ABSTRACT
Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for promoting the immunosuppressive capacity of TIMs.
Subject(s)
Methyltransferases , Neoplasms , Adenosine/metabolism , Animals , Humans , Immunosuppression Therapy , Methyltransferases/genetics , Methyltransferases/metabolism , Mice , Myeloid Cells/metabolism , RNA , Tumor MicroenvironmentABSTRACT
Stimulus-responsive shape-shifting polymers1-3 have shown unique promise in emerging applications, including soft robotics4-7, medical devices8, aerospace structures9 and flexible electronics10. Their externally triggered shape-shifting behaviour offers on-demand controllability essential for many device applications. Ironically, accessing external triggers (for example, heating or light) under realistic scenarios has become the greatest bottleneck in demanding applications such as implantable medical devices8. Certain shape-shifting polymers rely on naturally present stimuli (for example, human body temperature for implantable devices)8 as triggers. Although they forgo the need for external stimulation, the ability to control recovery onset is also lost. Naturally triggered, yet actively controllable, shape-shifting behaviour is highly desirable but these two attributes are conflicting. Here we achieved this goal with a four-dimensional printable shape memory hydrogel that operates via phase separation, with its shape-shifting kinetics dominated by internal mass diffusion rather than by heat transport used for common shape memory polymers8-11. This hydrogel can undergo shape transformation at natural ambient temperature, critically with a recovery onset delay. This delay is programmable by altering the degree of phase separation during device programming, which offers a unique mechanism for shape-shifting control. Our naturally triggered shape memory polymer with a tunable recovery onset markedly lowers the barrier for device implementation.
ABSTRACT
Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders. Here, we demonstrate that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitylates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of neural precursor cells. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.
Subject(s)
Adaptor Proteins, Signal Transducing , Brain , Neural Stem Cells , TOR Serine-Threonine Kinases , Ubiquitin-Protein Ligases , Animals , Mice , Brain/growth & development , Neural Stem Cells/metabolism , Sirolimus , TOR Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/metabolism , Adaptor Proteins, Signal Transducing/metabolismABSTRACT
INTRODUCTION: The joint associations across genetic risk, modifiable lifestyle factors, and inflammatory bowel disease (IBD) remains unclear. METHODS: Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into high, intermediate, and low genetic risk categories. Weighted healthy lifestyle scores were constructed based on 5 common lifestyle factors and categorized into favorable (4 or 5 healthy lifestyle factors), intermediate (3 healthy lifestyle factors), and unfavorable (0-2 healthy lifestyle factors) groups. Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for their associations. RESULTS: During the 12-year follow-up, 707 cases with CD and 1576 cases with UC were diagnosed in the UK Biobank cohort. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk with no multiplicative interaction between them. The HR of CD and UC were 2.24 (95% CI 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with a high genetic risk, respectively. The HR of CD and UC for individuals with an unfavorable lifestyle were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively. The HR of individuals with a high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI 1.58-2.66 for UC) were reduced nearly by half, compared with those with a high genetic risk but an unfavorable lifestyle (4.40, 95% CI 2.91-6.66 for CD and 4.44, 95% CI 3.34-5.91 for UC). DISCUSSION: Genetic and lifestyle factors were independently associated with susceptibility to incident CD and UC. Adherence to a favorable lifestyle was associated with a nearly 50% lower risk of CD and UC among participants at a high genetic risk.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Adult , Humans , Prospective Studies , Inflammatory Bowel Diseases/complications , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/complications , Crohn Disease/epidemiology , Crohn Disease/genetics , Crohn Disease/complications , Risk Factors , Life Style , IncidenceABSTRACT
