Integrating HYDRUS-2D and Bayesian Networks for simulating long-term sludge land application: Uncovering heavy metal mobility and pollution risk in the soil-groundwater environment.

The release of sludge-derived heavy metals (HMs) to soil and their subsequent migration into groundwater poses a significant challenge for safe and low-carbon sludge land application. This study developed a predictive framework to simulate 60-year sludge land application, evaluating the risk of HMs pollution in the soil-groundwater environment and assessing the influence of soil and water properties. HYDRUS-2D simulations revealed that highly mobile Cu, Ni, and Zn penetrated a 10 m soil layer over a 60-year period, contributing to groundwater pollution. In contrast, Cr was easily sequestered within the topsoil layer after 5-years continuous operation. The non-equilibrium parameter α could serve as an indicator for assessing their potential risk. Furthermore, the limited soil adsorption sites for Pb (f = 0.02772) led to short-term (1-year) groundwater pollution at a 0.5 m-depth. Bayesian Networks model outcomes indicated that humic-like organics crucially influenced HMs transformation, enhancing the desorption of Cd, Cu, Ni, Pb, and Zn, while inhibiting the desorption for Cr. Additionally, electrical conductivity promoted the release of most HMs, in contrast to the Mn mineralogy in soil. This study bridges the gap between the macro-level HMs migration trends and the micro-level adsorption-desorption characteristics, providing guidance for the safe land application of sewage sludge. ENVIRONMENTAL IMPLICATION: This study introduces a framework integrating HYDRUS-2D simulations with Bayesian Networks to assess the risks of groundwater pollution by heavy metals (HMs) over a 60-year sludge application. Sludge-derived Cu, Ni, and Zn are found to penetrate soil up to 10 m and exceed safety limits, with the non-equilibrium parameter α serving as an indicator for pollution risk. The importance of nutrients from sludge-amended soil for the transformation of HMs in the subsurface environment highlights the need for enhanced sludge management, specifically through more detailed regulation of nutrient composition. These findings contribute to developing precise strategies for the long-term sludge land application.

Bicyclol mitigates lipopolysaccharide-induced acute lung injury through myeloid differentiation factor 88 inhibition.

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses.

Impact of co-substrate molecular weight on methane production potential, microbial community dynamics, and metabolic pathways in waste activated sludge anaerobic co-digestion.

Proteins and carbohydrates are important organics in waste activated sludge, and greatly affect methane production and microbial community composition in anaerobic digestion systems. Here, a series of co-substrates with different molecular weight were applied to investigate the interactions between microbial dynamics and the molecular weight of co-substrates. Biochemical methane production assays conducted in batch co-digesters showed that feeding high molecular weight protein and carbohydrate substrates resulted in higher methane yield and production rates. Moreover, high-molecular weight co-substrates increased the microbial diversity, enriched specific microbes including Longilinea, Anaerolineaceae, Syner-01, Methanothrix, promoted acidogenic and acetoclastic methanogenic pathways. Low-molecular weight co-substrates favored the growth of JGI-0000079-D21, Armatimonadota, Methanosarcina, Methanolinea, and improved hydrogenotrophic methanogenic pathway. Besides, Methanoregulaceae and Methanolinea were indicators of methane yield. This study firstly revealed the complex interactions between co-substrate molecular weight and microbial communities, and demonstrated the feasibility of adjusting co-substrate molecular weight to improve methane production process.

TMC7 functions as a suppressor of Piezo2 in primary sensory neurons blunting peripheral mechanotransduction.

The transmembrane channel-like (TMC) protein family comprises eight members, with TMC1 and TMC2 being extensively studied. This study demonstrates substantial co-expression of TMC7 with the mechanosensitive channel Piezo2 in somatosensory neurons. Genetic deletion of TMC7 in primary sensory ganglia neurons in vivo enhances sensitivity in both physiological and pathological mechanosensory transduction. This deletion leads to an increase in proportion of rapidly adapting (RA) currents conducted by Piezo2 in dorsal root ganglion (DRG) neurons and accelerates RA deactivation kinetics. In HEK293 cells expressing both proteins, TMC7 significantly suppresses the current amplitudes of co-expressed Piezo2. Our findings reveal that TMC7 and Piezo2 exhibit physical interactions, and both proteins also physically interact with cytoskeletal ß-actin. We hypothesize that TMC7 functions as an inhibitory modulator of Piezo2 in DRG neurons, either through direct inhibition or by disrupting the transmission of mechanical forces from the cytoskeleton to the channel.

