Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted ...a multicenter, prospective clinical study which recruited 4,245 high‐risk CRC individuals defined as having positive risk‐adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT‐sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT‐sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT‐sDNA test was 91.9% (95% CI, 86.8–95.3), compared with 62.4% (95% CI, 54.9–69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3–68.3) for FIT‐sDNA test, compared with 30.9% (95% CI, 26.3–35.6) for FIT (P < 0.001). Multitarget FIT‐sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT‐sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.
We conducted a multicenter, prospective clinical study which recruited 4,245 high‐risk CRC individuals to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT‐sDNA) test for CRC screening. We found that the FIT‐sDNA test detected more colorectal advanced neoplasia than FIT. It indicated that in areas with limited colonoscopy resources, the FIT‐sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.
Semiconducting polymers (SPs) have shown great feasibility as candidates for near-infrared-II (NIR-II) fluorescence imaging-navigated photothermal therapy due to their strong light-harvesting ability ...and flexible tunability. However, the fluorescence signal of traditional SPs tends to quench in their aggregate states owing to the strong π-π stacking, which can lead to the radiative decay pathway shutting down. To address this issue, aggregation-induced emission effect has been used as a rational tactic to boost the aggregate-state fluorescence of NIR-II emitters. In this contribution, we developed a precise molecular engineering tactic based on the block copolymerizations that integrate planar and twisted segments into one conjugated polymer backbone, providing great flexibility in tuning the photophysical properties and photothermal conversion capacity of SPs. Two monomers featured with twisted and planar architectures, respectively, were tactfully incorporated via a ternary copolymerization approach to produce a series of new SPs. The optimal copolymer (SP2) synchronously shows desirable absorption ability and good NIR-II quantum yield on the premise of maintaining typical aggregation-induced emission characteristics, resulting in balanced NIR-II fluorescence brightness and photothermal property. Water-dispersible nanoparticles fabricated from the optimal SP2 show efficient photothermal therapeutic effects both in vitro and in vivo. The in vivo investigation reveals the distinguished NIR-II fluorescence imaging performance of SP2 nanoparticles and their photothermal ablation toward tumor with prominent tumor accumulation ability and excellent biocompatibility.
Mountain-cultivated ginseng (MCG) and cultivated ginseng (CG) both belong to Panax ginseng and have similar ingredients. However, their pharmacological activities are different due to their ...significantly different growth environments.
An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS)-based approach was developed to distinguish MCG and CG. Multivariate statistical methods, such as principal component analysis and supervised orthogonal partial-least-squares discrimination analysis were used to select the influential components.
Under optimized UPLC-QTOF-MS/MS conditions, 40 ginsenosides in both MCG and CG were unambiguously identified and tentatively assigned. The results showed that the characteristic components of CG and MCG included ginsenoside Ra3/isomer, gypenoside XVII, quinquenoside R1, ginsenoside Ra7, notoginsenoside Fe, ginsenoside Ra2, ginsenoside Rs6/Rs7, malonyl ginsenoside Rc, malonyl ginsenoside Rb1, malonyl ginsenoside Rb2, palmitoleic acid, and ethyl linoleate. The malony ginsenosides are abundant in CG, but higher levels of the minor ginsenosides were detected in MCG.
This is the first time that the differences between CG and MCG have been observed systematically at the chemical level. Our results suggested that using the identified characteristic components as chemical markers to identify different ginseng products is effective and viable.
Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimer's disease (AD). In the present study, we examined ...neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice. The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of Aβ1–40 and Aβ1–42 in the hippocampus and cortex through increased activity of β- and γ-secretases accompanied with increased expression of amyloid precursor protein (APP). LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT1R) and NF-κB p65 in the hippocampus and cortex. Pretreatment with pranlukast (1.5 ng/mouse, intracerebroventricularly), a CysLT1R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits. Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro. Moreover, LTD4-induced increases in CysLT1R and NF-κB p65 in the brain were also attenuated by pranlukast. These results suggest that LTD4 increases Aβ peptide burden via activation of CysLT1R, which further affects APP levels and activity of β- and γ-secretases via the NF-κB pathway. Our findings identify CysLT1R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT1R in neuroinflammatory diseases such as AD.
► LTD4 may induce cognitive impairment in mice. ► LTD4-induced cognitive impairment is mediated by activation of CysLT1R. ► CysLT1R-trigered NF-κB signaling promotes Aβ generation through β-secretase pathway.
The main goal of spinal cord rehabilitation is to restore walking ability and improve walking quality after spinal cord injury (SCI). The spatiotemporal parameters of walking and the parameters of ...plantar pressure can be obtained using a plantar pressure analysis system. Previous studies have reported step asymmetry in patients with bilateral SCI. However, the asymmetry of other parameters in patients with SCI has not been reported. This was a prospective, cross-sectional study, which included 23 patients with SCI, aged 48.1 ± 14.5 years, and 28 healthy subjects, aged 47.1 ± 9.8 years. All subjects underwent bare foot walking on a plantar pressure measurement device to measure walking speed and spatiotemporal parameters. Compared with healthy subjects, SCI patients had slower walking speed, longer stride time and stance time, larger stance phase percentage, and shorter stride length. The peak pressures under the metatarsal heads and toe were lower in SCI patients than in healthy subjects. In the heel, regional impulse and the contact area percentage in SCI patients were higher than those in healthy subjects. The symmetry indexes of stance time, step length, maximum force, impulse and contact area were increased in SCI patients, indicating a decline in symmetry. The results confirm that the gait quality, including spatiotemporal variables and plantar pressure parameters, and symmetry index were lower in SCI patients compared with healthy subjects. Plantar pressure parameters and symmetry index could be sensitive quantitative parameters to improve gait quality of SCI patients. The protocols were approved by the Clinical Research Ethics Committee of Shengjing Hospital of China Medical University (approval No. 2015PS54J) on August 13, 2015. This trial was registered in the ISRCTN Registry (ISRCTN42544587) on August 22, 2018. Protocol version: 1.0.
Peptide-inhibitor hits were designed with small molecules published before used as the starting point through structure-based drug design and biochemically and structurally characterized the ...interaction modes between the FK1 domain of FKBP51 and hits.
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FKBP51 is well-known as a cochaperone of Hsp90 machinery and implicated in many human diseases including stress-related diseases, tau-mediated neurodegeneration and cancers, which makes FKBP51 an attractive drug target for the therapy of FKBP51-associated diseases. However, it has been reported that only nature product rapamycin, cyclosporine A, FK506 and its derivatives exhibit good binding affinities when bound to FKBP51 by now. Given the advantages of peptide-inhibitors, we designed and obtained 20 peptide-inhibitor hits through structure-based drug design. We further characterized the interaction modes of the peptide-inhibitor hits on the FK1 domain of FKBP51 by biochemical and structural biology methods. Structural analysis revealed that peptide-inhibitor hits form U-shaped conformations and occupy the FK506 binding pocket and share similar interaction modes with FK506. Using molecular dynamics simulations, we delved into the interaction dynamics and found that hits are anchored to the FK506 binding pocket in a quite stable conformation. Meanwhile, it was shown that interactions between FK1 and peptide-inhibitor hits are mainly attributed to the hydrogen bond networks comprising I87 and Y113 and FPF cores of peptide-inhibitors involved extensive hydrophobic interactions. We presumed that the peptide design strategy based on the small molecule structure probably shed new lights on the peptide-inhibitor discovery of other targets. The findings presented here could also serve as a structural basis and starting point facilitating the optimization and generation of FKBP51 peptide-inhibitors with better bio-activities.
As a serious complication after allogenic hematopoietic stem cell transplantation (allo-HSCT), venous thromboembolism (VTE) is significantly related to increased nonrelapse mortality. Therefore ...distinguishing patients at high risk of death who should receive specific therapeutic management is key to improving survival. This study aimed to establish a machine learning-based prognostic model for the identification of post-transplantation VTE patients who have a high risk of death. We retrospectively evaluated 256 consecutive VTE patients who underwent allo-HSCT at our center between 2008 and 2019. These patients were further randomly divided into (1) a derivation (80%) cohort of 205 patients and (2) a test (20%) cohort of 51 patients. The least absolute shrinkage and selection operator (LASSO) approach was used to choose the potential predictors from the primary dataset. Eight machine learning classifiers were used to produce 8 candidate models. A 10-fold cross-validation procedure was used to internally evaluate the models and to select the best-performing model for external assessment using the test cohort. In total, 256 of 7238 patients were diagnosed with VTE after transplantation. Among them, 118 patients (46.1%) had catheter-related venous thrombosis, 107 (41.8%) had isolated deep-vein thrombosis (DVT), 20 (7.8%) had isolated pulmonary embolism (PE), and 11 (4.3%) had concomitant DVT and PE. The 2-year overall survival (OS) rate of patients with VTE was 68.8%. Using LASSO regression, 8 potential features were selected from the 54 candidate variables. The best-performing algorithm based on the 10-fold cross-validation runs was a logistic regression classifier. Therefore a prognostic model named BRIDGE was then established to predict the 2-year OS rate. The areas under the curves of the BRIDGE model were 0.883, 0.871, and 0.858 for the training, validation, and test cohorts, respectively. The Hosmer-Lemeshow goodness-of-fit test showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that VTE patients could benefit from the clinical application of the prognostic model. A BRIDGE risk score calculator for predicting the study result is available online (47.94.162.105:8080/bridge/). We established the BRIDGE model to precisely predict the risk for all-cause death in VTE patients after allo-HSCT. Identifying VTE patients who have a high risk of death can help physicians treat these patients in advance, which will improve patient survival.
The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including alpha-1, alpha-2, beta-1, and beta-2 ...subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the alpha-2 adrenergic antagonist idazoxan (0.1-2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5-2.5 mg/kg, i.p.) or centrally (1-10 microg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the beta-adrenergic antagonists propranolol and CGP-12177 or the alpha-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of beta-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in beta-1, beta-2, or both beta-1 and beta-2 adrenergic receptors. In addition, desipramine (3-30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both beta-1 and beta-2 adrenergic receptors. As antagonism of presynaptic alpha-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic alpha-2 adrenergic receptors play an important role in its antidepressant effects.
In article number 1902374, Vellaisamy A. L. Roy, Ye Zhou, Su‐Ting Han, and co‐workers demonstrate a photonic synaptic transistor based on a hybrid light‐tunable charge trapping medium. The device ...shows excellent data storage performance and can be optically operated in the volatile or non‐volatile memory feature, enabling concomitant short‐term and long‐term neuroplasticity.
To compare the outcome of acid reflux prevention by Dor fundoplication after laparoscopic Heller myotomy (LHM) for achalasia.
Electronic database PubMed, Ovid (Evidence-Based Medicine Reviews, EmBase ...and Ovid MEDLINE) and Cochrane Library were searched between January 1995 and September 2012. Bibliographic citation management software (EndNote X3) was used for extracted literature management. Quality assessment of random controlled studies (RCTs) and non-RCTs was performed according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 and a modification of the Newcastle-Ottawa Scale, respectively. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by sequentially omitting each study.
Finally, 6 studies, including a total of 523 achalasia patients, compared Dor fundoplication with other types of fundoplication after LHM (Dor-other group), and 8 studies, including a total of 528 achalasia patients, compared Dor fundoplication with no fundoplication after LHM (Dor-no group). Dor fundoplication was associated with a significantly higher recurrence rate of clinical regurgitation and pathological acid reflux compared with the other fundoplication group (OR = 7.16, 95%CI: 1.25-40.93, P = 0.03, and OR = 3.79, 95%CI: 1.23-11.72, P = 0.02, respectively). In addition, there were no significant differences between Dor fundoplication and no fundoplication in all subjects. Other outcomes, including complications, dysphagia, postoperative physiologic testing, and operation-related data displayed no significant differences in the two comparison groups.
Dor fundoplication is not the optimum procedure after LHM for achalasia. We suggest more attention should be paid on quality of life among different fundoplications.
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