Patients with conventional adenoma removal are recommended to undergo colonoscopy surveillance to prevent colorectal cancer (CRC). However, evidence supporting the guidelines of colonoscopy surveillance is limited, especially among the Chinese population. We investigated the association between colonoscopy adenoma findings and CRC risk among individuals aged 40 to 74 years who underwent baseline colonoscopy from 2007 to 2016 in Jiashan and Haining, Zhejiang, China; 34 382 participants were categorized into advanced adenoma, nonadvanced adenoma and no adenoma based on adenoma findings. A multivariable Cox regression model was used to estimate the hazard ratio (HR) of CRC incidence with adjustment for potential confounding factors. After a median follow-up time of 7.7 years, 113 incident cases of CRC were identified (18 occurred in 1632 participants with advanced adenoma, 16 in 3973 participants with nonadvanced adenoma and 79 in 28 777 participants with no adenoma). Compared to no adenoma group, the adjusted HR for CRC in advanced adenoma group was 4.01 (95% CI, 2.37-6.77). For nonadvanced adenomas, individuals with ≥3 adenomas showed an increased risk of CRC (HR, 3.65; 95% CI, 1.43-9.31), but no significantly increased risk of CRC was found for 1 to 2 nonadvanced adenomas, compared to those with no adenoma. Our study suggested that the risk of subsequent CRC increased in individuals with high-risk adenoma (at least one advanced adenoma or ≥3 nonadvanced adenomas), but not in those with 1 to 2 nonadvanced adenomas. These results provide the first evidence from the Chinese population for the current surveillance guidelines.
Subject(s)
Adenoma/surgery , Colonoscopy , Colorectal Neoplasms/etiology , Early Detection of Cancer , Adult , Aged , Female , Humans , Male , Middle Aged , Proportional Hazards Models , Risk FactorsABSTRACT
BACKGROUND: Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. PATIENTS AND METHODS: Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. RESULTS: OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3ß, we verified GSK3ß was over-activated in OLA1-KO cell lines. CONCLUSION: OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3ß.
Subject(s)
Adenosine Triphosphatases , Colorectal Neoplasms , GTP-Binding Proteins , Adenosine Triphosphatases/genetics , Antigens, Neoplasm , Carbonic Anhydrase IX/metabolism , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Colorectal Neoplasms/pathology , GTP-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Humans , RNA, Messenger , Retrospective StudiesABSTRACT
BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/surgery , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Laparoscopy , Aged , Capecitabine , Chemotherapy, Adjuvant , Colorectal Neoplasms/pathology , Costs and Cost Analysis , Deoxycytidine/therapeutic use , Female , Fluorouracil/therapeutic use , Humans , Length of Stay , Leucovorin/therapeutic use , Male , Middle Aged , Organoplatinum Compounds/therapeutic use , Oxaloacetates , Prospective Studies , Quality of Life , Treatment OutcomeABSTRACT
The utility of a prediction model depends on its generalizability to patients drawn from different but related populations. We explored whether a semi-supervised learning model could improve the generalizability of colorectal cancer (CRC) risk prediction relative to supervised learning methods. Data on 113,141 patients diagnosed with nonmetastatic CRC from 2004 to 2012 were obtained from the Surveillance Epidemiology End Results registry for model development, and data on 1149 patients from the Second Affiliated Hospital, Zhejiang University School of Medicine, who were diagnosed between 2004 and 2011, were collected for generalizability testing. A clinical prediction model for CRC survival risk using a semi-supervised logistic regression method was developed and validated to investigate the model discrimination, calibration, generalizability, interpretability and clinical usefulness. Rigorous model performance comparisons with other supervised learning models were performed. The area under the curve of the logistic membership model revealed a large heterogeneity between the development cohort and validation cohort, which is typical of generalizability studies of prediction models. The discrimination was good for all models. Calibration was poor for supervised learning models, while the semi-supervised logistic regression model exhibited a good calibration on the validation cohort, which indicated good generalizability. Clinical usefulness analysis showed that semi-supervised logistic regression can lead to better clinical outcomes than supervised learning methods. These results increase our current understanding of the generalizability of different models and provide a reference for predictive model development for clinical decision-making.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , Models, Statistical , Supervised Machine Learning , Adolescent , Adult , Aged , Aged, 80 and over , Child , Diagnosis, Computer-Assisted , Female , Humans , Male , Middle Aged , Prognosis , Risk , Survival Analysis , Young AdultABSTRACT
