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We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.
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Two-dimensional metal-organic framework (MOF) crystalline materials possess promising potential in the electrochemical sensing process owing to their tunable structures, high specific surface area, and abundant metal active sites; however, developing MOF-based nonenzymatic glucose (Glu) sensors which combine electrochemical activity and environmental stability remains a challenge. Herein, utilizing the tripodic nitrogen-bridged 1,3,5-tris(1-imidazolyl) benzene (TIB) linker, Co2+ and Ni2+, two 2D isomorphic crystalline materials, including Co/Ni-MOF {[Co (TIB)]·2BF4} (CTGU-31) and {[Ni(TIB)]·2NO3} (CTGU-32), with a binodal (3, 6)-connected kgd topological net were firstly synthesized and fabricated with conducting acetylene black (AB). When modified on a glassy carbon electrode, the optimized AB/CTGU-32 (1:1) electrocatalyst demonstrated a higher sensitivity of 2.198 µA µM-1 cm-2, a wider linear range from 10 to 4000 µM, and a lower detection limit (LOD) value (0.09 µM, S/N = 3) compared to previously MOF-based Glu sensors. Moreover, AB/CTGU-32 (1:1) exhibited desirable stability for at least 2000 s during the electrochemical process. The work indicates that MOF-based electrocatalysts are a promising candidate for monitoring Glu and demonstrate their potential for preliminary screening for diabetes.
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Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Carbono/química , Níquel/química , Electrodos , Acetileno , Glucosa/químicaRESUMEN
PURPOSE: To investigate the role of lymph node ratio (LNR) in young patients with gastric cancer (GC) and develop nomograms to predict the survival of young GC patients. METHODS: This retrospective study enrolled stage I-III GC patients before the age of 40 between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models were used to determine the prognosticators and create the nomograms incorporating LNR to predict overall survival (OS) and cancer-specific survival (CSS). The discriminating superiority of the nomograms was examined using calibration curves, C-index, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and integrated discrimination improvement (IDI) by comparing with the TNM staging. The performance of the nomograms for risk stratification was analyzed by the Kaplan-Meier method. RESULTS: Based on the significant prognosticators identified in multivariate survival analysis, the nomograms were established and showed LNR as the third strongest predictor. The C-index of the nomograms for OS and CSS were higher than those of the TNM staging (OS: 0.773 vs 0.665; CSS: 0.769 vs 0.666). The ROC curves for the nomograms to predict survival exhibited superior sensitivity and specificity when compared with the TNM staging. The calibration plots, DCA curves, and IDI values of the nomograms also demonstrated adequate fit and ideal net benefit in prediction and clinical utility. The Kaplan-Meier analysis observed remarkable differences in patients divided into different risk subgroups (P < .001). CONCLUSIONS: These results found the clinical outperformance of the LNR-based nomograms for predicting survival in young stage I-III GC patients. Our nomograms may improve accuracy of survival risk prediction and facilitate individualized care of young stage I-III GC patients.
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Nomogramas , Neoplasias Gástricas , Humanos , Pronóstico , Neoplasias Gástricas/diagnóstico , Índice Ganglionar , Estudios Retrospectivos , Estadificación de Neoplasias , Programa de VERFRESUMEN
Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Antígeno B7-H1 , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Oxaliplatino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Pulsed electric field (PEF) is a nonthermal technology resulting in the rupture of cell membranes and increasing the electrical conductivity and the permeability of intracellular material. There was little work about the safety of food treated by PEF. The acute, subacute oral, and genetic toxicities were investigated to explore the safety of canola oil extracted by aid of PEF treatment (PTCO). The results showed that no negative consequences were caused by PEF. PTCO was regarded as practically non-toxic with a LD50 higher than 40 g/kg bw. No oil intake-related mortality, clinical, weight gain and organ coefficient abnormalities were observed. The histopathological symptoms indicated a mild load but not obvious toxicities on liver and kidney. The 28-day subacute toxicity test confirmed that less than 10 g/kg·d bw of oil intake did not exhibit any intake-related changes in physical, physiological, biochemical, hematological, and histopathological signs. The less than 4 of atherosclerosis index suggested that no risk of cardiovascular disease caused by PTCO intake. It was speculated that the PEF treatment would not cause any safety issues to food products.