The transmembrane channel-like 6 (TMC6) in primary sensory neurons involving thermal sensation via modulating M channels.

Introduction: The transmembrane channel-like (TMC) protein family contains eight members, TMC1-TMC8. Among these members, only TMC1 and TMC2 have been intensively studied. They are expressed in cochlear hair cells and are crucial for auditory sensations. TMC6 and TMC8 contribute to epidermodysplasia verruciformis, and predispose individuals to human papilloma virus. However, the impact of TMC on peripheral sensation pain has not been previously investigated. Methods: RNAscope was employed to detect the distribution of TMC6 mRNA in DRG neurons. Electrophysiological recordings were conducted to investigate the effects of TMC6 on neuronal characteristics and M channel activity. Zn2+ indicators were utilized to detect the zinc concentration in DRG tissues and dissociated neurons. A series of behavioural tests were performed to assess thermal and mechanical sensation in mice under both physiological and pathological conditions. Results and Discussion: We demonstrated that TMC6 is mainly expressed in small and medium dorsal root ganglion (DRG) neurons and is involved in peripheral heat nociception. Deletion of TMC6 in DRG neurons hyperpolarizes the resting membrane potential and inhibits neuronal excitability. Additionally, the function of the M channel is enhanced in TMC6 deletion DRG neurons owing to the increased quantity of free zinc in neurons. Indeed, heat and mechanical hyperalgesia in chronic pain are alleviated in TMC6 knockout mice, particularly in the case of heat hyperalgesia. This suggests that TMC6 in the small and medium DRG neurons may be a potential target for chronic pain treatment.

Mechanistic insight into the aggregation ability of anammox microorganisms: Roles of polarity, composition and molecular structure of extracellular polymeric substances.

The chemical characteristics of extracellular polymeric substances (EPS) of anammox bacteria (AnAOB) play a crucial role in the rapid enrichment of AnAOB and the stable operation of wastewater anammox processes. To clarify the influential mechanisms of sludge EPS on AnAOB aggregation, multiple parameters, including the polarity distribution, composition, and molecular structure of EPS, were selected, and their quantitative relationship with AnAOB aggregation was analyzed. Compared to typical anaerobic sludge (anaerobic floc and granular sludge), the anammox sludge EPS exhibited higher levels of tryptophan-like substances (44.82-56.52 % vs. 2.57-39.81 %), polysaccharides (40.02-53.49 mg/g VSS vs. 30.22-41.69 mg/g VSS), and protein structural units including α-helices (20.70-23.98 % vs. 16.48-19.32 %), ß-sheets (37.43-42.98 % vs. 25.78-36.72 %), and protonated nitrogen (Npr) (0.065-0.122 vs. 0.017-0.061). In contrast, it had lower contents of ß-turns (20.95-27.39 % vs. 28.17-39.04 %). These biopolymers were found to originate from different genera of AnAOB. Specifically, the α-helix-rich proteins were mainly derived from Candidatus Kuenenia, whereas the extracellular proteins related to tryptophan and Npr were closely associated with Candidatus Brocadia. Critically, these EPS components could drive anammox aggregation through interactions. Substantial amounts of tryptophan-like substances facilitated the formation of ß-sheet structures and the exposure of internal hydrophobic clusters, which benefited the anammox aggregation. Meanwhile, extracellular proteins with high Npr content played a pivotal role in the formation of mixed protein-polysaccharide gel networks with the electronegative regions of polysaccharides, which could be regarded as the key component in the maintenance of anammox sludge stability. These findings provide a comprehensive understanding of the multifaceted roles of EPS in driving anammox aggregation and offer valuable insights into the development of EPS regulation strategies aimed at optimizing the anammox process.