BACKGROUND: An increasing number of studies have identified spatial differences in colorectal cancer survival. However, little is known about the spatially varying effects of predictors in survival prediction modeling studies of colorectal cancer that have focused on estimating the absolute survival risk for patients from a wide range of populations. This study aimed to demonstrate the spatially varying effects of predictors of survival for nonmetastatic colorectal cancer patients. METHODS: Patients diagnosed with nonmetastatic colorectal cancer from 2004 to 2013 who were followed up through the end of 2013 were extracted from the Surveillance Epidemiology End Results registry (Patients: 128061). The log-rank test and the restricted mean survival time were used to evaluate survival outcome differences among spatial clusters corresponding to a widely used clinical predictor: stage determined by AJCC 7th edition staging system. The heterogeneity test, which is used in meta-analyses, revealed the spatially varying effects of single predictors. Then, considering the above predictors in a standard survival prediction model based on spatially clustered data, the spatially varying coefficients of these models revealed that some covariate effects may not be constant across the geographic regions of the study. Then, two types of survival prediction models (a statistical model and a machine learning model) were built; these models considered the predictors and enabled survival prediction for patients from a wide range of geographic regions. RESULTS: Based on univariate and multivariate analysis, some prognostic factors, such as "TNM stage", "tumor size" and "age at diagnosis," have significant spatially varying effects among different regions. When considering these spatially varying effects, machine learning models have fewer assumption constraints (such as proportional hazard assumptions) and better predictive performance compared with statistical models. Upon comparing the concordance indexes of these two models, the machine learning model was found to be more accurate (0.898[0.895,0.902]) than the statistical model (0.732 [0.726, 0.738]). CONCLUSIONS: Based on this study, it's recommended that the spatially varying effect of predictors should be considered when building survival prediction models involving large-scale and multicenter research data. Machine learning models that are not limited by the requirement of a statistical hypothesis are promising alternative models.
Subject(s)
Colorectal Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Female , Humans , Kaplan-Meier Estimate , Machine Learning , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Prognosis , Proportional Hazards Models , SEER Program , Spatial Analysis , United States/epidemiologyABSTRACT
BACKGROUND: To revise the American Joint Committee on Cancer TNM staging system for colorectal cancer (CRC) based on a nomogram analysis of Surveillance, Epidemiology, and End Results (SEER) database, and to prove the rationality of enhancing T stage's weighting in our previously proposed T-plus staging system. METHODS: Total 115,377 non-metastatic CRC patients from SEER were randomly grouped as training and testing set by ratio 1:1. The Nomo-staging system was established via three nomograms based on 1-year, 2-year and 3-year disease specific survival (DSS) Logistic regression analysis of the training set. The predictive value of Nomo-staging system for the testing set was evaluated by concordance index (c-index), likelihood ratio (L.R.) and Akaike information criteria (AIC) for 1-year, 2-year, 3-year overall survival (OS) and DSS. Kaplan-Meier survival curve was used to valuate discrimination and gradient monotonicity. And an external validation was performed on database from the Second Affiliated Hospital of Zhejiang University (SAHZU). RESULTS: Patients with T1-2 N1 and T1N2a were classified into stage II while T4 N0 patients were classified into stage III in Nomo-staging system. Kaplan-Meier survival curves of OS and DSS in testing set showed Nomo-staging system performed better in discrimination and gradient monotonicity, and the external validation in SAHZU database also showed distinctly better discrimination. The Nomo-staging system showed higher value in L.R. and c-index, and lower value in AIC when predicting OS and DSS in testing set. CONCLUSION: The Nomo-staging system showed better performance in prognosis prediction and the weight of lymph nodes status in prognosis prediction should be cautiously reconsidered.
Subject(s)
Colorectal Neoplasms/epidemiology , Nomograms , Prognosis , Colorectal Neoplasms/pathology , Female , Humans , Kaplan-Meier Estimate , Male , Neoplasm Staging , SEER ProgramABSTRACT
BACKGROUND AND OBJECTIVE: Clinical prognosis prediction plays an important role in clinical research and practice. The construction of prediction models based on electronic health record data has recently become a research focus. Due to the lack of external validation, prediction models based on single-center, hospital-specific datasets may not perform well with datasets from other medical institutions. Therefore, research investigating prognosis prediction model construction based on a collaborative analysis of multi-center electronic health record data could increase the number and coverage of patients used for model training, enrich patient prognostic features and ultimately improve the accuracy and generalization of prognosis prediction. MATERIALS AND METHODS: A web service for individual prognosis prediction based on multi-center clinical data collaboration without patient-level data sharing (POPCORN) was proposed. POPCORN focuses on solving key issues in multi-center collaborative research based on electronic health record systems; these issues include the standardization of clinical data expression, the preservation of patient privacy during model training and the effect of case mix variance on the prediction model construction and application. POPCORN is based on a multivariable meta-analysis and a Bayesian framework and can construct suitable prediction models for multiple clinical scenarios that can effectively adapt to complex clinical application environments. RESULTS: POPCORN was validated using a joint, multi-center collaborative research network between China and the United States with patients diagnosed with colorectal cancer. The performance of the models based on POPCORN was comparable to that of the standard prognosis prediction model; however, POPCORN did not expose raw patient data. The prediction models had similar AUC, but the BMA model had the lowest ECI across all prediction models, indicating that this model had better calibration performance than the other models, especially for patients in Chinese hospitals. CONCLUSIONS: The POPCORN system can build prediction models that perform well in complex clinical application scenarios and can provide effective decision support for individual patient prognostic predictions.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/epidemiology , Decision Support Systems, Clinical , Electronic Health Records , Internet , Access to Information , Aged , Algorithms , Bayes Theorem , Calibration , China , Diagnosis, Computer-Assisted , Female , Humans , Information Dissemination , International Cooperation , Male , Middle Aged , Probability , Prognosis , Reproducibility of Results , United StatesABSTRACT
The inflammasome is a caspase-1-activating complex that is implicated in a growing number of acute and chronic pathologies. Interest has increased in identifying small molecular inhibitors of inflammasome signaling because of its role in clinically relevant diseases. It was recently reported that the protein tyrosine kinase, Syk, regulates pathogen-induced inflammasome signaling by phosphorylating a molecular switch on the adapter protein ASC. However, several aspects of the role of Syk in inflammasome signaling and the effects of its inhibition remain unclear. The aim of the present study is to explore in detail the effects of the oxindole Syk inhibitor OXSI-2 on various aspects of nigericin-induced inflammasome signaling. Our results indicate that OXSI-2 inhibits inflammasome assembly, caspase-1 activation, IL-1ß processing and release, mitochondrial ROS generation, and pyroptotic cell death. Using a novel live cell potassium sensor we show that Syk inhibition with OXSI-2 has no effect on potassium efflux kinetics and that blockade of potassium efflux with extracellular potassium alters Syk phosphorylation. The effects of OXSI-2 identified in this study provide context for the role of Syk in inflammasome signaling and demonstrate its importance in oxidative signaling upstream of inflammasome activation and downstream of ion flux.
Subject(s)
Indoles/administration & dosage , Inflammasomes/metabolism , Potassium/metabolism , Pyroptosis/physiology , Signal Transduction/physiology , Sulfonamides/administration & dosage , Animals , Cell Line , Dose-Response Relationship, Drug , Drug Interactions , Intracellular Signaling Peptides and Proteins , Macrophages/drug effects , Macrophages/pathology , Macrophages/physiology , Metabolic Clearance Rate/drug effects , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Nigericin/administration & dosage , Oxindoles , Protein-Tyrosine Kinases , Pyroptosis/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Syk KinaseABSTRACT
An ideal fluorescent dye for staining cell organelles should have multiple properties including specificity, stability, biocompatibility, and a large Stokes shift. Tunable photophysical properties enable 1,8-naphthalimide to serve as an excellent fluorophore in biomedical applications. Many naphthalimide derivatives have been developed into drugs, sensors, and other dyes. In this study, a series of 1,8-naphthalimide derivatives targeting live cell mitochondria were synthesized. Among these probes, Mt-4 was characterized as the best one, with highly specific mitochondrial localization, low cytotoxicity, and a large Stokes shift. More importantly, Mt-4 stood out as a potential mitochondrial dye for living-cell experiments involving induced mitochondrial stress arising from the treatments because Mt-4 shows enhanced fluorescence in mitochondrial stress situations.
Subject(s)
Fluorescent Dyes/chemistry , Mitochondria/metabolism , Naphthalimides/chemistry , Cell Survival , Fluorescent Dyes/chemical synthesis , HeLa Cells , Humans , Molecular StructureABSTRACT
A novel actinomycete, designated strain 1H-HV4T, was isolated from the head of Camponotus japonicas Mayr, which was collected from Northeast Agriculture University (Harbin, Heilongjiang, China). Chemotaxonomic properties of this strain were consistent with those of members of the genus Nocardia. The cell wall contained meso-diaminopimelic acid and whole-cell sugars were galactose, glucose and arabinose. The predominant menaquinone was MK-8(H4,ω-cycl). The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major fatty acids were identified as C18:0 10-methyl, C16:0, C18:1ω9c and C16:1ω7c. Mycolic acids were found to be present. 16S rRNA gene sequence analysis also showed that strain 1H-HV4T was a member of the genus Nocardia, with the highest sequence similarities to Nocardia salmonicida JCM 4826T (97.39%), Nocardia soli JCM 11441T (97.12%) and Nocardia cummidelens JCM 11439T (97.08%). 16S rRNA gene sequence similarities to type strains of other members of the genus Nocardia were less than 97%. However, DNA-DNA relatedness values and phenotypic data demonstrated that strain1H-HV4T was clearly distinguished from all closely related species of the genus Nocardia. It is concluded that the isolate can be classified as representing a novel species of the genus Nocardia, for which the name Nocardia camponoti is proposed. The type strain is 1H-HV4T (=DSM 100526T=CGMCC 4.7278T).
Subject(s)
Ants/microbiology , Nocardia/classification , Phylogeny , Animals , Bacterial Typing Techniques , Base Composition , China , DNA, Bacterial/genetics , Diaminopimelic Acid/chemistry , Fatty Acids/chemistry , Molecular Sequence Data , Nocardia/genetics , Nocardia/isolation & purification , Nucleic Acid Hybridization , Phospholipids/chemistry , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Vitamin K 2/analogs & derivatives , Vitamin K 2/chemistryABSTRACT
Regulation of intracellular potassium (K(+) ) concentration plays a key role in metabolic processes. So far, only a few intracellular K(+) sensors have been developed. The highly selective fluorescent K(+) sensor KS6 for monitoring K(+) ion dynamics in mitochondria was produced by coupling triphenylphosphonium, borondipyrromethene (BODIPY), and triazacryptand (TAC). KS6 shows a good response to K(+) in the range 30-500â mM, a large dynamic range (Fmax /F0 ≈130), high brightness (Ïf =14.4 % at 150â mM of K(+) ), and insensitivity to both pH in the range 5.5-9.0 and other metal ions under physiological conditions. Colocalization tests of KS6 with MitoTracker Green confirmed its predominant localization in the mitochondria of HeLa and U87MG cells. K(+) efflux/influx in the mitochondria was observed upon stimulation with ionophores, nigericin, or ionomycin. KS6 is thus a highly selective semiquantitative K(+) sensor suitable for the study of mitochondrial potassium flux in live cells.
