAL have garnered increased attention due to their outstanding pharmacological and biological properties. Previous research has established that PAL-derived polysaccharides exhibit antioxidant, anti-inflammatory, antidiabetic, antitumor, antimicrobial, immune-regulatory, intestinal health-promoting, antiviral, and other effects. Nevertheless, a comprehensive summary of the research related to Plantago asiatica L. polysaccharides (PALP) has not been reported to date. In this paper, we review the methods for isolation and purification, physiochemical properties, structural features, and biological activities of PALP. To provide a foundation for research and application in the fields of medicine and food, this review also outlines the future development prospects of plantain polysaccharides.

Evaluating the effect of body mass index and 25-hydroxy-vitamin D level on basal cell carcinoma using Mendelian randomization.

Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[- 0.22, - 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.

Nanomedicine-mediated regulated cell death in cancer immunotherapy.

Immunotherapy has attracted widespread attention in cancer treatment and has achieved considerable success in the clinical treatment of some tumors, but it has a low response rate in most tumors. To achieve sufficient activation of the immune response, significant efforts using nanotechnology have been made to enhance cancer immune response. In recent years, the induction of various regulated cell death (RCD) has emerged as a potential antitumor immuno-strategy, including processes related to apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and cuproptosis. In particular, damage-associated molecular patterns (DAMPs) released from the damaged membrane of dying cells act as in situ adjuvants to trigger antigen-specific immune responses by the exposure of an increased antigenicity. Thus, RCD-based immunotherapy offers a new approach for enhancing cancer treatment efficacy. Furthermore, incorporation with multimodal auxiliary therapies in cell death-based immunotherapy can trigger stronger immune responses, resulting in more efficient therapeutic outcome. This review discusses different RCD modalities and summarizes recent nanotechnology-mediated RCDs in cancer immunotherapy.

Indirubin derivatives as bifunctional molecules inducing DNA damage and targeting PARP for the treatment of cancer.

Based on the facts that significant synergistic effect existed between PARP inhibitors and DNA damage agents and the DNA damage caused by indirubin's derivatives, we herein adopted the strategy to combine the pharmacophores of PARP inhibitors and the unique scaffold of indirubin to design a series of bifunctional molecules inducing DNA damage and targeting PARP. After SAR studies, the most potent compound 12a, encoded as KWWS-12a, exhibited improved inhibitory effect against PARP1 compared with PARP1 inhibitor Olaparib (IC50 = 1.89 nM vs 7.48 nM) and enhanced antiproliferative activities than the combination of Olaparib and indirubin-3'-monoxime towards HCT-116 cells (IC50 = 0.31 µM vs 1.37 µM). In the normal NCM-460 cells, 12a showed low toxicity (IC50 > 60 µM). The mechanism research indicated that 12a could increase the levels of γH2AX concentration dependently, arrest the cell cycle in S phase and induce apoptosis in HCT-116 cells. In vivo experiments showed that 12a displayed more significant antitumor potential than that of the positive controls. Our studies demonstrated that 12a could be a promising candidate for cancer therapy.

Non-invasive diagnosis of primary Sjögren's syndrome using ultrasonography and transcriptome biomarkers.

Diagnosing primary Sjögren's syndrome (pSS) is difficult due to clinical heterogeneity and the absence of non-invasive specific biomarkers. To develop non-invasive pSS diagnosis methods that integrate classic clinical indexes, major salivary gland ultrasonography (SGUS), and gene expression profiles shared by labial gland and peripheral blood, we conducted a study on a cohort of 358 subjects. We identified differentially expressed genes (DEGs) in glands and blood that were enriched in defense response to virus and type I interferon production pathways. Four upregulated DEGs common in glands and blood were identified as hub genes based on the protein-protein interaction networks. A random forest model was trained using features, including SGUS, anti-SSA/Ro60, keratoconjunctivitis sicca tests, and gene expression levels of MX1 and RSAD2. The model achieved comparable pSS diagnosis accuracy to the golden standard method based on labial gland biopsy. Our findings implicate this novel model as a promising diagnosis technique of pSS.

Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy.

Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.

Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA.

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC50 = 1.96 µM), MDA-MB-468 (IC50 = 2.81 µM) and BT-549 (IC50 = 2.37 µM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10-20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.