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Electricidad , Hígado , Conductividad Eléctrica , Riñón , Aceite de Brassica napusRESUMEN
A low-molecular-weight polysaccharide named MCGP-L was extracted and purified from the roots of Mountain cultivated ginseng (Panax ginseng C. A. Meyer). The polysaccharide MCGP-L was purified by molecular exclusion chromatography using the Sephadex G-25 column. The average molecular weight of MCGP-L was estimated to be 3 × 103 kDa. Monosaccharide composition analysis showed MCGP-L was composed of three kinds of monosaccharide: D-glucose, D-galactose and D-mannose. The physicochemical properties and structural characteristics of MCGP-L were investigated by the combination of chemical and instrumental analysis such as methylation analysis, High Performance Gel-Permeation Chromatography (HPGPC), High Performance Liquid Chromatography (HPLC) and Nuclear Magnetic Resonance (NMR). The backbone of MCGP-L was composed of (1â4)-linked-α-D-Glcp residues and with branch chain substituted at O-6 position of (1â4,6)-linked-α-D-Glcp. The branch chain consists of â6)-α-D-Galp-(1â, â2)-α-D-Manp-(1â and ß-D-Glcp-(1â.
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Panax , Manosa , Peso Molecular , Monosacáridos , PolisacáridosRESUMEN
During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underlying mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cellâcell contact, which makes epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.
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Colesterol/metabolismo , Farnesiltransferasa/metabolismo , Pericardio/metabolismo , Animales , Células Cultivadas , Desarrollo Embrionario/fisiología , Femenino , Corazón/fisiología , Masculino , Ratones , Ratones Noqueados , Miocardio/metabolismo , Embarazo , Transducción de Señal/fisiologíaRESUMEN
An unprecedented Mo-organic molecular cage built on interesting {MoVI2O5} secondary building blocks and BTC ligands, which has been successfully synthesized and systematically characterized, presents the first example of an isopolyoxomolybdates(vi)-organic molecular cage. An investigation into the related Cs+-exchange experiment was performed in detail.
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Neuropathic pain is still a critical public health problem worldwide. Thereby, the search for novel and more effective strategies against neuropathic pain is urgently considered. It is known that neuroinflammation plays a crucial role in the pathogenesis of neuropathic pain. SedumLineare Thunb. (SLT), a kind of Chinese herb originated from the whole grass of Crassulaceae plant, was reported to possess anti-inflammatory activity. However, whether SLT has anti-nociceptive effect on neuropathic pain and its possible underlying mechanisms remains poorly elucidated. In this study, a rat model of neuropathic pain induced by spared nerve injury (SNI)was applied. SLT (p.o.) was administered to SNI rats once every day lasting for 14 days. Pain-related behaviors were assessed by using paw withdrawal threshold (PWT) and CatWalk gait parameters. Expression levels of inflammatory mediators and pain-related signaling molecules in the spinal cord were detected using western blotting assay. The results revealed that SLT (30, 100, and 300 mg/kg, p.o.) treatment for SNI rats ameliorated mechanical hypersensitivity in a dose-dependent manner. Application of SLT at the most effective dose of 100 mg/kg to SNI rats not only significantly blocked microglial activation, but also markedly reduced the protein levels of spinal HMGB1, TLR4, MyD88, TRAF6, IL-1ß, IL-6, and TNF-α, along with an enhancement in gait parameters. Furthermore, SLT treatment dramatically inhibited the phosphorylation levels of both IKK and NF-κB p65 but obviously improved both IκB and IL-10 protein expression in the spinal cord of SNI rats. Altogether, these data suggested that SLT could suppress spinal TLR4/NF-κB signaling pathway in SNI rats, which might at least partly contribute to its anti-nociceptive action, indicating that SLT may serveas a potential therapeutic agent for neuropathic pain.