Subject(s)
Boron Compounds/chemistry , Fluorescent Dyes/chemistry , Mitochondria/metabolism , Potassium/analysis , Cations, Monovalent/analysis , Cations, Monovalent/metabolism , Cell Line , HeLa Cells , Humans , Microscopy, Fluorescence/methods , Optical Imaging/methods , Potassium/metabolism , Potassium Channels/metabolismABSTRACT
Total-body PET, an emerging technique, enables high-quality simultaneous total-body dynamic PET acquisition and accurate kinetic analysis. It has the potential to facilitate the study of multiple tracers while minimizing radiation dose and improving tracer-specific imaging. This advancement holds promise for enhancing the development and clinical evaluation of drugs, particularly radiopharmaceuticals. Multiple clinical trials are using a total-body PET scanner to explore existing and innovative radiopharmaceuticals. However, challenges persist, along with the opportunities, with regard to the use of total-body PET in drug development and evaluation. Specifically, considerations relate to the role of total-body PET in clinical pharmacologic evaluations and its integration into the theranostic paradigm. In this review, state-of-the-art total-body PET and its potential roles in pharmaceutical research are explored.
Subject(s)
Drug Development , Positron-Emission Tomography , Whole Body Imaging , Humans , Positron-Emission Tomography/methods , Radiopharmaceuticals , AnimalsABSTRACT
Nearly twenty-five percent of colorectal cancer (CRC) patients develop metachronous colorectal liver metastasis (CRLM) after curative surgery. Hepatosteatosis is the most prevalent liver condition worldwide, but its impact on the incidence of metachronous CRLM is understudied. In the present study, we aimed to investigate the predictive value of hepatic steatosis on the development of metachronous CRLM. First, a nested case-control study was conducted, enrolling stage I to III CRC patients in the National Colorectal Cancer Cohort (NCRCC) database. Metachronous CRLM patients and recurrence-free patients were matched via propensity-score matching. Fatty liver was identified based on treatment-naïve CT scans and the degree of hepatic fibrosis was scored. Multivariable analysis was conducted to investigate the association between fatty liver and metachronous CRLM. In our database, a total of 414 patients were included. Metachronous CRLM patients had considerably higher rates of hepatic steatosis (30.9% versus 15.9%, P<0.001) and highly fibrotic liver (11.6% versus 2.9%, P=0.001) compared to recurrence-free patients. Multivariable analysis showed that fatty liver (odds ratios [OR]=1.99, 95% confidence interval [CI] 1.19-3.30, P=0.008) and fibrotic liver (OR=4.27, 95% CI 1.54-11.81, P=0.005) were associated with high risk of metachronous CRLM. Further, a systematic literature review was performed to assess available evidence on the association between hepatosteatosis and development of metachronous CRLM. In the systematic review, 1815 patients were pooled from eligible studies, and hepatic steatosis remained a significant risk factor for metachronous CRLM (OR=1.90, 95% CI 1.35-2.66, P<0.001, I2=25.3%). In conclusion, our data suggest that patients with a steatotic liver and a high fibrosis score at CRC diagnosis have elevated risk of developing metachronous CRLM.
