Ribosomal protein L22 like 1: a promising biomarker for lung adenocarcinoma.

No studies have reported the effect of ribosomal protein L22 like 1 (RPL22L1) in lung adenocarcinoma (LUAD). Therefore, we aimed to systematically investigate the role of RPL22L1 in LUAD. The expression of RPL22L1 was analyzed using TCGA, GEO, TIMER, UALCAN databases, and validated by immunohistochemistry (IHC). Gene methylation analysis was performed using the UALCAN, GSCA and MethSurv databases. The immune infiltrates were investigated using the Single Sample Gene Set Enrichment Analysis (ssGSEA), TIMER database, and TISCH database. The results demonstrated that RPL22L1 was up-regulated in LUAD, and verified by IHC. Kaplan-Meier analysis suggested that patients with high RPL22L1 expression had poor prognosis. Multivariate analysis confirmed that RPL22L1 was an independent prognostic factor. Furthermore, RPL22L1 overexpression was associated with hypomethylation, and two CpGs of RPL22L1 were significantly associated with prognosis. Up-regulated RPL22L1 was enriched in MYC targets, E2F targets, G2M checkpoint, mTORC1 signaling, cell cycle, and so on. Moreover, RPL22L1 expression was negatively correlated with immune cell infiltration, and patients with high RPL22L1 expression had lower immune, stromal, and estimate scores. Single-cell analysis suggested that RPL22L1 might have a potential function in the tumor microenvironment (TME) of LUAD. In conclusion, RPL22L1 may be a promising biomarker for LUAD.

Analysis of the treatment and prognosis of 266 cases of extranodal natural killer/T-cell lymphoma, nasal type in a single medical center.

Objective: To assess the impact of different treatment strategies and risk factors on the prognosis of patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL) in a single medical center. Methods and analysis: The clinical features of 266 patients with ENKTL were retrospectively analyzed, among whom those in stages I and II received sandwich therapy, while those in stages III and IV underwent chemotherapy plus autologous hematopoietic stem cell transplantation. The Kaplan-Meier curves, univariate and multivariate Cox regression analyses were employed for survival and prognosis analysis. Statistical significance was set at P<0.05. Results: Following treatment, the post-intervention outcomes demonstrated a complete remission (CR) rate of 71.05% and a partial remission (PR) rate of 3.76%. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 70.4% and 70.9%, respectively. In addition, the PFS for patients in stage I/II was 79.8%, with an OS of 81.1%, whereas for those in stage III/IV, the PFS was 41.7% and the OS was 40.9%. Notably, the achievement of CR immediately after treatment was an independent prognostic factor (P<0.001). Patients in stage I/II depicted a favorable 5-year OS rate, while those in stage III/IV manifested a less favorable prognosis. Conclusion: Stages of the disease and whether CR was achieved following treatment are important factors determining the survival and prognosis of patients with ENKTL. Further researches focusing on disease onset and mechanisms of drug resistance will contribute to better management of ENKTL.

Effects of perceived stress on turnover intention of female healthcare staff: a serial multiple mediation model.

BACKGROUND: Healthcare staff in China, especially females, work in a high-pressure, high-load, and high-risk environment, which affects the physical and mental health, the efficiency and quality of work, and increases turnover intention. The present study investigated the relationship between perceived stress and turnover intention in female healthcare staff, and the effects of future-oriented coping and work-family balance on this relationship. METHODS: Four hundred thirty-five female medical workers were recruited to perform a perceived stress scale, future-oriented coping inventory, work-family balance scale and turnover intention scale. Meanwhile, serial multiple mediation analysis was performed using PROCESS. RESULTS: 1) Perceived stress positively predicted the level of turnover intention in female healthcare staff; 2) Preventive coping and proactive coping showed mediation effects on the relationship between perceived stress and turnover intention, and preventive coping positively related to proactive coping; 3) The work-family balance also showed mediation effects on the relationship between perceived stress and turnover intention; 4) Preventive coping, proactive coping and work-family balance showed a serial multiple mediation on the relationship between perceived stress and turnover intention in female healthcare workers. CONCLUSIONS: Perceived stress affects the level of turnover intention in female healthcare staff through preventive coping, proactive coping, and work-family balance. In addition, the sequential model of future-oriented coping was validated among female healthcare staff.

