Development of an effective meropenem/KPC-2 inhibitor combination to combat infections caused by carbapenem-resistant K. pneumoniae.

The global public health threat of bacterial antibiotic resistance continues to escalate and necessitates the implementation of urgent measures to expand our arsenal of antimicrobial drugs. In this study, we identified a benzoxaborane compound, namely 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2178), which can effectively inhibit the catalytic activity of the Klebsiella pneumoniae carbapenemase (KPC-2) enzyme. The efficacy of AN2718 as an inhibitor for the KPC-2 enzyme was verified through various assays, including enzyme activity assays and isothermal titration calorimetry. Results of multiple biochemical assays, minimum inhibitory concentration assay, and time-killing assay also showed that binding of AN2718 to KPC-2 enabled the restoration of the bactericidal effect of meropenem. The survival rate of mice infected by carbapenem-resistant, high-virulence strains increased significantly upon treatment with this agent. Most importantly, the meropenem and AN2718 combination is effective on KPC-2 mutations such as KPC-33 that were clinically evolved and exhibited resistance to ceftazidime-avibactam upon the clinical uses of this drug for a couple of years. Comprehensive safety tests both in vitro and in vivo, such as cytotoxicity, haemolytic activity, and cytochrome P450 inhibition assays demonstrated that AN2718 was safe for clinical use. These promising data indicate that AN2718 has a high potential for being approved for the treatment of drug resistant bacterial infections, including those caused by the Ceftazidime-Avibactam resistant strains. To conclude, the compound AN2718 can be regarded as a valuable addition to the current antimicrobial armamentarium and a promising tool to combat antimicrobial resistance.

Effects of returning peach branch waste to fields on soil carbon cycle mediated by soil microbial communities.

In recent years, the rise in greenhouse gas emissions from agriculture has worsened climate change. Efficiently utilizing agricultural waste can significantly mitigate these effects. This study investigated the ecological benefits of returning peach branch waste to fields (RPBF) through three innovative strategies: (1) application of peach branch organic fertilizer (OF), (2) mushroom cultivation using peach branches as a substrate (MC), and (3) surface mulching with peach branches (SM). Conducted within a peach orchard ecosystem, our research aimed to assess these resource utilization strategies' effects on soil properties, microbial community, and carbon cycle, thereby contributing to sustainable agricultural practices. Our findings indicated that all RPBF treatments enhance soil nutrient content, enriching beneficial microorganisms, such as Humicola, Rhizobiales, and Bacillus. Moreover, soil AP and AK were observed to regulate the soil carbon cycle by altering the compositions and functions of microbial communities. Notably, OF and MC treatments were found to boost autotrophic microorganism abundance, thereby augmenting the potential for soil carbon sequestration and emission reduction. Interestingly, in peach orchard soil, fungal communities were found to contribute more greatly to SOC content than bacterial communities. However, SM treatment resulted in an increase in the presence of bacterial communities, thereby enhancing carbon emissions. Overall, this study illustrated the fundamental pathways by which RPBF treatment affects the soil carbon cycle, providing novel insights into the rational resource utilization of peach branch waste and the advancement of ecological agriculture.

Clinical study of UMP and RIRS in 1.0-2.0 cm diameter renal/upper ureteral calculi.

BACKGROUND: The purpose of this study was to compare the efficacy and safety of Ultra-mini-percutaneous nephrolithotomy (UMP) and Retrograde intrarenal surgery (RIRS) for renal/upper ureteral calculi in 1.0-2.0 cm diameter. METHODS: From October 2017 to October 2022, the surgical treatment of patients with renal/upper ureteral calculi in 1.0-2.0 cm diameter who were admitted to our hospital was retrospectively analyzed. They were divided into two groups, the UMP group (sixty-two cases) and the RIRS group (one hundred and nine cases), according to the different surgical methods. Baseline data includes general information, stone size, location, CT value, hydronephrosis, creatinine level, etc. RESULTS: Intraoperative blood loss was 33.6 ± 8.5 ml in the UMP group was significantly more than 4.3 ± 0.7 ml in the RIRS group (P < 0.05). Intraoperative renal pelvis pressure of UMP group 10.5 ± 1.3 mmHg was significantly lower than RIRS group 23.6 ± 5.6 mmHg (P < 0.05). The incidence of postoperative infection was higher in the RIRS group (thirteen cases [11.93%]), and one case ([1.61%]) in the UMP group (P < 0.05). Routine CT scans on the second day and two months after surgery showed that the stone clearance rates in the UMP group were 87.1% and 93.5%, respectively, higher than those in the RIRS group (69.7% and 79.8%, respectively; P < 0.05). CONCLUSION: UMP has the advantage of a higher stone-free rate but a higher risk of injury and bleeding. The advantages of RIRS include less trauma, less bleeding, and faster recovery, but lower stone-free rates and a higher risk of infection.