ABSTRACT
BACKGROUND: Colorectal cancer is a leading cause of cancer-related deaths worldwide, with approximately 1.9 million new cases and over 935,000 deaths in 2020. Right-sided colon cancer, a subset of colorectal cancer, represents a significant health burden. Laparoscopic colon surgery has significantly improved postoperative recovery. The superiority of one approach or landmark over another is still argued about due to the lack of large-scale prospective studies. However, deep understanding both of the anatomical variation and characteristics of each approach is of extreme importance to minimizing adverse effects and maximizing patient benefit after laparoscopic right hemicolectomy. Among these, the cranial-to-caudal approach offers advantages such as reduced intraoperative blood loss, shorter operation time, and decreased risk of vascular injury. The purpose of this study is to compare the efficacy and safety of two cranial-to-caudal approaches for laparoscopic right hemicolectomy (LRH). Specifically, the study aims to evaluate the differences between the conventional cranial-to-caudal approach with medial ligation of the middle colic vein (MCV), and the cranial-to-caudal approach with cranial MCV ligation and surgical trunk sheath opening (CC-plus). The goal is to determine which method offers superior outcomes in terms of intraoperative blood loss, operation time, and overall patient recovery. MATERIALS AND METHODS: This single-center retrospective study compared two cranial-to-caudal approaches for LRH. The study included 51 patients who underwent LRH between January 2021 and November 2023 at the Second Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups: Group A (26 patients) used the cranial-to-caudal approach with medial ligation of the middle colic vein (MCV), and Group B (25 patients) used the cranial-to-caudal approach with cranial MCV ligation and surgical trunk sheath opening (CC-plus). General characteristics, intraoperative parameters, and postoperative outcomes were compared. Statistical analysis was performed using SPSS version 20.0, with significance set at p < 0.05. RESULTS: There were no significant differences between the groups regarding age, gender, tumor location, or clinical staging. All patients achieved R0 resection with no perioperative deaths. The CC-plus group had significantly reduced intraoperative blood loss and shorter operation time compared to the CC group (p < 0.05). No significant differences were found in first postoperative exhausting time, first postoperative defecation time, and postoperative hospital stay between the two groups. Furthermore, no significant differences were evaluated in postoperative complications (surgical site infection (SSI), ileus or bowel obstruction, refractory diarrhea, anastomotic leakage, deep vein thrombosis (DVT), hemorrhage) between the two groups on a median follow up of 12.6 months. Pathological examination showed no significant differences in total lymph nodes dissected and tumor stage. CONCLUSIONS: The cranial-to-caudal approach with MCV ligation via the cranial approach (CC-plus) is a safe and effective method for LRH, offering advantages in terms of reduced operation time and intraoperative blood loss. This study's findings suggest that the CC-plus approach may be superior to the conventional cranial-to-caudal approach.
ABSTRACT
Background: Traditional right hemicolectomy (TRH) is the standard treatment for patients with nonmetastatic right colon cancer. However, the ileocecum, a vital organ with mechanical and immune functions, is removed in these patients regardless of the tumor location. This study aimed to evaluate the technical and oncological safety of laparoscopic ileocecal-sparing right hemicolectomy (LISH). Method: Patients who underwent LISH at two tertiary medical centers were matched 1:2 with patients who underwent TRH by propensity score matching based on sex, age, body mass index, tumor location, and disease stage. Data on surgical and perioperative outcomes were collected. Oncological safety was evaluated in a specimen-oriented manner. Lymph nodes (LNs) near the ileocolic artery (ICA) were examined independently in the LISH group. Disease outcomes were recorded for patients who completed one year of follow-up. Results: In all, 34 patients in the LISH group and 68 patients in the TRH group were matched. LISH added 8 minutes to the dissection of LNs around the ileocolic vessels (groups 201/201d, 202, and 203 LNs), without affecting the total operation time, blood loss, or perioperative adverse event rate. Compared with TRH, LISH had a comparable lymphadenectomy quality, specimen quality, and safety margin while preserving a more functional bowel. The LISH group had no cases of LN metastasis near the ICA. No difference was detected in the recurrence rate at the 1-year follow-up time point between the two groups. Conclusion: In this dual-center study, LISH presented comparable surgical and oncological safety for patients with hepatic flexure or proximal transverse colon cancer.
ABSTRACT
Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4+T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers.