A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury.

JOURNAL/nrgr/04.03/01300535-202502000-00028/figure1/v/2024-05-28T214302Z/r/image-tiff Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI (QK) are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases. However, conventional topical drug delivery often results in a burst release of the drug, leading to transient retention (inefficacy) and undesirable diffusion (toxicity) in vivo. Therefore, a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke. Matrix metalloproteinase-2 (MMP-2) is gradually upregulated after cerebral ischemia. Herein, vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG (TIMP) and customizable peptide amphiphilic (PA) molecules to construct nanofiber hydrogel PA-TIMP-QK. PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro. The results indicated that PA-TIMP-QK promoted neuronal survival, restored local blood circulation, reduced blood-brain barrier permeability, and restored motor function. These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

The effect of agitating buffy coats on platelet quality before soft spin.

BACKGROUND: Platelet plays a vital role in both physiological and pathological processes. However, the limited storage time of platelet in vitro poses an immense challenge for its applications because of the increased risk of bacterial contamination and platelet storage lesions. Agitation can inhibit lesions by facilitating continuous oxygenation of platelets and permitting excess carbon dioxide to be removed during storage. However, it is still not known whether agitating BCs gives a positive effect on platelet quality. OBJECTIVES: To evaluate the quality difference between platelet concentrates (PCs) from buffy coats (BCs) held rest and agitation. METHODS: Samples were withdrawn for cell count, blood gas analysis, free hemoglobin level, hypotonic shock response, maximum aggregation rate, activation marker expression (CD62P and CD42b) and coagulation function. RESULTS: We found the PCs prepared from the agitating BCs had fewer residual WBCs, exhibited a better gas exchange ability, slower metabolism (higher pH, higher content glucose, and lower lactic acid levels), better hypotonic shock response, and lower levels of CD62P. The TEG-PC assays showed no difference in coagulation function. CONCLUSION: Our findings showed that BC can be agitated overnight before a soft spin.

A high-precision oasis dataset for China from remote sensing images.

High-resolution oasis maps are imperative for understanding ecological and socio-economic development of arid regions. However, due to the late establishment and relatively niche nature of the oasis discipline, there are no high-precision datasets related to oases in the world to date. To fill this gap, detailed visual interpretation of remote sensing images on Google Earth Professional or Sentinel-2 was conducted in summer 2020, and for the first time, a high-precision dataset of China's oases (abbreviation HDCO) with a resolution of 1 meter was constructed. HDCO comprises 1,466 oases with a total area of 277,375.56 km2. The kappa coefficient for this dataset validated by the field survey was 0.8686 and the AUC value for the ROC curve was 0.935. In addition, information on the geographic coordinates, climatic conditions, major landforms, and hydrological features of each oasis was added to the attribute table of the dataset. This dataset enables researchers to quantitatively monitor location and area of oases, fosters exploration of the relationship between oases and human under climate change and urbanization.

Comprehensive application of AI algorithms with TCR NGS data for glioma diagnosis.

T-cell receptor (TCR) detection can examine the extent of T-cell immune responses. Therefore, the article analyzed characteristic data of glioma obtained by DNA-based TCR high-throughput sequencing, to predict the disease with fewer biomarkers and higher accuracy. We downloaded data online and obtained six TCR-related diversity indices to establish a multidimensional classification system. By comparing actual presence of the 602 correlated sequences, we obtained two-dimensional and multidimensional datasets. Multiple classification methods were utilized for both datasets with the classification accuracy of multidimensional data slightly less to two-dimensional datasets. This study reduced the TCR ß sequences through feature selection methods like RFECV (Recursive Feature Elimination with Cross-Validation). Consequently, using only the presence of these three sequences, the classification AUC value of 96.67% can be achieved. The combination of the three correlated TCR clones obtained at a source data threshold of 0.1 is: CASSLGGNTEAFF_TRBV12_TRBJ1-1, CASSYSDTGELFF_TRBV6_TRBJ2-2, and CASSLTGNTEAFF_TRBV12_TRBJ1-1. At 0.001, the combination is: CASSLGETQYF_TRBV12_TRBJ2-5, CASSLGGNQPQHF_TRBV12_TRBJ1-5, and CASSLSGNTIYF_TRBV12_TRBJ1-3. This method can serve as a potential diagnostic and therapeutic tool, facilitating diagnosis and treatment of glioma and other cancers.