Observation of discrete-light temporal refraction by moving potentials with broken Galilean invariance.

Refraction is a basic beam bending effect at two media's interface. While traditional studies focus on stationary boundaries, moving boundaries or potentials could enable new laws of refractions. Meanwhile, media's discretization plays a pivotal role in refraction owing to Galilean invariance breaking principle in discrete-wave mechanics, making refraction highly moving-speed dependent. Here, by harnessing a synthetic temporal lattice in a fiber-loop circuit, we observe discrete time refraction by a moving gauge-potential barrier. We unveil the selection rules for the potential moving speed, which can only take an integer v = 1 or fractional v = 1/q (odd q) value to guarantee a well-defined refraction. We observe reflectionless/reflective refractions for v = 1 and v = 1/3 speeds, transparent potentials with vanishing refraction/reflection, refraction of dynamic moving potential and refraction for relativistic Zitterbewegung effect. Our findings may feature applications in versatile time control and measurement for optical communications and signal processing.

The effect of physical exercise intervention on the ability of daily living in patients with Alzheimer's dementia: a meta-analysis.

Objective: To systematically evaluate the effect of physical exercise intervention on the activities of daily living (ADL) on patients with Alzheimer's dementia (AD) and explore the optimal exercise scheme. Methods: PubMed, EMBASE, the Cochrane Library, Web of Science, and Science Direct databases were searched from 1987 to December 2023 to collect randomized controlled trials (RCTs). Two investigators independently screened the literature and extracted data according to the inclusion and exclusion criteria. The quality of the included studies was evaluated using Cochrane Review Manager 5.3. And STATA 16.0 was used for performing the meta-analysis. Results: Fifteen randomized controlled trials were included. The results of the meta-analysis showed that physical exercise had a positive effect on the improvement of ADL in patients with AD [standardized mean difference (SMD) = 0.312, 95% confidence interval (CI 0.039-0.585), P = 0.02], and the difference was statistically significant. The results of subgroup analysis showed that anaerobic exercises such as strength and balance training with a medium cycle of 12-16 weeks and lasting 30-45 min each time were more ideal for the improvement of basic daily living ability of AD patients. Conclusion: Physical exercise can effectively improve activities of daily living in patients with Alzheimer's dementia and it may be a potential non-drug treatment for AD patients.

Design, synthesis and antibacterial activity evaluation of ebselen derivatives in NDM-1 producing bacteria.

New Delhi-ß-lactamase-1 (NDM-1) is a type of metal-ß-lactamase. NDM-1-expressing bacteria can spread rapidly across the globe via plasmid transfer, which greatly undermines the clinical efficacy of the carbapenem. Research on NDM-1 inhibitors has attracted extensive attention. However, there are currently no clinically available NDM-1 inhibitors. Our research group has reported that 1,2-benzisoselenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem (Mem) against NDM-1 producing strains. In this study, 22 compounds were designed and synthesized, which restored the Mem susceptibility of NDM-1-expressing Escherichia coli. and its minimum inhibitory concentration (MIC) was reduced by 2-16 times. Representative compound A4 showed significant synergistic antibacterial activity against NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) isolates. The in vitro NDM-1 enzyme inhibitory activity test showed that the IC50 was 1.26 ± 0.37 µM, which had low cytotoxicity. When combined with meropenem, it showed good combined antibacterial activity. Electrospray ionization mass spectrometry (ESI-MS) analysis demonstrates that compound A4 covalently binds to NDM-1 enzyme. In summary, compound A4 is a potent NDM-1 covalent inhibitor and provides a potential lead compound for drug development in resistant bacteria.

Lipase-Responsive Lignin Composite Nanoparticles for the Delivery of Insoluble Bioactives.