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach.

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens. Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data. Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8-1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328-677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%). Conclusion: In conclusion, this study's PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.

Case Report: Gas in the esophagus, stomach wall and portal vein with congenital hypertrophic pyloric stenosis.

Background: CHPS dramatically affects infant growth and development and can even cause aspiration resulting from esophageal reflux. There is potential danger. CHPS is common, while CHPS with gas in the stomach wall and portal vein is rare. Gas in the stomach wall and portal vein are often the key features of more serious disease. It can be easily mistaken as a serious disease when patients with CHPS have gas in the stomach wall and portal vein. Case presentation: A 56-day-old baby was hospitalized for aspiration pneumonia after vomiting without bile for 20 days. Compared with vomiting, which is the most common symptom, pneumonia tends to attract more attention. Because of pneumonia, a chest CT scan was performed and revealed massive gas accumulation in the walls of the esophagus, stomach, and portal vein. Therefore, NEC was considered first and was treated conservatively for one week. However, the vomiting continued, and CHPS was confirmed by ultrasound. The delay in CHPS diagnosis was due to insufficient recognition of the signs of gas accumulation. Because of inexperience and lack of knowledge about CHPS with gastrointestinal pneumatosis, physicians failed to make an early accurate diagnosis. Case 2 was a 29-day-old male who was admitted to the hospital with vomiting without bile. He was examined by ultrasound, which revealed gas in the stomach wall and portal vein after admission to the hospital. No peritonitis was found after a detailed and comprehensive physical examination. Emergency life-threatening diseases such as NEC were quickly ruled out. He received surgery as soon as possible and had an uneventful recovery with no complications. Conclusion: CHPS may present with gas in the gastric or esophageal wall and portal vein, which is not a contraindication to surgery.

Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach.

PURPOSE: Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug-drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite). METHODS: The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients. RESULTS: The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5-2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160 µM·h and Cmax < 8.9 µM), the appropriate dosing regimens were identified. The appropriate dosage is 600 mg once daily (OD) when administered alone, reduced to 200 mg and 400 mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone. CONCLUSION: The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.

Anesthetic Management of a Patient With Hemoglobin M Disease Undergoing Laparoscopic Uterine Myomectomy: A Case Report.

Hemoglobin M (Hb M) is a group of abnormal Hb variants that form methemoglobin, which leads to cyanosis. Patients with Hb M appear cyanotic but are usually asymptomatic. Cyanosis with low peripheral oxygen saturation is unresponsive to oxygen therapy despite normal partial pressure of oxygen. As such, close attention should be paid during anesthesia. We report the first case of a Hb M patient undergoing laparoscopic uterine myomectomy under general anesthesia.

Novel nomogram for predicting survival in advanced non-small cell lung cancer receiving anti-PD-1 plus chemotherapy with or without antiangiogenic therapy.

Background: This study aimed to develop and validate a novel nomogram to predict survival in advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD-1) inhibitor plus chemotherapy with or without antiangiogenic therapy. Methods: A total of 271 patients with advanced NSCLC who received anti-PD-1 plus chemotherapy with or without antiangiogenic therapy were enrolled in our center and randomized into the training cohort (n = 133) and the internal validation cohort (n = 138). Forty-five patients from another center were included as an independent external validation cohort. The nomogram was created based on the multivariate Cox regression analysis to predict overall survival (OS) and progression-free survival (PFS). The performance of the nomogram was assessed using the concordance index (C-index), the time-dependent area under the receiver operating (ROC) curves (AUCs), calibration curves, and decision curve analysis (DCA). Results: Four factors significantly associated with OS were utilized to create a nomogram to predict OS: Eastern Cooperative Oncology Group performance status (ECOG PS), programmed cell death-ligand 1 (PD-L1) expression, chemotherapy cycle, and pretreatment lactate dehydrogenase-albumin ratio (LAR). Six variables significantly associated with PFS were incorporated into the development of a nomogram for predicting PFS: ECOG PS, histology, PD-L1 expression, chemotherapy cycle, pretreatment platelet to lymphocyte (PLR), and pretreatment LAR. The C-indexes of the nomogram for predicting OS and PFS were 0.750 and 0.747, respectively. The AUCs for predicting the 6-month, 12-month, and 18-month OS and PFS were 0.847, 0.791, and 0.776 and 0.810, 0.787, and 0.861, respectively. The calibration curves demonstrated a good agreement between predictions and actual observations. The DCA curves indicated that the nomograms had good net benefits. Furthermore, the nomogram model was well-validated in the internal and external cohorts. Conclusion: The novel nomogram for predicting the prognosis of advanced NSCLC receiving anti-PD-1 plus chemotherapy with or without antiangiogenic therapy may help guide clinical treatment decisions.