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Analgésicos/farmacología , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Neuralgia/prevención & control , Umbral del Dolor/efectos de los fármacos , Extractos Vegetales/farmacología , Sedum , Médula Espinal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Analgésicos/aislamiento & purificación , Animales , Antiinflamatorios/aislamiento & purificación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuralgia/metabolismo , Neuralgia/fisiopatología , Extractos Vegetales/aislamiento & purificación , Ratas Sprague-Dawley , Sedum/química , Transducción de Señal , Médula Espinal/metabolismo , Médula Espinal/fisiopatologíaRESUMEN
The current study develops an effective, convenient, low-cost, and environmentally friendly method for determining trans-resveratrol (TRA) in peanut oils, the unique proportion of peanut oil, by employing natural cotton fibers without any pretreatment as extraction sorbent and an in-syringe extraction device. The primary factors affecting the extraction recovery are optimized in detail. The condition of 200.0 mg of cotton fibers, six push-pull times, 2.0 mL of n-hexane as washing solvent and 2.0 mL of ethanol as desorption solvent is selected as the best. The linear range is demonstrated to be 10-1000 ng/g with a satisfactory correlation coefficient (R2 = 0.9995), while the limit of detection is calculated as 2.47 ng/g. In addition, the recoveries of TRA are obtained in the range of 93.8-104.4% with RSDs less than 5.5%. Finally, the developed method is successfully applied to determine TRA concentrations in commercial peanut oils and other edible oils.
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Arachis/química , Cromatografía Líquida de Alta Presión/métodos , Fibra de Algodón , Aceite de Cacahuete/química , Resveratrol/análisis , Adsorción , Arachis/metabolismo , Hexanos/química , Isomerismo , Límite de Detección , Reproducibilidad de los Resultados , Resveratrol/aislamiento & purificación , Extracción en Fase Sólida/instrumentación , Extracción en Fase Sólida/métodos , Espectrofotometría UltravioletaRESUMEN
Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality; thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.
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Distocia/etiología , Distocia/fisiopatología , Farnesiltransferasa/deficiencia , Predisposición Genética a la Enfermedad , Complejos Multienzimáticos/deficiencia , Contracción Uterina/genética , Animales , Biomarcadores , Modelos Animales de Enfermedad , Distocia/metabolismo , Farnesiltransferasa/metabolismo , Femenino , Estudios de Asociación Genética , Células de la Granulosa/citología , Células de la Granulosa/metabolismo , Infertilidad/genética , Ratones , Ratones Noqueados , Complejos Multienzimáticos/metabolismo , Organogénesis/genética , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/metabolismo , Fenotipo , Embarazo , Unión Proteica , Transducción de Señal , Útero/embriología , Útero/metabolismo , Útero/fisiopatología , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
BACKGROUND: Heterotopic pancreas is a common lesion found in the gastrointestinal tract and is usually considered a benign disease. Reports of malignant change of heterotopic pancreas are scarce. CASE SUMMARY: A 44-year-old Chinese female underwent a gastroscopy to assess abdominal distension that had persisted for 2 months. A protruding lesion in the gastric antrum was revealed but no malignant tissue was found in the biopsy specimen. The patient's symptom persisted and progressed to repeated vomiting. Endoscopy after 4 months revealed obstruction of the gastric outlet caused by the protruding lesion. A distal gastrectomy was performed. Histopathological examination of the surgical specimen showed the malignant transformation of aberrant pancreas in the stomach. Chemotherapy consisting of folinic acid, fluorouracil, and oxaliplatin was administered for three cycles, and was changed to gemcitabine monotherapy because of adverse effects and increased serum tumor marker levels. The patient remained asymptomatic during a 12-month follow-up. CONCLUSION: Pancreatic heterotopy should be considered as source of a potentially malignant lesion, and early treatment or close monitoring for aberrant pancreas is recommended.
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OBJECTIVE: The prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, and the risk of infection has increased due to the use of immunosuppressive and biologic medications. Some of these infections can be prevented with vaccinations. The aim of this study was to evaluate the vaccination practices of Chinese gastroenterologists for patients with IBD. METHODS: Questionnaires based on quick response codes were sent using email and the WeChat platform to gastroenterologists at 20 hospitals in China. The vaccination practices of the gastroenterologists, including vaccinating for hepatitis B, hepatitis A, and varicella, were assessed. RESULTS: Of the 468 gastroenterologists who received the questionnaire, 307 (65.6%) completed it. Of the gastroenterologists who were most concerned about hepatitis B; 83.4% always or frequently asked about an infection history, 53.7% took an immunization history, and 73.6% tested patients for hepatitis B infection. However, few gastroenterologists did so for hepatitis A or varicella. The proportion of patients who were asked about an infection and immunization history and tested for varicella infection was 16.0%, 15.0%, and 9.4%, respectively. Only a few gastroenterologists recommended vaccination for patients without an infection before IBD medical treatment (26.7% for hepatitis A, 45.6% for hepatitis B, and 28% for varicella vaccination). CONCLUSION: Vaccination practices for patients with IBD used by Chinese gastroenterologists vary greatly, suggesting that education about immunization is needed.
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Fármacos Gastrointestinales/efectos adversos , Hepatitis Viral Humana/prevención & control , Enfermedades Inflamatorias del Intestino/terapia , Vacunación , Infección por el Virus de la Varicela-Zóster/prevención & control , Vacunas Virales/uso terapéutico , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Vacuna contra la Varicela/uso terapéutico , China/epidemiología , Femenino , Gastroenterología/estadística & datos numéricos , Fármacos Gastrointestinales/uso terapéutico , Encuestas de Atención de la Salud , Conocimientos, Actitudes y Práctica en Salud , Vacunas contra la Hepatitis A/uso terapéutico , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis Viral Humana/etiología , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Práctica Profesional/estadística & datos numéricos , Vacunación/estadística & datos numéricos , Infección por el Virus de la Varicela-Zóster/etiología , Vacunas contra Hepatitis Viral/uso terapéuticoRESUMEN
PURPOSE: To compare the incidence of postoperative pain of chronic periapical periodontitis patients with root canal therapy between Han and Uygur, and the effect of ibuprofen in reducing endodontic flare-up after single-visit root canal therapy between Uyghur and Han patients with chronic apical periodontitis, in order to provide a basis for clinical administration. METHODS: Two hundred and fifty Uyghur and 250 Han patients with chronic apical periodontitis in their incisor, canine and premolar were collected, and randomly divided into 2 groups: experimental group and control group. After single-visit root canal therapy, Uyghur patients in the experimental group (UEG) and Han patients in the experimental group (HEG) took ibuprofen capsules according to the drug instructions; while Uyghur patients in the control group (UCG) and Han patients in the control group(HCG) took placebo capsules. Both doctors and patient kept blind from the drug capsules and group of the patients. The incidence, degree of endodontic Flare-up at 6, 12, 24, 48, 72 hours and 1 week after root canal therapy were recorded and analyzed by χ2 test using SPSS11.0 software package. RESULTS: During the experiment, the incidence of E flare-up in Uygur patients was higher than in Han patients; the incidence of E flare-up in different groups in orders from high to low was: UCG>HCG>UEG>HEG. Chi-square test showed that there were significant differences between the two groups. In view of time distribution, most of flare-up happened between 24~48 hours after root canal therapy with the highest degree in all 4 groups. Regardless of the incidence or degree of flare-up, HEG and HCG were significantly greater than UEG and UCG. CONCLUSIONS: Ibuprofen can reduce and prevent flare-up for both Uyghur and Han patients, but it has better effect on Han patients.