Low solubility and chemical instability are the main problems with insoluble bioactives. Lignin, with its exceptional biological properties and amphiphilicity, holds promise as a delivery system material. In this study, glycerol esters were incorporated into alkali lignin (AL) through ether and ester bonds, resulting in the successful synthesis of three hydrophobically modified alkali lignins (AL-OA, AL-OGL, and AL-SAN-OGL). Subsequently, lignin composite nanoparticles (LNPs@BC) encapsulating ß-carotene were prepared using antisolvent and sonication techniques. The encapsulation rates were determined to be 37.69 ± 2.21%, 84.01 ± 5.55%, 83.82 ± 5.23%, and 83.11 ± 5.85% for LNP@BC-1, LNP@BC-2, LNP@BC-3, and LNP@BC-4, respectively, with AL, AL-OA, AL-OGL, and AL-SAN-OGL serving as the wall materials under optimized preparation conditions. The antioxidant properties and UV-absorbing capacity of the four lignins were characterized, demonstrating their efficacy in enhancing the oxygen and photostability of ß-carotene. Following 6 h of UV irradiation, LNP@BC-4 exhibited a retention rate of 83.03 ± 2.85% for ß-carotene, while storage under light-protected conditions at 25 °C for 7 days retained 73.33 ± 7.62% of ß-carotene. Furthermore, the encapsulated ß-carotene demonstrated enhanced thermal and storage stability. In vitro release experiments revealed superior stability of LNPs@BC in simulated gastric fluid (SGF), with ß-carotene retention exceeding 77% in both LNP@BC-3 and LNP@BC-4. LNP@BC-4 exhibited the highest bioaccessibility in simulated intestinal fluid (SIF) at 46.96 ± 0.80%, that LNP@BC-1 only achieved 10.87 ± 0.90%. The enzymatic responsiveness of AL-OGL and AL-SAN-OGL was confirmed. Moreover, LNPs@BC exhibited no cytotoxicity toward L929 cells and demonstrated excellent hemocompatibility. In summary, this study introduces a novel enzyme-responsive modified lignin that has promising applications in the fields of food, biomedicine, and animal feed.

Dynamic effective connectivity in the cerebellar dorsal dentate nucleus and the cerebrum, cognitive impairment, and clinical correlates in patients with schizophrenia.

BACKGROUND: Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown. METHODS: Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t-tests and correlation analysis. RESULTS: We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance. CONCLUSIONS: This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ.

A Clinical Comparative Study of Thoracoscopic Anatomical Lesion Resection and Lobectomy in the Treatment of Congenital Lung Malformations.

BACKGROUND: To explore the safety and feasibility of HuaXi thoracoscopic anatomical lesion resection (HX-TALR) in the treatment of congenital lung malformations (CLMs) in children. METHODS: A retrospective review of clinical data was conducted for patients who underwent HX-TALR and thoracoscopic lobectomy (TL) in our hospital from October 2017 to March 2023. Intraoperative and postoperative outcomes were compared between the HX-TALR and TL groups. RESULTS: There were 485 patients in this study, 267 of whom underwent HX-TALR and 218 of whom underwent TL. All patients underwent thoracoscopic surgery without conversion to open surgery. No patients had major complications, including bronchopleural fistula, hemorrhage, atelectasis, recurrence or reoperation. The operative time, intraoperative bleeding volume, cases with thoracic drainage tubes, postoperative hospital stay, and cases with postoperative fever in HX-TALR were greater than those in TL (P < 0.05). CONCLUSIONS: HX-TALR is safe, feasible, and retains all normal lung tissue while removing the lesion, which is expected to become the preferable operation for the treatment of CLMs. HX-TALR is a new and technically challenging procedure that needs to be carried out after training. LEVEL OF EVIDENCE: Level IV.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma.

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

Exposure to ambient temperature and heat index in relation to DNA methylation age: A population-based study in Taiwan.

BACKGROUND: Climate change caused an increase in ambient temperature in the past decades. Exposure to high ambient temperature could result in biological aging, but relevant studies in a warm environment were lacking. We aimed to study the exposure effects of ambient temperature and heat index (HI) in relation to age acceleration in Taiwan, a subtropical island in Asia. METHODS: The study included 2,084 participants from Taiwan Biobank. Daily temperature and relative humidity data were collected from weather monitoring stations. Individual residential exposure was estimated by ordinary kriging. Moving averages of ambient temperature and HI from 1 to 180 days prior to enrollment were calculated to estimate the exposure effects in multiple time periods. Age acceleration was defined as the difference between DNA methylation age and chronological age. DNA methylation age was calculated by the Horvath's, Hannum's, Weidner's, ELOVL2, FHL2, phenotypic (Pheno), Skin & blood, and GrimAge2 (Grim2) DNA methylation age algorithms. Multivariable linear regression models, generalized additive models (GAMs), and distributed lag non-linear models (DLNMs) were conducted to estimate the effects of ambient temperature and HI exposures in relation to age acceleration. RESULTS: Exposure to high ambient temperature and HI were associated with increased age acceleration, and the associations were stronger in prolonged exposure. The heat stress days with maximum HI in caution (80-90°F), extreme caution (90-103°F), danger (103-124°F), and extreme danger (>124°F) were also associated with increased age acceleration, especially in the extreme danger days. Each extreme danger day was associated with 571.38 (95 % CI: 42.63-1100.13), 528.02 (95 % CI: 36.16-1019.87), 43.9 (95 % CI: 0.28-87.52), 16.82 (95 % CI: 2.36-31.28) and 15.52 (95 % CI: 2.17-28.88) days increase in the Horvath's, Hannum's, Weidner's, Pheno, and Skin & blood age acceleration, respectively. CONCLUSION: High ambient temperature and HI may accelerate biological aging.

Association between degree centrality and neurocognitive impairments in patients with Schizophrenia: A Longitudinal rs-fMRI Study.

BACKGROUND: Evidence indicates that patients with schizophrenia (SZ) experience significant changes in their functional connectivity during antipsychotic treatment. Despite previous reports of changes in brain network degree centrality (DC) in patients with schizophrenia, the relationship between brain DC changes and neurocognitive improvement in patients with SZ after antipsychotic treatment remains elusive. METHODS: A total of 74 patients with acute episodes of chronic SZ and 53 age- and sex-matched healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS), Symbol Digit Modalities Test, digital span test (DST), and verbal fluency test were used to evaluate the clinical symptoms and cognitive performance of the patients with SZ. Patients with SZ were treated with antipsychotics for six weeks starting at baseline and underwent MRI and clinical interviews at baseline and after six weeks, respectively. We then divided the patients with SZ into responding (RS) and non-responding (NRS) groups based on the PANSS scores (reduction rate of PANSS ≥50%). DC was calculated and analyzed to determine its correlation with clinical symptoms and cognitive performance. RESULTS: After antipsychotic treatment, the patients with SZ showed significant improvements in clinical symptoms, semantic fluency performance. Correlation analysis revealed that the degree of DC increase in the left anterior inferior parietal lobe (aIPL) after treatment was negatively correlated with changes in the excitement score (r = -0.256, p = 0.048, adjusted p = 0.080), but this correlation failed the multiple test correction. Patients with SZ showed a significant negative correlation between DC values in the left aIPL and DST scores after treatment, which was not observed at the baseline (r = -0.359, p = 0.005, adjusted p = 0.047). In addition, we did not find a significant difference in DC between the RS and NRS groups, neither at baseline nor after treatment. CONCLUSIONS: The results suggested that DC changes in patients with SZ after antipsychotic treatment are correlated with neurocognitive performance. Our findings provide new insights into the neuropathological mechanisms underlying antipsychotic treatment of SZ.

The "quadrant-sandwich" method in clockwise modular D2 lymph node dissection in laparoscopic total gastrectomy: a retrospective cohort study.

Background: For patients who need laparoscopic radical gastrectomy, lymph node dissection (LND) and optimization of surgical procedures are particularly important. This study introduces the "quadrant-sandwich" method in clockwise modular D2 LND and evaluates the advantages and safety of this method. Methods: The clinical data of 108 laparoscopic total gastrectomy patients admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2019 to January 2022 were retrospectively analyzed. Based on the different LND processes, 55 patients were allocated to the observation group, which underwent clockwise modular LND using the "quadrant-sandwich method", and 53 patients were allocated to the control group, which underwent traditional LND. The effectiveness and safety of the approach in terms of operation time, blood loss, lymph node yield, postoperative recovery and postoperative complications were observed in the two groups. Results: There was no statistical difference between the baseline data of the two groups. In relation to the surgery, the observation group had an operation time of 227.0±48.5 minutes, and intraoperative bleeding of 100.0 mL [inter-quartile range (IQR), 30.0-200.0 mL], while the control group had an operation time of 247±41.5 minutes, and intraoperative bleeding of 180.0 mL (IQR, 130.0-245.0 mL). There were statistically significant differences between the two groups in terms of the operation time and intraoperative bleeding (P=0.001, P=0.020). In relation to the LND, there were no statistically significant differences between the two groups in terms of the total number of lymph nodes in each division, and the number of positive lymph nodes. In relation to the post-operative results, there were no statistically significant differences between the two groups in terms of the post-operative pathological stage, first postoperative oral feeding, post-operative hospitalization time, and post-operative complications. Conclusions: Clockwise modular D2 LND using the "quadrant-sandwich method" is potentially safe and feasible in laparoscopic total gastrectomy. It not only ensures the thoroughness of the LND, but also ensures and efficient and fast surgical process, shortens the operation time, and reduces the amount of intraoperative bleeding.

Postoperative superior anastomotic leakage classification and treatment strategy for postoperative esophagogastric junction cancer.

Background: At present, anastomotic fistula cannot be avoided after adenocarcinoma of the esophagogastric junction (AEG). Once the anastomotic leakage occurs, the posterior mediastinum and the left thoracic cavity are often seriously infected, which further impairs respiratory and circulatory function, heightening the danger of the disease course. The aim of this study was to identify the characteristics of superior anastomotic leakage after surgery for AEG and recommend corresponding treatment strategies to improve the diagnosis and treatment of superior anastomotic leakage after surgery for AEG. Methods: The clinical data of 57 patients with superior anastomotic leakage after surgery for AEG in the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to March 2019 were retrospectively analyzed, including 27 cases referred from external hospitals and 30 cases at the Affiliated Cancer Hospital of Zhengzhou University. According to the diameter and risk level of anastomotic leakage, the high anastomotic leakage is divided into types I, II, III, and IV. Results: Patients with preoperative comorbidities or those treated with the transabdominal approach or laparoscopic surgery often had type I and type II anastomotic leakage; meanwhile, patients with preoperative comorbidities and sacral perforation or those treated with a thoracic and abdominal approach or open surgery often had type III and IV fistula. The difference between types I-II and types III-IV was statistically significant (P<0.05). The mortality rate of patients with type III and type IV leakage was 14.8% within 90 days after operation, while no deaths occurred among patients with type I and type II leakage, and the difference in mortality between the two groups was statistically significant (P<0.05). Conclusions: After surgery for AEG, suitable treatment measures should be adopted according to the type of superior anastomotic leakage that occurs. Types III and IV superior anastomotic leakages are associated with higher mortality and require greater attention from surgeons.

Clinicopathological features and prognoses in younger and older patients with mismatch repair defects colorectal cancer: a retrospective comparative cohort study.

Background: Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effects of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) patients. However, due to the low mutation rate of MSI-H/deficient mismatch repair (dMMR) in the overall population, some doctors are of the view that testing this indicator increases the burden on patients, and consequently some patients fail to receive the most beneficial treatment methods. In order to provide testing criteria for younger patients with a higher proportion of MSI-H, we designed this retrospective controlled study. Methods: A retrospective analysis was conducted of 1,901 patients who were admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to December 2019 and underwent CRC-related gene testing. For this analysis, 100 patients aged 40 or younger are defined as the young group, and 305 patients aged 71 and older but younger than 80 are defined as the elderly group. We included patients who met the following criteria: (I) underwent preoperative colonoscopy or gastroscopy and were diagnosed with CRC; (II) received perioperative adjuvant therapy; (III) underwent curative surgery for CRC. Each patient was followed up from the time of surgery until April 30, 2023, or death, with follow-up visits scheduled every 3 months for the first 2 years after surgery, and every 6 months thereafter. Clinical characteristics such as age, gender, body mass index (BMI), tumor depth (T), number of metastatic lymph nodes (N), distant metastasis (M), tumor, node, metastasis (TNM) stage, extent of surgical resection, tumor size, tumor location, differentiation grade, and carcinoembryonic antigen (CEA) levels were collected. The microsatellite instability (MSI) status was analyzed using fluorescence in situ hybridization (FISH). Results: In young CRC patients, the proportion of MSI-H is higher than in elderly CRC patients (33% vs. 10.16%, P<0.001). The proportion of poorly differentiated tumors is also higher in young CRC patients compared to elderly CRC patients (53% vs. 31.15%, P<0.001). However, there were no significant differences in clinical characteristics between young and elderly CRC patients. In terms of prognosis, survival analysis of the young group showed that MSI status [hazard ratio (HR) =0.26, 95% confidence interval (CI): 0.08-0.88, P=0.03], TNM staging (HR =3.84, 95% CI: 1.38-10.71, P=0.010) were associated with the prognosis of CRC patients. Conclusions: The mutation rate of MSI-H is higher in young CRC patients compared to older. Our study further confirms that MSI-H can serve as a favorable prognostic marker for CRC patients. This finding may provide valuable guidance for clinicians in terms of prognosis assessment and treatment selection. If feasible, we hope that MSI testing can be performed for all CRC patients to enable targeted testing, with particular attention to monitoring the MSI status in young patients. This will aid clinicians in selecting appropriate treatment strategies for these patients.

The landscape of immune checkpoint-related long non-coding RNAs core regulatory circuitry reveals implications for immunoregulation and immunotherapy responses.

Long non-coding RNAs (lncRNAs) could modulate expression of immune checkpoints (ICPs) by cooperating with immunity genes in tumor immunization. However, precise functions in immunity and potential for predicting ICP inhibitors (ICI) response have been described for only a few lncRNAs. Here we present an integrated framework that leverages network-based analyses and Bayesian network inference to identify the regulated relationships including lncRNA, ICP and immunity genes as ICP-related LncRNAs mediated Core Regulatory Circuitry Triplets (ICP-LncCRCTs) that can make robust predictions. Hub ICP-related lncRNAs such as MIR155HG and ADAMTS9-AS2 were highlighted to play central roles in immune regulation. Specific ICP-related lncRNAs could distinguish cancer subtypes. Moreover, the ICP-related lncRNAs are likely to significantly correlated with immune cell infiltration, MHC, CYT. Some ICP-LncCRCTs such as CXCL10-MIR155HG-ICOS could better predict one-, three- and five-year prognosis compared to single molecule in melanoma. We also validated that some ICP-LncCRCTs could effectively predict ICI-response using three kinds of machine learning algorithms follow five independent datasets. Specially, combining ICP-LncCRCTs with the tumor mutation burden (TMB) improves the prediction of ICI-treated melanoma patients. Altogether, this study will improve our grasp of lncRNA functions and accelerating discovery of lncRNA-based biomarkers in ICI treatment.

Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy.

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced cancer cell apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

Development of a Novel Endometrial Signature Based on Endometrial microRNA for Determining the Optimal Timing for Embryo Transfer.

Though tremendous advances have been made in the field of in vitro fertilization (IVF), a portion of patients are still affected by embryo implantation failure issues. One of the most significant factors contributing to implantation failure is a uterine condition called displaced window of implantation (WOI), which refers to an unsynchronized endometrium and embryo transfer time for IVF patients. Previous studies have shown that microRNAs (miRNAs) can be important biomarkers in the reproductive process. In this study, we aim to develop a miRNA-based classifier to identify the WOI for optimal time for embryo transfer. A reproductive-related PanelChip® was used to obtain the miRNA expression profiles from the 200 patients who underwent IVF treatment. In total, 143 out of the 167 miRNAs with amplification signals across 90% of the expression profiles were utilized to build a miRNA-based classifier. The microRNA-based classifier identified the optimal timing for embryo transfer with an accuracy of 93.9%, a sensitivity of 85.3%, and a specificity of 92.4% in the training set, and an accuracy of 88.5% in the testing set, showing high promise in accurately identifying the WOI for the optimal timing for embryo transfer.

The effect of incentive policies on the diffusion of construction and demolition waste recycling: A government perspective.

Construction and demolition (C&D) waste recycling plays a significant role in waste reduction and carbon reduction, which is critical for sustainable development. However, due to various limitations such as financial problems, C&D waste recycling industry is not well developed in developing countries. To address this problem, this study combines complex network theory and evolutionary game theory to analyse the diffusion of C&D waste recycling behaviour among enterprises under governmental incentive policies within a complex network context. The results demonstrate that the size of the network has limited effects on behaviour diffusion in Watts-Strogatz small-world network. Additionally, the study highlights the clear impact of governmental incentive probability, initial rate and connection degree on the diffusion path. By quantitatively investigating the effects of incentive tools, this study contributes to the knowledge of C&D waste management and provides valuable implications for stakeholders seeking to promote the diffusion of C&D waste recycling.