An emerging role of arecoline on growth performance, intestinal digestion and absorption capacities and intestinal structural integrity of adult grass carp (Ctenopharyngodon idella).

Arecoline is an alkaloid with important pharmacological effects in the plant areca nut, which has been demonstrated to be an agonist of muscarinic receptors (M receptor). This study explored the influences of dietary arecoline on growth performance, intestinal digestion and absorption abilities, antioxidant capacity, and the apical junction complex (AJC) of adult grass carp (Ctenopharyngodon idella). Adult grass carp (608 to 1512 g) were fed at 6 graded levels of dietary arecoline (0, 0.5, 1.0, 1.5, 2.0, and 2.5 mg/kg diet) for 9 weeks. The results suggested that appropriate dietary supplementation of arecoline (1.0 mg/kg) increased growth parameters and intestinal growth in adult grass carp (P < 0.05), enhanced digestion and absorption capacities (P < 0.05), up-regulated muscarinic receptor 3 (M3) mRNA level (P < 0.05), increased the content of neuropeptide fish substance P (P < 0.05), improved antioxidant capacity by activating the Keap1a/Nrf2 signaling pathway (P < 0.05), reduced intestinal mucosal permeability (P < 0.05), and increased mRNA levels of tight junction (TJ) and adherent junction AJ-related proteins in fish by inhibiting the RhoA/ROCK signaling pathway (RhoA/ROCK/MLCK/NMII) (P < 0.05). In addition, the appropriate arecoline supplementation for adult grass carp was determined to be 1.20, 1.21, 1.07, and 1.19 mg/kg based on percentage weight gain, lipase activity, serum diamine oxidase, and protein carbonyl, respectively. Overall, to the best of our knowledge, we investigated for the first time the effects and possible mechanisms of dietary arecoline on intestinal digestive and absorptive capacities and structural integrity in fish and evaluated the appropriate level of supplementation.

The multi-kingdom microbiome of the goat gastrointestinal tract.

BACKGROUND: Goat is an important livestock worldwide, which plays an indispensable role in human life by providing meat, milk, fiber, and pelts. Despite recent significant advances in microbiome studies, a comprehensive survey on the goat microbiomes covering gastrointestinal tract (GIT) sites, developmental stages, feeding styles, and geographical factors is still unavailable. Here, we surveyed its multi-kingdom microbial communities using 497 samples from ten sites along the goat GIT. RESULTS: We reconstructed a goat multi-kingdom microbiome catalog (GMMC) including 4004 bacterial, 71 archaeal, and 7204 viral genomes and annotated over 4,817,256 non-redundant protein-coding genes. We revealed patterns of feeding-driven microbial community dynamics along the goat GIT sites which were likely associated with gastrointestinal food digestion and absorption capabilities and disease risks, and identified an abundance of large intestine-enriched genera involved in plant fiber digestion. We quantified the effects of various factors affecting the distribution and abundance of methane-producing microbes including the GIT site, age, feeding style, and geography, and identified 68 virulent viruses targeting the methane producers via a comprehensive virus-bacterium/archaea interaction network. CONCLUSIONS: Together, our GMMC catalog provides functional insights of the goat GIT microbiota through microbiome-host interactions and paves the way to microbial interventions for better goat and eco-environmental qualities. Video Abstract.

Effect of acute normovolemic hemodilution on anesthetic effect, plasma concentration, and recovery quality in elderly patients undergoing spinal surgery.

OBJECTIVE: To explore the effect of acute normovolemic hemodilution (ANH) on the anesthetic effect, plasma concentration, and postoperative recovery quality in elderly patients undergoing spinal surgery. METHODS: A total of 60 cases of elderly patients aged 65 to 75 years who underwent elective multilevel spinal surgery were assigned randomly into the ANH group (n = 30) and control group (n = 30). Hemodynamic and blood gas analysis indexes were observed and recorded before ANH (T1), after ANH (T2), immediately after postoperative autologous blood transfusion (T3), 10 min (T4), 20 min (T5), 30 min (T6), 40 min (T7), and 50 min (T8) after the transfusion, and at the end of the transfusion (i.e., 60 min; T9). At T3 ~ 9, bispectral index (BIS) and train-of-four (TOF) stimulation were recorded and the plasma propofol/cisatracurium concentration was determined. The extubation time and recovery quality were recorded. RESULTS: The ANH group presented a lower MAP value and a higher SVV value at T2, and shorter extubation and orientation recovery time (P < 0.05) compared with the control group. BIS values at T8 and T9 were lower in the ANH group than those in the control group (P < 0.05). TOF values at T7 ~ 9 were lower in the ANH group than those in the control group (P < 0.05). There were no statistically significant differences in the postoperative plasma concentrations of propofol and cisatracurium between the groups (P > 0.05). CONCLUSION: During orthopedic surgery, the plasma concentration of elderly patients is increased after autologous blood transfusion of ANH, and the depth of anesthesia and muscle relaxant effect are strengthened, thus leading to delayed recovery of respiratory function and extubation.

Unveiling the Electrolyte Cations Dependent Kinetics on CoOOH-Catalyzed Oxygen Evolution Reaction.

The electrolyte cations-dependent kinetics have been widely observed in many fields of electrocatalysis, however, the exact mechanism of the influence on catalytic performance is still a controversial topic of considerable discussion. Herein, combined with operando X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM), we verify that the electrolyte cations could intercalate into the layer of pristine CoOOH catalyst during the oxygen evolution reaction (OER) process, while the bigger cations lead to enlarged interlayer spacing and increased OER activity, following the order Cs+ >K+ >Na+ >Li+ . X-ray absorption spectroscopy (XAS), in situ Raman, in situ Ultraviolet-visible (UV/Vis) spectroscopy, in situ XAS spectroscopy, cyclic voltammetry (CV), and theoretical calculations reveal that the intercalation of electrolyte cations efficiently modify the oxidation states of Co by enlarging the Co-O bonds, which in turn enhance the d-band center of Co, optimize the adsorption strength of oxygen intermediates, facilitate the formation of OER active Co(IV) species, and reduce the energy barrier of the rate-determing step (RDS), thereby enhancing the OER activity. This work not only provides an informative picture to understand the complicated dependence of OER kinetics on electrolyte cations, but also sheds light on understanding the mechanism of other electrolyte cation-targeted electrocatalysis.

Risk prediction of second primary malignancies in patients after rectal cancer: analysis based on SEER Program.

BACKGROUND: This study will focus on exploring the clinical characteristics of rectal cancer (RC) patients with Second Primary Malignancies (SPMs) and constructing a prognostic nomogram to provide clinical treatment decisions. METHODS: We determined the association between risk factors and overall survival (OS) while establishing a nomogram to forecast the further OS status of these patients via Cox regression analysis. Finally, we evaluated the performance of the prognostic nomogram to predict further OS status. RESULTS: Nine parameters were identified to establish the prognostic nomogram in this study, and, the C-index of the training set and validation set was 0.691 (95%CI, 0.662-0.720) and 0.731 (95%CI, 0.676-0.786), respectively. The calibration curve showed a high agreement between the predicted and actual results, and the receiver operating characteristic (ROC) curves verified the superiority of our model for clinical usefulness. In addition, the nomogram classification could more precisely differentiate risk subgroups and improved the discrimination of SPMs' prognosis. CONCLUSIONS: We systematically explored the clinical characteristics of SPMs after RC and constructed a satisfactory nomogram.

Effects of blood components of preoperative autologous blood donation on functions of myelopoietic stem cells.

OBJECTIVE: To explore the effects of preoperative autologous whole blood donation and autologous pure red blood cell (RBC) donation on hematopoietic stem cells (HSC), clarify the effects of transfusion by different blood components on HSC, and improve the treatment effect of autotransfusion. METHODS: Forty healthy male New Zealand rabbits were divided into five groups (n = 8) at random: control (Group A), surgery alone (Group B), surgery + blood sampling (Group C), surgery + preoperative autologous whole blood autotransfusion (Group D), and surgery + preoperative autologous pure RBC autotransfusion (Group E). The rabbits' bone marrow was collected before surgery (T1), 6 h after surgery (T2), and 24 h after surgery (T3) to detect the CD34+ cell count, the reactive oxygen species (ROS) concentration, the ratio of senescent cells, and the expression of HSC-related proteins (p53 and p21). RESULTS: Compared with groups A and B, the percentage of CD34+ cells in groups D and E at each time point was significantly increased, while the proportion of senescent cells, ROS, p53 and p21 were significantly decreased (P<0.05). Compared with Group C, the percentage of CD34+ cells at T2 and T3 rose significantly, while the ratio of senescent cells, the ROS concentration, and the content of p53 and p21 declined significantly in Groups D and E (P < 0.05). Compared with Group D, the ratio of senescent cells at T2 declined significantly, the percentage of CD34+ cells at T3 rose significantly, and the ROS concentration at T2 and T3 declined significantly in Group E (P < 0.05). CONCLUSION: From the perspective of HSC, collection and transfusion of pure RBC is more beneficial to postoperative recovery of patients than whole blood transfusion.

First-generation EGFR-TKI plus bevacizumab and chemotherapy for advanced EGFR-mutated non-squamous non-small-cell lung cancer: a retrospective study.

BACKGROUND: This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224-0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1-2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. CONCLUSIONS: First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.

A Comprehensive Analysis of Triplophysa labiata (Kessler, 1874) Mitogenome and Its Phylogenetic Implications within the Triplophysa Genus.

In order to resolve the long-standing controversy surrounding the relationships within the Triplophysa genus, we conducted an extensive analysis of the complete mitogenome of Triplophysa labiata using DNBSEQ short reads. Additionally, we reconstructed the phylogeny of the Nemacheilidae family using mitogenome data. By comparing all available mitogenomes within the Triplophysa genus, we gained valuable insights into its evolutionary history. Our findings revealed that the mitogenome sequence of T. labiata is circular, spanning a length of 16,573 bp. It encompasses 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and a control region (D-loop). Among the PCGs, the start codon ATG was commonly observed, except in cox1, while the stop codons TAA/TAG/T were found in all PCGs. Furthermore, purifying selection was evident across all PCGs. Utilizing maximum likelihood (ML) methods, we employed the 13 PCGs and the concatenated nucleotide sequences of 30 Triplophysa mitogenomes to infer the phylogeny. Our results strongly supported the division of the Triplophysa genus into four primary clades. Notably, our study provides the first evidence of the close relationship between T. labiata and T. dorsalis. These findings serve as a significant foundation for future investigations into the mitogenomics and phylogeny of Nemacheilidae fishes, paving the way for further advancements in this field of research.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Isolation of Tulasnella spp. from Cultivated Paphiopedilum Orchids and Screening of Germination-Enhancing Fungi.