Nomogram to Predict Tube Occlusion During Hyperthermic Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei.

OBJECTIVE: To investigate the factors contributing to the blockage of perfusion tubes during hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal pseudomyxoma peritonei (PMP) undergoing combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy treatment, and to construct a nomogram for predicting the risk of tube occlusion. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Gastrointestinal Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China, from June 2017 to December 2023. METHODOLOGY: Tube occlusion was defined as the inability to achieve 30 minutes of continuous unobstructed perfusion. Statistical methods such as univariate analysis, multivariate analysis, and Lasso regression were employed for data analysis. RESULTS: The results revealed that 27% of the 383 hyperthermic intraperitoneal chemotherapy perfusion treatments resulted in the tube occlusion events. Multivariate logistic regression analysis identified age, CA-125, CA19-9, and pathological type as the independent risk factors. A nomogram predicting the tube occlusion was constructed and validated for its predictive accuracy and clinical utility. CONCLUSION: This study successfully developed a nomogram to predict the tube occlusion risk during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy treatment for patients with pseudomyxoma peritonei, providing valuable guidance for clinical practice and aiding in personalised treatment decisions to improve patient prognosis. However, further research is needed to validate the reliability and clinical applicability of the model, as well as to investigate the impact of tube occlusion on treatment outcomes and corresponding management strategies. KEY WORDS: Pseudomyxoma peritonei, Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy treatment, Tube occlusion, Nomogram.

Tailoring Dzyaloshinskii-Moriya Interaction and Spin-Hall Topological Hall Effect in Insulating Magnetic Oxides by Interface Engineering.

Chiral spin textures, as exotic phases in magnetic materials, hold immense promise for revolutionizing logic, and memory applications. Recently, chiral spin textures have been observed in centrosymmetric magnetic insulators (FMI), due to an interfacial Dzyaloshinskii-Moriya interaction (iDMI). However, the source and origin of this iDMI remain enigmatic in magnetic insulator systems. Here, the source and origin of the iDMI in Pt/Y3Fe5O12 (YIG)/substrate structures are deeply delved by examining the spin-Hall topological Hall effect (SH-THE), an indication of chiral spin textures formed due to an iDMI. Through carefully modifying the interfacial chemical composition of Pt/YIG/substrate with a nonmagnetic Al3+ doping, the obvious dependence of SH-THE on the interfacial chemical composition for both the heavy metal (HM)/FMI and FMI/substrate interfaces is observed. The results reveal that both interfaces contribute to the strength of the iDMI, and the iDMI arises due to strong spin-orbit coupling and inversion symmetry breaking at both interfaces in HM/FMI/substrate. Importantly, it is shown that nonmagnetic substitution and interface engineering can significantly tune the SH-THE and iDMI in ferrimagnetic iron garnets. The approach offers a viable route to tailor the iDMI and associated chiral spin textures in low-damping insulating magnetic oxides, thus advancing the field of spintronics.

Risk factors for thrombotic events in systemic lupus erythematosus patients with antiphospholipid antibodies: insights from morphometric measurements of carotid arteries.

Objective: To identify the correlation between thrombosis and atherosclerosis in systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies (aPLs) (SLE/aPLs) through high-resolution magnetic resonance imaging (HR-MRI) of the carotid artery. Methods: A single-center, cross-sectional study was conducted. We collected consecutive patients with SLE/aPLs and healthy controls who underwent carotid HR-MRI examinations. The morphometric characteristics of the common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA), and carotid bulb (Sinus) were measured, and the differences in morphometric parameters between different groups were analyzed. Results: A total of 144 carotid arteries were analyzed. Compared with the control group, the wall area, wall thickness (WT and WTmax), and normalized wall index of CCA, ICA, ECA, and Sinus were increased in patients with SLE/aPLs, and the total vascular area (TVA) of CCA, ICA, and Sinus, and the bifurcation angle (BIFA) of ICA-ECA were also increased. A negative lupus anticoagulant (LAC) (with or without positive anticardiolipin antibody (aCL) or anti-ß2glycoprotein antibody (aß2GPI)) contributed to illustrating lower increased TVA and thickened vessel walls of CCA and ICA in SLE/aPLs patients without thrombotic events. Logistic regression analysis showed that WTmaxSinus and WTmaxGlobal were independent risk factors for thrombotic events in SLE/aPLs patients. The receiver operator characteristic curve showed that the cut-off value of WTmaxSinus was 2.855 mm, and WTmaxGlobal was 3.370 mm. Conclusion: HR-MRI ensures the complete and accurate measurement of carotid morphometric parameters. Compared with the control group, the carotid artery in patients with SLE/aPLs is mainly characterized by diffusely thickened vessel walls, and the patients with thrombotic events showed additional higher vascular area of CCA and ICA, and BIFA of ICA-ECA without significant change in lumen area. The carotid arteries of SLE/aPLs patients with thrombotic events exhibited significant vessel wall thickening in all segments except ECA compared to those without thrombotic events. LAC-negative and non-thrombotic events distinguish relatively early atherosclerosis in the carotid arteries in patients with SLE/aPLs. Patients with SLE/aPLs that possess circumscribed thickened carotid vessel walls (>3.370 mm), particularly thickened at the Sinus (>2.855 mm), may require management strategies for the risk of thrombotic events.

Correlation analysis of interstitial maturity and prognosis of colorectal cancer: Meta-analysis.

BACKGROUND: To investigate the relationship between interstitial maturity and prognosis of colorectal cancer. AIM: To examine the correlation between interstitial maturity and the prognosis of colorectal cancer. METHODS: The paper database PubMed, EMBASE, Cochranelibrary, Springerlink, CNKI, and Wanfang database were searched until December 2023. "tumor stroma maturity" "desmoplastic stroma reaction" "desmoplastic reaction" "stroma reaction" "degree of stroma reaction "" stroma classification" "stroma density" "colorectal cancer" "colon cancer" "rectal cancer" "prognosis" were searched for the search terms. Two system assessors independently screened the literature quality according to the inclusion exclusion criteria, Quality evaluation and data extraction were performed for the included literatures, and meta-analysis was performed for randomized control trials included at using Review Manager 5.2 software. RESULTS: Finally, data of 9849 patients with colorectal cancer from 19 cosets in 15 literatures were included, including 4339 patients with mature type (control group), 3048 patients with intermediate type (intermediate group) and 2456 patients with immature type (immature group). The results of meta-analysis showed: Relapse-free survival [hazard ratio (HR) = 2.66, 95% confidence interval (CI): 2.30-3.08; P < 0.00001], disease-free survival (HR = 3.68, 95%CI: 2.33-5.81; P < 0.00001) and overall survival (HR = 1.70, 95%CI: 1.53-1.87; P < 0.00001) were significantly lower than those in mature group (control group); relapse-free survival (HR = 1.36, 95%CI: 1.17-1.59; P < 0.0001) and disease-free survival rate (HR = 1.85, 95%CI: 1.53-2.24; P < 0.0001) was significantly lower than the mature group (control group). CONCLUSION: There is the correlation between tumor interstitial maturity and survival prognosis of colorectal cancer, and different degrees of tumor interstitial maturity have a certain impact on the quality of life of colorectal cancer patients.

Effect of capsule treatment on visual acuity and quality after phacoemulsification lens implantation in myopic patients with cataract.

BACKGROUND: Cataracts pose a significant clinical burden due to their complex pathogenesis. In recent years, an increase in cataracts coexisting with myopia has heightened the incidence of retinopathy and posterior vitreous detachment. Additionally, symptoms of ocular axis elongation, lens nucleus hardening, and vitreous liquefaction have become more prevalent. While conventional extracapsular cataract extraction is commonly employed, it often yields suboptimal visual outcomes. Subsequent advancements in cataract phacoemulsification and lens implantation surgeries have gained widespread acceptance for their ability to improve refraction and significantly improve uncorrected visual acuity. AIM: To investigate the effect of capsular treatment after phacoemulsification lens implantation in myopic patients with cataract. METHODS: We selected 110 patients (with 134 eyes) with myopia and cataracts treated. These patients were categorized into two groups: an observation group (57 patients with 70 eyes) and a control group (53 patients with 64 eyes). The control group underwent cataract phacoemulsification and lens implantation, while the observation group received a refined capsular treatment based on the control group's procedure. We assessed the differences in visual acuity and quality between the two groups before and after surgery. RESULTS: At six months post-operation, the observation group exhibited significantly improved far vision, intermediate vision, near vision, lower objective scattering index, higher Modulation transfer function cut-off frequency, and overall vision metrics at different contrast levels (100%, 20% and 9%) compared to the control group (P < 0.05). The total score of the National Eye Institute Visual Function Questionnaire in the observation group at 6 months after operation was significantly higher than that in the control group (P < 0.05). No significant difference in the incidence of adverse reactions was observed between the observation group and control group (P > 0.05). CONCLUSION: Capsular treatment demonstrates efficacy in improving visual acuity and quality after phacoemulsification lens implantation in myopic patients with cataracts, warranting its clinical application.

Germline variants in acquired aplastic anemia: current knowledge and future perspectives.

Aplastic anemia (AA) is a disease characterized by hematopoiesis failure, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. Besides confirmed genomic mutations that contribute to inherited AA (such as pathogenic mutations of TERT and TERC), germline variants, often in heterozygous states, also play an unignorable role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes (IBMFS) and inborn errors of immunity (IEI), contribute to the disease possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. This article explores the nuanced association between acquired AA and germline variants, detailed the clinical significance of germline variants in diagnosing and clinical management of this condition. More works are encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutation participate as secondary "hit" in the development of bone marrow failure.

Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment.

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.

Serum Fatty Acid Profiles and Neurofilament Light Chain Levels in the General Population.

BACKGROUND: Previous studies have demonstrated associations between fatty acids and neurological disorders. However, no studies have examined the relationship between serum fatty acid levels and serum neurofilament light chain (NfL), a biomarker of neurological disorders. OBJECTIVE: This study aimed to comprehensively investigate the intricate relationship between 30 serum fatty acids and serum NfL levels in a nationally representative sample of U.S. adults, utilizing data from the 2013-2014 National Health and Nutrition Examination Survey. METHODS: Employing a cross-sectional analysis, multivariable linear regression models were utilized to explore the associations between 30 serum fatty acids and serum NfL levels. This analysis involved adjustment for potential confounding variables, including age, sex, race, body-mass index (BMI), smoking status, hyperlipidemia, and diabetes, to clarify the association between serum fatty acids and serum NfL levels. RESULTS: The analysis revealed that certain fatty acids exhibited distinct associations with serum NfL levels. Notably, Docosanoic acid (22:0) and Tricosanoic acid (C23:0) were found to be inversely associated with serum NfL levels (ß = -0.280, 95% CI: -0.525, -0.035; ß = -0.292, 95% CI: -0.511, -0.072). Conversely, Palmitoleic acid (16:1n-7) demonstrated a positive association with serum NfL levels (ß = 0.125, 95% CI: 0.027, 0.222). Notably, these associations remained significant even after adjustment for potential confounders. CONCLUSIONS: Individuals with high relative concentrations of certain saturated fatty acids exhibited decreased serum NfL, whereas those with high relative concentrations of certain monounsaturated fatty acids showed increased serum NfL. These findings contribute to a deeper understanding of the potential impact of serum fatty acids on NfL levels, shedding light on novel avenues for further investigation and potential interventions in the context of neurological health.

Atf4 protects islet ß-cell identity and function under acute glucose-induced stress but promotes ß-cell failure in the presence of free fatty acid.

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in ß-cell failure and type 2 diabetes (T2D) via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in ß-cells is dispensable for glucose homeostasis in young mice, but it is required for ß-cell function during aging and under obesity-related metabolic stress. Henceforth, aged Atf4- deficient ß-cells display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced loss-of identity and dysfunction. At molecular level, Atf4 -deficient ß-cells down-regulate genes involved in protein translation, reducing ß-cell identity gene products under high glucose. They also upregulate several genes involved in lipid metabolism or signaling, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for ß-cell identity and function under high glucose, but this paradoxically induces ß-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting ß-cells from metabolic stress-induced failure. Highlights: Atf4 is dispensable in ß-cells in young miceAtf4 protects ß-cells under high glucoseAtf4 exacerbate fatty acid-induced ß-cell defectsAtf4 activates translation but depresses lipid-metabolism.

Multimodal biosensing systems based on metal nanoparticles.

Biosensors are currently among the most commonly used devices for analysing biomarkers and play an important role in environmental detection, food safety, and disease diagnosis. Researchers have developed multimodal biosensors instead of single-modal biosensors to meet increasing sensitivity, accuracy, and stability requirements. Metal nanoparticles (MNPs) are beneficial for preparing core probes for multimodal biosensors because of their excellent physical and chemical properties, such as easy regulation and modification, and because they can integrate diverse sensing strategies. This review mainly summarizes the excellent physicochemical properties of MNPs applied as biosensing probes and the principles of commonly used MNP-based multimodal sensing strategies. Recent applications and possible improvements of multimodal biosensors based on MNPs are also described, among which on-site inspection and sensitive detection are particularly important. The current challenges and prospects for multimodal biosensors based on MNPs may provide readers with a new perspective on this field.

Interaction of antiphospholipid antibodies with endothelial cells in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease with arteriovenous thrombosis and recurrent miscarriages as the main clinical manifestations. Due to the complexity of its mechanisms and the diversity of its manifestations, its diagnosis and treatment remain challenging issues. Antiphospholipid antibodies (aPL) not only serve as crucial "biomarkers" in diagnosing APS but also act as the "culprits" of the disease. Endothelial cells (ECs), as one of the core target cells of aPL, bridge the gap between the molecular level of these antibodies and the tissue and organ level of pathological changes. A more in-depth exploration of the relationship between ECs and the pathogenesis of APS holds the potential for significant advancements in the precise diagnosis, classification, and therapy of APS. Many researchers have highlighted the vital involvement of ECs in APS and the underlying mechanisms governing their functionality. Through extensive in vitro and in vivo experiments, they have identified multiple aPL receptors on the EC membrane and various intracellular pathways. This article furnishes a comprehensive overview and summary of these receptors and signaling pathways, offering prospective targets for APS therapy.

Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity.

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

Compare clinical efficacy and safety of neoadjuvant therapy and neoadjuvant chemoradiotherapy for locally advanced rectal cancer: Meta-analysis.

BACKGROUND: To compare the efficacy and safety of total neoadjuvant therapy (TNT) and neoadjuvant chemoradiotherapy (nCRT) in the treatment of middle and low locally advanced rectal cancer. Our study will systematically collect and integrate studies to evaluate the ability of these two treatments to improve tumor shrinkage rates, surgical resection rates, tumor-free survival, and severe adverse events. AIM: To provide clinicians and patients with more reliable treatment options to optimize treatment outcomes and quality of life for patients with locally advanced rectal cancer by comparing the advantages and disadvantages of the two treatment options. METHODS: A full search of all clinical studies on the effectiveness and safety of TNT and nCRT for treating locally advanced rectal cancer identified in Chinese (CNKI, Wanfang, China Biomedical Literature Database) and English (PubMed, Embase) databases was performed. Two system assessors independently screened the studies according to the inclusion and exclusion criteria. Quality evaluation and data extraction were performed for the included literature. We used RevMan 5.3 software to perform a meta-analysis of the pathologic complete response (pCR) rate, T stage degradation rate, resection 0 (R0) rate, anal grade 3/4 acute toxicity rate, perioperative complications, overall survival (OS), and disease-free survival (DFS) in the TNT and nCRT groups. RESULTS: Finally, 14 studies were included, six of which were randomized controlled studies. A total of 3797 patients were included, including 1865 in the TNT group and 1932 in the nCRT group. The two sets of baseline data were comparable. The results of the meta-analysis showed that the pCR rate [odds ratio (OR) = 1.57, 95% confidence interval (CI): 1.30-1.90, P < 0.00001], T stage degradation rate (OR = 2.16, 95%CI: 1.63-2.57, P < 0.00001), and R0 resection rate (OR = 1.42, 95%CI: 1.09-1.85, P = 0.009) were significantly greater in the nCRT group than in the nCRT group. There was no significant difference in the incidence of grade 3/4 acute toxicity or perioperative complications between the two groups. The 5-year OS [hazard ratio (HR) = 0.84, 95%CI: 0.69-1.02, P = 0.08] and DFS (HR = 0.94, 95%CI: 0.03-1.39, P = 0.74) of the TNT group were similar to those of the nCRT group. CONCLUSION: TNT has greater clinical efficacy and safety than nCRT in the treatment of locally advanced rectal cancer.

m3C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response.

The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m3C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/2B-, METTL6-, and METTL2A/2B/6-dependent m3C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m3C32 on tRNA-Ser-GCT isodecoders is only observed with combined METTL2A/2B/6 deletion. Ribo-Seq reveals altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed altered cell cycle, slowed proliferation, and increased cisplatin sensitivity phenotypes of METTL2A/2B/6-deficient cells. Thus, we define METTL2A/2B/6-dependent methylomes and uncover a particular requirement of m3C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.

Conditional survival and the prognostic value of serum carcinoembryonic antigen level in oldest old with colorectal cancer.

BACKGROUND: To evaluate the clinical value of serum CEA levels and their implications on the diagnostic value of the conventional TNM staging system in the oldest-old patients with colorectal cancer (CRC). METHODS: The recruited subjects were colorectal cancer patients aged 85 and older. The cutoff value for normal CEA level is 5 ng/mL. Patients with elevated CEA levels were categorized as stage C1, and those with normal CEA levels as stage C0. A number of Cox proportional hazard regression models were established to evaluate the prognosis of different prognostic factors with hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier method was utilized to display the disparate prognostic impact of multiple clinicopathological factors with the log-rank test. RESULTS: A total of 17,359 oldest-old patients diagnosed with CRC were recruited from the SEER database. The conditional survival of oldest-old patients with CRC was dismal with a 1-year conditional survival of only 11%, 18%, and 30% for patients surviving 1, 3, and 5 years, respectively. Patients with stage C1 exhibited a 48.5% increased risk of CRC-specific mortality compared with stage C0 (HR = 1.485, 95%CI = 1.393-1.583, using stage C0 patients as the reference, P < 0.001). All the stage C0 patients indicated lower HRs relative to the corresponding stage C1 patients. CONCLUSIONS: Dismal conditional survival of oldest-old patients with CRC should be given additional consideration. C stage influences the prognosis of oldest-old patients with CRC.