Urethral Microenvironment Adapted Sodium Alginate/Gelatin/Reduced Graphene Oxide Biomimetic Patch Improves Scarless Urethral Regeneration.

The nasty urine microenvironment (UME) is an inherent obstacle that hinders urethral repair due to fibrosis and swelling of the oftentimes adopted hydrogel-based biomaterials. Here, using reduced graphene oxide (rGO) along with double-freeze-drying to strengthen a 3D-printed patch is reported to realize scarless urethral repair. The sodium alginate/gelatin/reduced graphene oxide (SA/Gel/rGO) biomaterial features tunable stiffness, degradation profile, and anti-fibrosis performance. Interestingly, the 3D-printed alginate-containing composite scaffold is able to respond to Ca2+ present in the urine, leading to enhanced structural stability and strength as well as inhibiting swelling. The investigations present that the swelling behaviors, mechanical properties, and anti-fibrosis efficacy of the SA/Gel/rGO patch can be modulated by varying the concentration of rGO. In particular, rGO in optimal concentration shows excellent cell viability, migration, and proliferation. In-depth mechanistic studies reveal that the activation of cell proliferation and angiogenesis-related proteins, along with inhibition of fibrosis-related gene expressions, play an important role in scarless repair by the 3D-printed SA/Gel/rGO patch via promoting urothelium growth, accelerating angiogenesis, and minimizing fibrosis in vivo. The proposed strategy has the potential of resolving the dilemma of necessary biomaterial stiffness and unwanted fibrosis in urethral repair.

Lymphocyte recovery from radiation-induced lymphopenia in locally advanced esophageal squamous cell carcinoma: correlations with prognosis and lymphocyte-related organs.

BACKGROUND: Limited studies explored the relationship between lymphocyte recovery after definitive concurrent chemoradiotherapy (dCCRT) and prognosis in esophageal squamous cell carcinoma (ESCC). METHODS: ESCC patients with obtainable absolute lymphocyte counts (ALCs) at 6 months after dCCRT were screened from prospective trials. Patients were divided into groups according to the grade of ALC nadir during radiotherapy (G4 or G1-3) and lymphocyte recovery status, which was assessed by lymphocyte recovery index (LRI), calculated as the ratio of post- to pre-treatment lymphocyte counts. Cox analysis was conducted to evaluate the prognostic significance of lymphocyte recovery status. Irradiated relative volumes of the bone marrow (BM) and spleen and effective dose to immune cells (EDIC) were collected to identify their impacts on lymphocyte recovery status by logistic analysis. RESULTS: 232 patients were enrolled. In 69 patients with G4 ALC nadir (group A and B) and 163 patients with G1-3 ALC nadir (group C and D) during dCCRT, 27 (group A) and 67 (group C) patients showed an insufficient level of lymphocyte recovery (LRI < 60%), and 42 (group B) and 96 (group D) patients showed a satisfactory level of lymphocyte recovery (LRI ≥ 60%). Cox multivariable analysis revealed that inadequate lymphocyte recovery was significantly associated with worse overall survival (HR, 2.80 and 1.70) and local recurrence-free survival (HR, 2.82 and 1.60) both in group A vs group B and group C vs group D. Logistic analysis identified BM V5 (OR 4.24 and 2.29) as an independent predictor of inadequate lymphocyte recovery from G4 or G1-3 ALC nadir, respectively. CONCLUSIONS: Insufficient lymphocyte recovery might serve as a valuable prognostic factor, regardless of whether patients experienced G4 or G1-3 ALC nadir during radiotherapy. Additionally, it was observed that a larger relative volume of BM receiving ≥ 5 Gy was correlated with a higher risk of insufficient lymphocyte recovery.

Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis.

BACKGROUND: Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. METHODS: The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-ß1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. RESULTS: TGF-ß1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-ß1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). CONCLUSION: Pd-MSCs-EVs ameliorated TGF-ß1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.

Tissue Engineering Graft for Urethral Reconstruction: Is It Ready for Clinical Application?

Despite developing surgical techniques in urethral surgery, the outcome and complications are still unsatisfactory. Alternative treatment modality has been coming up, particularly in patients with longer stricture, under revision surgery, and penile stricture. Tissue engineering grafts are a promising approach for substituting urethral reconstruction. Over the decades, numerous preclinical studies have been published to show the efficacy and safety of different origins of materials, the presence of autologous cells (acellular matrices or autologous cell-seeded matrices), and the construction of engineered tissue (patch or tubularized constructs) on animal models. However, the results of these studies have not yet reached the intended level for daily clinical practice. A PubMed database search was performed for articles, using specific keywords, published between 1998 and 2022, with a selection on using tissue-engineered grafts for urethroplasty. Many materials have been used as a graft, such as acellular bladder matrix, small intestinal submucosa, acellular dermal matrix, and polyglycolic acid with or without cells, and were evaluated according to the functional and anatomical outcomes comprising complications. According to current literature, tubularized scaffolds constructed from co-cultured cells have promising results for the future. However, high-quality evidence through randomized controlled studies with larger sample sizes, with a long-term follow-up is required to determine accurate outcomes.

Metastasis from small cell lung cancer to ovary: A case report.

Small cell lung cancer (SCLC) rarely metastasizes to the ovary, and is difficult to diagnose given its overlapping clinical features and histological characteristics with primary ovarian cancer. Since therapies for SCLC and primary ovarian cancer differ, it is important to determine the original site of ovarian lesions. This report describes the differential diagnosis of metastatic from primary ovarian cancer. A 46-year-old Chinese woman with a history of SCLC, confirmed by transbronchial lung biopsy in August 2018, presented with abdominal distension in December 2018. Ultrasound examination and whole abdomen computed tomography showed one mass in each ovary. A provisional diagnosis of ovarian tumor was given. A palliative total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed; and three postoperative courses of chemotherapies. The patient died from multiple organ failure in May 2019. Metastatic ovarian cancer from SCLC was determined based on characteristic histological and immunohistochemical staining.

Cell-Based Therapy for Urethral Regeneration: A Narrative Review and Future Perspectives.

Urethral stricture is a common urological disease that seriously affects quality of life. Urethroplasty with grafts is the primary treatment, but the autografts used in clinical practice have unavoidable disadvantages, which have contributed to the development of urethral tissue engineering. Using various types of seed cells in combination with biomaterials to construct a tissue-engineered urethra provides a new treatment method to repair long-segment urethral strictures. To date, various cell types have been explored and applied in the field of urethral regeneration. However, no optimal strategy for the source, selection, and application conditions of the cells is available. This review systematically summarizes the use of various cell types in urethral regeneration and their characteristics in recent years and discusses possible future directions of cell-based therapies.

Detection of lineage-reprogramming efficiency of tumor cells in a 3D-printed liver-on-a-chip model.

Background: The liver metastasis accompanied with the loss of liver function is one of the most common complications in patients with triple-negative breast cancers (TNBC). Lineage reprogramming, as a technique direct inducing the functional cell types from one lineage to another lineage without passing through an intermediate pluripotent stage, is promising in changing cell fates and overcoming the limitations of primary cells. However, most reprogramming techniques are derived from human fibroblasts, and whether cancer cells can be reversed into hepatocytes remains elusive. Methods: Herein, we simplify preparation of reprogramming reagents by expressing six transcriptional factors (HNF4A, FOXA2, FOXA3, ATF5, PROX1, and HNF1) from two lentiviral vectors, each expressing three factors. Then the virus was transduced into MDA-MB-231 cells to generated human induced hepatocyte-like cells (hiHeps) and single-cell sequencing was used to analyze the fate for the cells after reprogramming. Furthermore, we constructed a Liver-on-a-chip (LOC) model by bioprinting the Gelatin Methacryloyl hydrogel loaded with hepatocyte extracellular vesicles (GelMA-EV) bioink onto the microfluidic chip to assess the metastasis behavior of the reprogrammed TNBC cells under the 3D liver microenvironment in vitro. Results: The combination of the genes HNF4A, FOXA2, FOXA3, ATF5, PROX1 and HNF1A could reprogram MDA-MB-231 tumor cells into human-induced hepatocytes (hiHeps), limiting metastasis of these cells. Single-cell sequencing analysis showed that the oncogenes were significantly inhibited while the liver-specific genes were activated after lineage reprogramming. Finally, the constructed LOC model showed that the hepatic phenotypes of the reprogrammed cells could be observed, and the metastasis of embedded cancer cells could be inhibited under the liver microenvironment. Conclusion: Our findings demonstrate that reprogramming could be a promising method to produce hepatocytes and treat TNBC liver metastasis. And the LOC model could intimate the 3D liver microenvironment and assess the behavior of the reprogrammed TNBC cells.

Deciphering the role of polystyrene microplastics in waste activated sludge anaerobic digestion: Changes of organics transformation, microbial community and metabolic pathway.

Microplastics are ubiquitous in the natural environment, which inevitably affect the relevant biochemical process. Nevertheless, the knowledge about the impacts of microplastics on organics transformation and corresponding microbial metabolism response in anaerobic environment is limited. Here, polystyrene (PS) microplastics were selected as model microplastics to explore their potential impacts on organics transformation, microbial community and metabolic pathway during sludge anaerobic digestion system operation. The results indicated that the PS microplastics exhibited the dose-dependent effects on methane production, i.e., the additive of 20-40 particles/g TS of PS microplastics improved the maximum methane yield by 3.38 %-8.22 %, whereas 80-160 particles/g TS additive led to a 4.78 %-11.04 % declining. Overall, PS microplastics facilitated the solubilization and hydrolysis of sludge, but inhibited the acidogenesis process. Key functional enzyme activities were stimulated under low PS microplastics exposure, whereas were almost severely inhibited due to the increased oxidative stress induced from excess PS microplastics. Microbial community and further metabolic analysis indicated that low PS microplastics improved the acetotrophic and hydrogenotrophic methanogenesis, while a high level of PS microplastics shifted methanogenesis from acetotrophic to hydrogenotrophic pathway. Further analysis showed that the reacted PS microplastics exhibited greater toxicity and ecological than the raw PS microplastics due to that they are more likely to adsorb contaminants. These findings revealed the dosage-dependent relationships between microplastics and organics transformation process in anaerobic environments, providing new insights for assessing the impact of PS microplastics on sludge anaerobic digestion.

A Pegylated Liposome Loaded with Raddeanin A for Prostate Cancer Therapy.

Introduction: Raddeanin A (RA), a potent triterpenoid extracted from Anemone raddeana Regel, has a moderate therapeutic effect on prostate cancer (PCa), correlating with serious biological toxicity. Therefore, a RA-loaded PEGylated liposome drug delivery system was devised in this study. Methods: Hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-Polyethyleneglycol-2000 (sodium salt) (DSPE-PEG2k), cholesterol (CHO), and RA were utilised to prepare a RA-loaded liposome (LRA) drug delivery system via the thin film hydration technique., The drug loading content was confirmed by high performance liquid chromatography. Dynamic light scattering was employed to evaluate the drug's particle size and stability. Methyl tetrazolium, colony formation, and Western blot (WB) were used in vitro to elucidate the inhibitory effect and mechanism of LRA on prostate cancer cells. Finally, xenograft model was used to confirm the tumor-inhibiting efficacy, clarify the mechanism, and determine the biosafety in mice. Results: LRA has stable physicochemical properties and a diameter of 173.5 15.3 nm. LRA inhibited the growth of prostate cancer cells in a dose- and time-dependent manner. LRA can substantially reduce the expression of AR and HMGB1, induce apoptosis, regulate the expression of cell cycle-related proteins in vitro and in vivo. The results of the biosafety tests demonstrated that LRA effectively reduced the adverse effects of RA. Conclusion: As a drug delivery system, LRA could effectively and safely inhibit the progression of prostate cancer.

Atrazine promotes breast cancer development by suppressing immune function and upregulating MMP expression.

There is evidence that the triazine herbicide atrazine, which is used extensively, is present in both surface water and groundwater, and its interfering effect on immune systems, endocrine systems, and tumours has been reported by laboratory and epidemiological studies. This study explored how atrazine affected 4T1 breast cancer cell development in vitro and in vivo. The obtained results showed that after exposure to atrazine, the cell proliferation and tumour volume were significantly increased and the expression of MMP2, MMP7, and MMP9 was upregulated. The thymus and spleen indices, the CD4 + and CD3 + lymphocyte percentages which from the spleen and inguinal lymph nodes, and the CD4 + /CD8 + ratio were noticeably lower than they were in the control group. Importantly, tumour-infiltrating lymphocytes such as CD4 + , CD8 + , and NK cells were decreased while Treg cells were increased. Moreover, IL-4 was increased and IFN-γ and TNF-α were decreased in the serum and tumour microenvironment. These results suggested that atrazine can suppress systemic as well as local tumour immune function and upregulate MMPs to promote breast tumour development.

MRI-based pre-Radiomics and delta-Radiomics models accurately predict the post-treatment response of rectal adenocarcinoma to neoadjuvant chemoradiotherapy.

Objectives: To develop and validate magnetic resonance imaging (MRI)-based pre-Radiomics and delta-Radiomics models for predicting the treatment response of local advanced rectal cancer (LARC) to neoadjuvant chemoradiotherapy (NCRT). Methods: Between October 2017 and August 2022, 105 LARC NCRT-naïve patients were enrolled in this study. After careful evaluation, data for 84 patients that met the inclusion criteria were used to develop and validate the NCRT response models. All patients received NCRT, and the post-treatment response was evaluated by pathological assessment. We manual segmented the volume of tumors and 105 radiomics features were extracted from three-dimensional MRIs. Then, the eXtreme Gradient Boosting algorithm was implemented for evaluating and incorporating important tumor features. The predictive performance of MRI sequences and Synthetic Minority Oversampling Technique (SMOTE) for NCRT response were compared. Finally, the optimal pre-Radiomics and delta-Radiomics models were established respectively. The predictive performance of the radionics model was confirmed using 5-fold cross-validation, 10-fold cross-validation, leave-one-out validation, and independent validation. The predictive accuracy of the model was based on the area under the receiver operator characteristic (ROC) curve (AUC). Results: There was no significant difference in clinical factors between patients with good and poor reactions. Integrating different MRI modes and the SMOTE method improved the performance of the radiomics model. The pre-Radiomics model (train AUC: 0.93 ± 0.06; test AUC: 0.79) and delta-Radiomcis model (train AUC: 0.96 ± 0.03; test AUC: 0.83) all have high NCRT response prediction performance by LARC. Overall, the delta-Radiomics model was superior to the pre-Radiomics model. Conclusion: MRI-based pre-Radiomics model and delta-Radiomics model all have good potential to predict the post-treatment response of LARC to NCRT. Delta-Radiomics analysis has a huge potential for clinical application in facilitating the provision of personalized therapy.

Immunotherapy progress and clinical strategy of unresectable locally advanced non-small cell lung cancer.

Non-small cell lung cancer negative for actionable molecular markers entered the splendid era of immunotherapy. This review aims to provide an evidence-based summary for immunotherapy for unresectable locally advanced non-small cell lung cancer, and references for clinical strategies of immunotherapy. Through literature review, the standard treatment for unresectable locally advanced non-small cell lung cancer should be radical concurrent radiotherapy and chemotherapy followed by consolidation immunotherapy. However, the efficacy of concurrent radiotherapy, chemotherapy combined with immunotherapy has not been improved, and its safety should be further validated. It is believed that induction immunotherapy plus concurrent radiotherapy and chemotherapy plus consolidation immunotherapy is promising. In clinical practice, the delineation of radiotherapy target should be relatively small. Pemetrexed combined with PD-1 inhibitor induces the strongest immunogenicity in chemotherapy, which is suggested by preclinical pathway study. Although there is no significant difference between PD1 and PD1 for effect, PD-L1 inhibitor is better in the combination treatment of radiotherapy which presents significantly less adverse events.

KNL1 is a prognostic and diagnostic biomarker related to immune infiltration in patients with uterine corpus endometrial carcinoma.

Background: The incidence and mortality of uterine corpus endometrial carcinoma (UCEC) are increasing yearly. There is currently no screening test for UCEC, and progress in its treatment is limited. It is important to identify new biomarkers for screening, diagnosing and predicting the outcomes of UCEC. A large number of previous studies have proven that KNL1 is crucial in the development of lung cancer, colorectal cancer and cervical cancer, but there is a lack of studies about the role of KNL1 in the development of UCEC. Methods: The mRNA and protein expression data of KNL1 in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and UALCAN databases and related clinical data were used to analyze the expression differences and clinical correlations of KNL1 in UCEC. A total of 108 clinical samples were collected, and the results of bioinformatics analysis were verified by immunohistochemistry. KNL1 and its related differentially expressed genes were used to draw a volcano map, construct a PPI protein interaction network, and perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA) and immune infiltration analysis to predict the function of KNL1 during UCEC progression. The prognostic data of TCGA and 108 clinical patients were used to analyze the correlation of KNL1 expression with the survival of patients, and KM survival curves were drawn. The UCEC cell lines Ishikawa and Hec-1-A were used to verify the function of KNL1. Results: KNL1 is significantly overexpressed in UCEC and is associated with a poor prognosis. KNL1 overexpression is closely related to cell mitosis, the cell cycle and other functions and is correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade and other characteristics of UCEC patients. Knockdown of KNL1 expression in UCEC cell lines can inhibit their proliferation, invasion, metastasis and other phenotypes. Conclusion: KNL1 is a prognostic and diagnostic biomarker associated with immune evasion in patients with UCEC.

Rare mutation-dominant compound EGFR-positive NSCLC is associated with enriched kinase domain-resided variants of uncertain significance and poor clinical outcomes.

BACKGROUND: Compound epidermal growth factor receptor (EGFR) mutations are less responsive to tyrosine kinase inhibitors (TKIs) than single EGFR mutations in non-small cell lung cancer (NSCLC). However, the detailed clinical characteristics and prognosis of various compound EGFR mutations remain to be elucidated. METHODS: We retrospectively studied the next-generation sequencing (NGS) data of treatment-naïve tumors from 1025 NSCLC patients with compound EGFR mutations, which were sub-categorized into different combinations of common mutations (19-Del and EGFR exon 21 p.L858R), rare mutations, and variants of uncertain significance (VUSs). Prognosis and drug resistance to first-line TKIs were analyzed in 174 and 95 patients, respectively. RESULTS: Compound EGFR mutations were enriched with EGFR exon 21 p.L858R and rare mutations, but not 19-Del (P < 0.001). The common + rare and rare + rare subtypes had fewer concurrent mutations in the PI3K pathway (P = 0.032), while the rare + rare and common + VUSs subtypes showed increased association with smoking- and temozolomide-related mutational signatures, respectively (P < 0.001). The rare mutation-dominant subtypes (rare + VUSs and rare + rare) had the worst clinical outcomes to first-line TKIs (P < 0.001), which was further confirmed using an external cohort (P = 0.0066). VUSs in the rare + VUSs subtype selectively reside in the EGFR kinase domain (P < 0.001), implying these tumors might select additional mutations to disrupt the regulation/function of the kinase domain. CONCLUSIONS: Different subtypes of compound EGFR mutations displayed distinct clinical features and genetic architectures, and rare mutation-dominant compound EGFR mutations were associated with enriched kinase domain-resided VUSs and poor clinical outcomes. Our findings help better understand the oncogenesis of compound EGFR mutations and forecast prognostic outcomes of personalized treatments.