Ex situ conservation, an important way to increase the survival and sustainability of endangered species, is widely used in the conservation of endangered orchids. However, long-term ex situ conservation might affect the dominant group of orchid symbiotic fungi, which are crucial for orchid growth and reintroduction. This study investigated the culturable Tulasnella spp. associated with Paphiopedilum orchids after long-term greenhouse cultivation, and identified germination-enhancing isolates. A total of 44 Tulasnella isolates were obtained from the roots of 14 Paphiopedilum spp., and 29 of them were selected for phylogenetic analysis. They clustered mainly with Tulasnella deliquescens, Tulasnella calospora, Tulasnella bifrons, and Tulasnella irregularis, but included two potential new groups. Compared with published uncultured data, most of the isolates were grouped together with the reported types, and the dominant Tulasnella associated with P. armeniacum and P. micranthum could still be isolated after ten years of cultivation, most of which were the first isolation. In vitro symbiotic germination showed that certain root isolates could promote seed germination (e.g., parm152 isolated from P. armeniacum, Php12 from P. hirsutissimum, and prhi68 from P. rhizomatosum). These data indicated that the dominant Tulasnella types colonizing the roots of cultivated Paphiopedilum are stable over time, and germination-enhancing fungi colonizing the roots would benefit for seed reproduction after population reintroduction into the wild.

Comprehensive machine learning-generated classifier identifies pro-metastatic characteristics and predicts individual treatment in pancreatic cancer: A multicenter cohort study based on super-enhancer profiling.

Rationale: Accumulating evidence illustrated that the reprogramming of the super-enhancers (SEs) landscape could promote the acquisition of metastatic features in pancreatic cancer (PC). Given the anatomy-based TNM staging is limited by the heterogeneous clinical outcomes in treatment, it is of great clinical significance to tailor individual stratification and to develop alternative therapeutic strategies for metastatic PC patients based on SEs. Methods: In our study, ChIP-Seq analysis for H3K27ac was performed in primary pancreatic tumors (PTs) and hepatic metastases (HMs). Bootstrapping and univariate Cox analysis were implemented to screen prognostic HM-acquired, SE-associated genes (HM-SE genes). Then, based on 1705 PC patients from 14 multicenter cohorts, 188 machine-learning (ML) algorithm integrations were utilized to develop a comprehensive super-enhancer-related metastatic (SEMet) classifier. Results: We established a novel SEMet classifier based on 38 prognostic HM-SE genes. Compared to other clinical traits and 33 published signatures, the SEMet classifier possessed robust and powerful performance in predicting prognosis. In addition, patients in the SEMetlow subgroup owned dismal survival rates, more frequent genomic alterations, and more activated cancer immunity cycle as well as better benefits in immunotherapy. Remarkably, there existed a tight correlation between the SEMetlow subgroup and metastatic phenotypes of PC. Among 18 SEMet genes, we demonstrated that E2F7 may promote PC metastasis through the upregulation of TGM2 and DKK1. Finally, after in silico screening of potential compounds targeted SEMet classifier, results revealed that flumethasone could enhance the sensitivity of metastatic PC to routine gemcitabine chemotherapy. Conclusion: Overall, our study provided new insights into personalized treatment approaches in the clinical management of metastatic PC patients.

Intraoperative blood auto-transfusion restrained the malignancy of Liver Cancer via regulating functions of tumor cells and Kuffer cells.

The role of IBA in regulating the recovery of liver cancer was investigated using a rat model of liver cancer and an intraoperative blood return model (IBA). SD rats were used to construct the IBA model. Kupffer cells were isolated from liver cancer tissues, and their biological characteristics were analyzed by flow cytometry. Comet assay was used to detect DNA damage in tumor cells; clone formation assay and transwell assay were used to detect tumor cell proliferation and migration ability. Western blot analysis was used to determine the changes in related signaling pathways. After the IBA treatment, the production of KCs was significantly promoted in rat liver cancer tissues, and the expression levels of cell cycle arrest proteins P53, AEN and CDKN1A were also significantly increased. In tumor cells, IBA induced cell cycle arrest and cellular DNA damage in a p53-mediated manner. In addition, the proliferation and migration of cancer cells were also significantly inhibited. Similar to the in vivo data, the expression of TP53, AEN and CDKN1A was also up-regulated. Our study showed that IBA can inhibit the malignant transformation of hepatocellular carcinoma by modulating the function-dependent p53-mediated pathway of tumor cells and KCs.