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Antiinflamatorios no Esteroideos/uso terapéutico , Ibuprofeno/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Periodontitis Periapical , Humanos , Periodontitis , Tratamiento del Conducto RadicularRESUMEN
BACKGROUND: Pigmented paraganglioma is a special type of paraganglioma, and it is rare in the thyroid. CASE PRESENTATION: We report a case of a 41-year-old woman who had complained of a mass in the thyroid gland. Histology revealed tumor cells arranged in a nest-like or organoid pattern, separated by delicate fibrovascular septa. Two distinct components were observed. In the first, which constituted the majority of the tumor cells, no pigments were observed. In the second, a few cells with pigment showed intercellular substance, but the structure was unclear. Using immunohistochemistry, cells in the first component were confirmed to be diffuse strong positive for synaptophysin, but negative for chromogranin A, pan-cytokeratin, calcitonin, and thyroglobulin. About 1% of tumor cells were stained by Ki-67. In the margins of the tumor, a few cells were observed to be positive for HMB-45 and Melan A after bleaching by oxalic acid. The stromal cells were positive for S-100. Using electron microscopy, a few cells containing many round melanin bodies with greater electron density granules of nonuniform size were observed. The diagnosis of primary melanotic paraganglioma of the thyroid gland was made. CONCLUSION: Primary melanotic paraganglioma of the thyroid gland is a rare, low malignant potential tumor. To the best of our knowledge, this is the first case described.
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OBJECTIVE: To evaluate the mucosal healing in the terminal ileum, colon and small bowel in patients receiving infliximab treatment for small bowel Crohn's disease (SBCD). METHODS: The clinical data of 18 patients with SBCD treated with infliximab were analyzed for laboratory findings (routine blood tests, C-reative protein, and albumin), Crohn's disease activity index (CDAI), Lewis score (LS), Crohn's disease simplified endoscopic score (SES-CD) and adverse effects before and after 30 weeks of infliximab treatment. RESULTS: SES-CD, LS, CDAI and CRP were all decreased significantly, but the body mass index and albumin were significantly increased in the 18 patients after 30 weeks of IFX treatment. Sixteen (88.9%) of the patients were in clinical remission, 10 (58.8%) showed terminal ileum and colonic mucosal healing, 4 (22.2%) showed small bowel mucosal healing, and 3 (17.6%) were in deep remission. The 4 patients with small bowel mucosal healing all showed terminal ileum and colon mucosal healing, and 6 patients with terminal ileum and colon mucosal healing did not show small bowel mucosal healing. CONCLUSION: Infliximab treatment can effectively reduce inflammatory activity, induce and maintain clinical remission of SBCD and achieve mucosal healing; small bowel mucosal healing occurs later than terminal ileum and colonic mucosal healing, indicating the importance of small bowel mucosal healing in efficacy analysis of the treatment.
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Enfermedades del Colon/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Enfermedades del Íleon/tratamiento farmacológico , Infliximab/uso terapéutico , Mucosa Intestinal/efectos de los fármacos , Humanos , Intestino Delgado , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Although previous studies have confirmed that 23S rRNA gene mutation could be responsible for most of macrolide resistance in M. catarrhalis, a recent study suggested otherwise. Next generation sequence based comparative genomics has revolutionized the mining of potential novel drug resistant mechanisms. In this study, two pairs of resistant and susceptible M. catarrhalis isolates with different multilocus sequence types, were investigated for potential differential genes or informative single nucleotide polymorphisms (SNPs). The identified genes and SNPs were evaluated in 188 clinical isolates. From initially 12 selected differential genes and 12 informative SNPs, 10 differential genes (mboIA, mcbC, mcbI, mboIB, MCR_1794, MCR_1795, lgt2B/C, dpnI, mcbB, and mcbA) and 6 SNPs (C619T of rumA, T140C of rplF, G643A of MCR_0020, T270G of MCR_1465, C1348A of copB, and G238A of rrmA) were identified as possibly linked to macrolide resistance in M. catarrhalis. Most of the identified differential genes and SNPs are related to methylation of ribosomal RNA (rRNA) or DNA, especially MCR_0020 and rrmA. Further studies are needed to determine the function and/or evolution process, of the identified genes or SNPs, to establish whether some novel or combined mechanisms are truly involved in M. catarrhalis macrolide resistance mechanism.
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Farmacorresistencia Bacteriana/genética , Macrólidos/farmacología , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/genética , Antibacterianos/farmacología , ADN Bacteriano/genética , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Tipificación de Secuencias Multilocus/métodos , Mutación/genética , ARN Ribosómico 23S/genéticaRESUMEN
Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies.