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1.
Gynecol Endocrinol ; : 1-7, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793358

RESUMO

Prenatal diagnosis of Down syndrome (DS) is based on calculated risk involving maternal age, biochemical and ultrasonographic markers, and, more recently, cell-free DNA (cfDNA). The present study was designed to identify Down Syndrome biomarkers in maternal serum. We quantified the changes in maternal serum protein levels between 10 non-pregnant women, 10 pregnant women with healthy fetuses, and 10 pregnant women with DS fetuses using isobaric tags for relative and absolute quantification (iTRAQ). We subsequently conducted a Gene Ontology (GO) analysis. A total of 470 proteins were identified, 11 of which had significantly different serum levels between the DS fetus group and Healthy fetuses group. Our data shows the identified proteins may be relevant to DS and constitute potential DS biomarkers.

2.
Biochem Genet ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696339

RESUMO

Mitochondrial DNA (mtDNA) has been widely employed as one tool for the studies of human migration and phylogenetic evolution owing to the characteristics of its lack of recombination and matrilineal inheritance. In this study, we analyze genetic distributions of 60 mtDNA markers in 126 unrelated individuals of Southern Shaanxi Han population and classify their haplogroups. Genetic distribution comparisons between Southern Shaanxi Han and other populations from different continents are conducted based on the same mtDNA markers. The majority of 60 mtDNA markers are polymorphic in Southern Shaanxi Han population. The most common haplogroups observed in Southern Shaanxi Han population are B5, followed by D5, A, D4e, and N9a1'3. Obtained matching probability for these 60 mtDNA markers indicates that the panel could be used as a valuable tool in forensic caseworks. Results of genetic distances (Fst) and multidimensional scaling analysis show that Southern Shaanxi Han population has relatively close genetic relationships with other Han populations in different regions. In conclusion, the panel comprising 60 mtDNA markers could be utilized for forensic applications in Southern Shaanxi Han population.

4.
Hum Mutat ; 2019 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-31680349

RESUMO

Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects. We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018. Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on disease-associated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

5.
Clin Infect Dis ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31626692

RESUMO

BACKGROUND: Platelet transfusion is common in dengue patients with thrombocytopenia. We previously showed in a randomized clinical trial that prophylactic platelet transfusion did not reduce clinical bleeding. In this study, we aimed to characterize the predictors and clinical outcomes of poor platelet recovery in transfused and nontransfused participants. METHODS: We analyzed patients from the Adult Dengue Platelet Study with laboratory-confirmed dengue with ≤20 000 platelets/µL and without persistent mild bleeding or any severe bleeding in a post hoc analysis. Poor platelet recovery was defined as a platelet count of ≤20 000/µL on Day 2. We recruited 372 participants from 5 acute care hospitals located in Singapore and Malaysia between 29 April 2010 and 9 December 2014. Of these, 188 were randomly assigned to the transfusion group and 184 to the control group. RESULTS: Of 360 patients, 158 had poor platelet recovery. Age, white cell count, and day of illness at study enrollment were significant predictors of poor platelet recovery after adjustment for baseline characteristics and platelet transfusion. Patients with poor platelet recovery had longer hospitalizations but no significant difference in other clinical outcomes, regardless of transfusion. We found a significant interaction between platelet recovery and transfusion; patients with poor platelet recovery were more likely to bleed if given a prophylactic platelet transfusion (odds ratio 2.34, 95% confidence interval 1.18-4.63). CONCLUSIONS: Dengue patients with thrombocytopenia who were older or presented earlier and with lower white cell counts were more likely to have poor platelet recovery. In patients with poor platelet recovery, platelet transfusion does not improve outcomes and may actually increase the risk of bleeding. The mechanisms of poor platelet recovery need to be determined. CLINICAL TRIALS REGISTRATION: NCT01030211.Dengue fever commonly results in thrombocytopenia. In this post hoc analysis, poor platelet recovery was associated with older ages, lower white cell counts, and earlier stages of illness at presentation, and resulted in longer hospitalizations.

7.
Drug Metab Dispos ; 47(12): 1425-1432, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31658948

RESUMO

Rat CYP2D1 has been considered as an ortholog of human CYP2D6 To assess the role of CYP2D1 in physiologic processes and drug metabolism, a CYP2D1-null rat model was generated with a CRISPR/Cas9 method. Seven base pairs were deleted from exon 4 of CYP2D1 of Sprague-Dawley wild-type (WT) rats. The CYP2D1-null rats were viable and showed no abnormalities in general appearance and behavior. The metabolism of venlafaxine (VLF) was further studied in CYP2D1-null rats. The V max and intrinsic clearance of the liver microsomes in vitro from CYP2D1-null rats were decreased (by ∼46% and ∼57% in males and ∼47% and ∼58% in females, respectively), while the Michaelis constant was increased (by ∼24% in males and ∼25% in females) compared with WT rats. In the pharmacokinetic studies, compared with WT rats, VLF in CYP2D1-null rats had significantly lower apparent total clearance and apparent volume of distribution (decreased by ∼36% and ∼48% in males and ∼23% and ∼25% in females, respectively), significantly increased area under the curve (AUC) from the time of administration to the last time point, AUC from the start of administration to the theoretical extrapolation, and C max (increased by ∼64%, ∼59%, and ∼26% in males and ∼43%, ∼35%, and ∼15% in females, respectively). In addition, O-desmethyl venlafaxine formation was reduced as well in CYP2D1-null rats compared with that in WT rats. Rat depression models were developed with CYP2D1-null and WT rats by feeding them separately and exposing them to chronic mild stimulation. VLF showed better efficacy in the WT depression rats compared with that in the CYP2D1-null rats. In conclusion, a CYP2D1-null rat model was successfully generated, and CYP2D1 was found to play a certain role in the metabolism and efficacy of venlafaxine. SIGNIFICANCE STATEMENT: A novel CYP2D1-null rat model was generated using CRISPR/Cas9 technology, and it was found to be a valuable tool in the study of the in vivo function of human CYP2D6. Moreover, our data suggest that the reduced O-desmethyl venlafaxine formation was associated with a lower VLF efficacy in rats.

8.
Mol Biol Cell ; 30(24): 2969-2984, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577526

RESUMO

The apical surface of the terminally differentiated mammalian urothelial umbrella cell is mechanically stable and highly impermeable, in part due to its coverage by urothelial plaques consisting of 2D crystals of uroplakin particles. The mechanism for regulating the uroplakin/plaque level is unclear. We found that genetic ablation of the highly tissue-specific sorting nexin Snx31, which localizes to plaques lining the multivesicular bodies (MVBs) in urothelial umbrella cells, abolishes MVBs suggesting that Snx31 plays a role in stabilizing the MVB-associated plaques by allowing them to achieve a greater curvature. Strikingly, Snx31 ablation also induces a massive accumulation of uroplakin-containing mitochondria-derived lipid droplets (LDs), which mediate uroplakin degradation via autophagy/lipophagy, leading to the loss of apical and fusiform vesicle plaques. These results suggest that MVBs play an active role in suppressing the excessive/wasteful endocytic degradation of uroplakins. Failure of this suppression mechanism triggers the formation of mitochondrial LDs so that excessive uroplakin membranes can be sequestered and degraded. Because mitochondrial LD formation, which occurs at a low level in normal urothelium, can also be induced by disturbance in uroplakin polymerization due to individual uroplakin knockout and by arsenite, a bladder carcinogen, this pathway may represent an inducible, versatile urothelial detoxification mechanism.

9.
Blood Cancer J ; 9(10): 83, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594919

RESUMO

Pomalidomide is a third generation immunomodulatory drug which in combination with dexamethasone, has been shown to be active in relapsed/refractory multiple myeloma. However, the data in Asian patients remain limited. We conducted a prospective phase two clinical trial in major cancer centers in Singapore, South Korea, Taiwan, Japan and Hong Kong to assess the efficacy and safety of pomalidomide and dexamethasone combination (PomDex) +/- cyclophosphamide in Asian patients with relapsed/refractory multiple myeloma who failed lenalidomide and bortezomib. Patients were treated with pomalidomide (4 mg daily for 21 days every 4 weeks) and dexamethasone (40 mg weekly). If there is less than a minimal response after three cycles of PomDex, cyclophosphamide 300 mg/m2 can be added (PomCyDex). A total of 136 patients were enrolled. The median PFS was 9 and 10.8 months for the PomDex and PomCyDex group, respectively. The median OS was 16.3 months. This regimen appears to be active across age groups and prior lines of treatment. This combination was overall well tolerated with grade 3 and 4 adverse events of mainly cytopenias. PomDex is highly active and well-tolerated in Asian patients. The addition of cyclophosphamide can improve the response and outcomes further in patients with suboptimal response to PomDex.

10.
Clin Infect Dis ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31641767

RESUMO

BACKGROUND: Klebsiella pneumoniae liver abscess (KLA) is emerging worldwide due to hypermucoviscous strains with a propensity for metastatic infection. Treatment includes drainage and prolonged intravenous antibiotics. We aimed to determine whether oral antibiotics were noninferior to continued intravenous antibiotics for KLA. METHODS: This noninferiority, parallel group, randomized, clinical trial recruited hospitalized adults with liver abscess and K. pneumoniae isolated from blood or abscess fluid who had received ≤7 days of effective antibiotics at 3 sites in Singapore. Patients were randomized 1:1 to oral (ciprofloxacin) or intravenous (ceftriaxone) antibiotics for 28 days. If day 28 clinical response criteria were not met, further oral antibiotics were prescribed until clinical response was met. The primary endpoint was clinical cure assessed at week 12 and included a composite of absence of fever in the preceding week, C-reactive protein <20 mg/L, and reduction in abscess size. A noninferiority margin of 12% was used. RESULTS: Between November 2013 and October 2017, 152 patients (mean age, 58.7 years; 25.7% women) were recruited, following a median 5 days of effective intravenous antibiotics. A total of 106 (69.7%) underwent abscess drainage; 71/74 (95.9%) randomized to oral antibiotics met the primary endpoint compared with 72/78 (92.3%) randomized to intravenous antibiotics (risk difference, 3.6%; 2-sided 95% confidence interval, -4.9% to 12.8%). Effects were consistent in the per-protocol population. Nonfatal serious adverse events occurred in 12/72 (16.7%) in the oral group and 13/77 (16.9%) in the intravenous group. CONCLUSIONS: Oral antibiotics were noninferior to intravenous antibiotics for the early treatment of KLA. CLINICAL TRIALS REGISTRATION: NCT01723150.

11.
Sci Signal ; 12(600)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551295

RESUMO

Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Cav3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.

12.
Glycobiology ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553041

RESUMO

Galectins are ß-galactoside-binding animal lectins primarily found in the cytosol, while their carbohydrate ligands are mainly distributed in the extracellular space. Cytosolic galectins are anticipated to accumulate on damaged endocytic vesicles through binding to glycans initially displayed on the cell surface and subsequently located in the lumen of the vesicles, and this can be followed by cellular responses. To facilitate elucidation of the mechanism underlying this process, we adopted a model system involving induction of endocytic vesicle damage with light that targets the endocytosed amphiphilic photosensitizer disulfonated aluminum phthalocyanine (AlPcS2a). We demonstrate the levels of galectins around damaged endosomes are dependent on the composition of carbohydrates recognized by the proteins. By super resolution imaging, galectin-3 and galectin-8 aggregates were found to be distributed in distinct microcompartments. Importantly, galectin accumulation is significantly affected when cell surface glycans are altered. Furthermore, accumulated galectins can direct autophagy adaptor proteins toward damaged endocytic vesicles, which are also significantly affected following alteration of cell surface glycans. We conclude cytosolic galectins control cellular responses reflecting dynamic modifications of cell surface glycans.

13.
Biomed Eng Online ; 18(1): 93, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492145

RESUMO

BACKGROUND: As the only arterial structure of which two main arteries merged into one, the vertebro-basilar (VA-BA) system is one of the favorite sites of cerebral atherosclerotic plaques. The aim of this study was to investigate the detailed hemodynamics characteristics in the VA-BA system. METHODS: A scale-up subject-specific flow phantom of VA-BA system was fabricated based on the computed tomography angiography (CTA) scanning images of a healthy adult. Flow fields in eight axial planes and six radial planes were measured and analyzed by using particle image velocimetry (PIV) under steady flow conditions of [Formula: see text], [Formula: see text]. A water-glycerin mixture was used as the working fluid. RESULTS: The flow in the current model exhibited highly three-dimensional characteristics. The confluence of VAs flow formed bimodal velocity distribution near the confluence apex. Due to the asymmetrical structural configuration, the bimodal velocity profile skewed towards left, and sharper peaks were observed under higher Reynolds condition. Secondary flow characterized by two vortices formed in the radial planes where 10 mm downstream the confluence apex and persists along the BA under both Reynolds numbers. The strength of secondary flow under [Formula: see text] is around 8% higher than that under [Formula: see text], and decayed nonlinearly along the flow direction. In addition, a low momentum recirculation region induced by boundary layer separation was observed near the confluence apex. The wall shear stress (WSS) in the recirculation area was found to be lower than 0.4 Pa. This region coincides well with the preferential site of vascular lesions in the VA-BA system. CONCLUSIONS: This preliminary study verified that the subject-specific in-vitro experiment is capable of reflecting the detailed flow features in the VA-BA system. The findings from this study may help to expand the understanding of the hemodynamics in the VA-BA system, and further clarifying the mechanism that underlying the localization of vascular lesions.

14.
J Obstet Gynaecol Res ; 45(11): 2267-2274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31411802

RESUMO

AIM: Subjects with germline BRCA1/2 mutations (gBRCAm) have an increased risk of developing breast cancer and ovarian cancer. At present, knowledge of BRCA1/2 mutation frequency in Chinese patients with ovarian cancer is still insufficient, and the detailed clinical information of these patients is poorly understood. METHODS: A total of 547 unselected ovarian cancer patients were enrolled, and their gBRCAm status was detected. Clinical characteristics including age, personal and family history, histopathologic diagnosis, carbohydrate antigen 125 (CA-125) level, ascites, Federation International of Gynecology and Obstetrics (FIGO) stage, residual lesions, platinum sensitivity, recurrence interval and survival information were collected. Accurate assessments of disease response were based on the RECIST standard or CA-125 level. RESULTS: In 547 patients with ovarian cancer, we detected 129 (23.6%) patients with pathogenic mutations, 84 patients with BRCA1 mutations (15.4%) and 45 patients with BRCA2 mutations (8.2%). Twenty-five novel mutations were identified, and the mutation of BRCA1, c.5470_5477del8, was the most common mutation in this study. BRCA1/2 mutations were significantly associated with age; personal and family history; FIGO stage; secondary recurrence interval; sensitivity to platinum in 1st, 2nd and 3rd line treatment; and response to doxorubicin liposomes. Patients with BRCA1/2 mutations showed significant advantages in 3- and 5-year survival rates but no advantage in long-term survival. CONCLUSION: BRCA1/2 mutation prevalence in Chinese ovarian cancer patients is higher than the international rate. We recommend BRCA1/2 testing for patients with family histories and personal histories of malignancy and genetic counseling for cancer in healthy people with high-risk family histories.

15.
Asia Pac J Clin Nutr ; 28(3): 567-576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464403

RESUMO

BACKGROUND AND OBJECTIVES: This study explored the appropriate classification of pre-pregnancy body mass index (BMI) in women of childbearing age in Beijing, China. METHODS AND STUDY DESIGN: Women with singleton pregnancies at more than 28 gestational weeks were retrospectively reviewed. Based on the pre-pregnancy BMI (kg/m2), these patients were divided into 7 groups: <18.5, >=18.5-22.9, >=23-23.9, >=24-24.9, >=25-27.9, >=28-29.9, and >=30. Pregnancy adverse outcomes, including gestational hypertension with or without preeclampsia, gestational diabetes mellitus, initial cesarean section, postpartum hemorrhage, macrosomia, large-for-gestational age infant and so on were recorded. Binary logistic regression analysis was used to calculate the uncorrected and corrected odds ratios and 95% confidence intervals, with the >=18.5-22.9 group serving as a reference. RESULTS: A total of 11,136 pregnant women were analyzed. Incidences of above mentioned six adverse outcomes were greater in women with higher pre-pregnancy BMI. The risks of the abovementioned six adverse outcomes were increased significantly among the >=23-23.9, >=24-24.9, >=25-27.9 groups and substantially higher in the >=28-29.9, >=30 groups after correction. <18.5 group showed an increased risk of small-for-gestational age infants. CONCLUSIONS: For women of childbearing age in Beijing, China, the optimal pre-pregnancy BMI range was >=18.5-22.9 kg/m2, with the cutoff value for overweight status being >=23.0 kg/m2 and the cutoff value for obesity being >=28.0 kg/m2.

16.
Environ Sci Pollut Res Int ; 26(27): 28352-28360, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31372954

RESUMO

The emergence of antibiotic resistance genes (ARGs) in microbes can be largely attributed to the abuse and misuse of antibiotics and biocides. Quaternary ammonium compounds (QACs) have been used worldwide as common disinfectants and detergents; however, their potential impact on the spread and diffusion of ARGs is still unknown. In this study, we detected the QAC resistance gene (qacEΔ1), the 1 integron gene (intI1), and 12 ARGs (sul1, sul2, cfr, cml, fexA, tetA, tetG, tetQ, tetX, ermB, blaTEM, and dfrA1) in 48 water samples from three watersheds by quantitative PCR (qPCR). We investigated the evolution of bacterial antibiotic resistance under QAC and antibiotic environmental pressures by long-term continuous culture. In addition, five QACs were selected to investigate the effect of QAC on the efficiency of conjugation transfer. The changes in bacterial cell membrane and production of reactive oxygen species (ROS) were detected by flow cytometry, revealing the mechanism by which QAC affects the spread of antibiotic resistance. Our results showed that the QAC resistance gene was ubiquitous in watersheds and it had significant correlation with intI1 and seven ARGs (r = 0.999, p < 0.01). QACs could increase the resistance of bacteria to multiple antibiotics. Furthermore, all five QACs promoted the conjugation transfer of the RP4 plasmid; the optimal concentration of QACs was about 10-1-10-2 mg/L and their transfer efficiencies were between 1.33 × 10-6 and 8.87 × 10-5. QACs enhanced membrane permeability of bacterial cells and stimulated bacteria to produce ROS, which potentially promoted the transfer of plasmids between bacteria. In conclusion, this study demonstrated that QACs may facilitate the evolution and gene transfer of antibiotic resistance gene among microbiome.

17.
Cancer Med ; 8(13): 5939-5947, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433117

RESUMO

BACKGROUND: Osimertinib yields significant tumor responses and durations of progression-free survival (PFS) in patients with acquired T790M mutations. However, the evidence supporting liquid biopsy-guided treatment is still limited. This study examined the real-world benefits of osimertinib in patients with tissue or plasma T790M mutations. METHODS: From January 2016 to June 2018, a total of 183 non-small-cell lung cancer patients were enrolled. The presence of the T790M mutation was assessed by either tissue or plasma. The PFS, overall survival, and tumor response rates of the patients were calculated and compared with those of previous clinical trials. RESULTS: T790M mutations were detected in 51.5% of the patients, including 64 of 140 (45.7%) who underwent liquid biopsies and 23 of 29 (79.3%) who underwent tumor biopsies. After excluding those in clinical trials, 46 patients received osimertinib, including 33 with positive plasma and 13 with positive tissue results for T790M mutations. The median PFS was 11.3 months (interquartile range: 5.2-NR) in all the T790M-positive patients and 10.1 months (interquartile range: 5.9-NR) in the plasma T790M-positive patients. The overall survival, meanwhile, was not reached, whereas the one-year survival rate was 66.1% in all the patients and 61.4% in those who were plasma T790M-positive. The objective response rate and disease control rate were 37.8% and 91.9% in all the patients and 34.6% and 92.3% in the plasma T790M-positive group, respectively. Using a Cox proportional hazards regression, we determined that male gender was a poor prognostic factor for PFS. CONCLUSIONS: In this retrospective real-world analysis, it was determined that both tissue and plasma T790M mutations can be used to guide treatment with osimertinib. Similar disease control rates and survival durations were observed in comparison to those of phase 3 clinical trials.

18.
J Phys Chem B ; 123(38): 8140-8153, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31379166

RESUMO

To explore the role of matching water affinities between the oppositely charged headgroups, the micellization of cetyltrimethylammonium bromide (CTA+Br-)/sodium dodecanoate (Na+L-) mixed system and the CTA+Br-/sodium dodecylsulfonate (Na+AS-) mixed system has been investigated by the surface tension method and molecular dynamic (MD) simulation. In comparison with the CTA+Br-/Na+L- system, the CTA+Br-/Na+AS- system shows stronger micelle formation ability, smaller critical micelle concentration (cmc), and stronger synergistic effect arising from the higher degree of matching water affinities between the headgroups CTA+ and AS-. To explore the role of matching water affinities between the oppositely charged constituent counterions, the micellization of CTA+X-/Y+L- mixed systems with various counterions has been investigated. The higher degree of matching water affinities between counterions X- and Y+ and the higher degree of mismatching water affinities between headgroups and counterions are unfavorable to the screening effect of counterions on the electrostatic attraction between headgroups CTA+ and L-, leading to stronger micelle formation ability and smaller cmc and vice versa. MD simulation results also indicate that, for the mixed micellization of cationic/anionic surfactants, the role of matching water affinities between oppositely charged headgroups is more important than that between oppositely charged constituent counterions.

19.
Sci Rep ; 9(1): 10898, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358767

RESUMO

When breast cancer patients start to exhibit resistance to hormonal therapy or chemotherapy, the mTOR inhibitor everolimus can be considered as an alternative therapeutic agent. Everolimus can deregulate the PI3K/AKT/mTOR pathway and affect a range of cellular functions. In some patients, the agent does not exhibit the desired efficacy and, even worse, not without the associated side effects. This study assessed the use of immunofluorescence (IF) as a modality to fill this unmet need of predicting the efficacy of everolimus prior to administration. Cell viability and MTT assays based on IF intensities of pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 on breast cancer cells (Hs578T, MCF7, BT474, MDA-MB-231) and patient-derived cell culture from metastatic sites (ABC-82T and ABC-16TX1) were interrogated. Results show that independent pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 IF expressions can classify data into different groups: everolimus sensitive and resistant. The combined IF baseline intensity of these proteins is predictive of the efficacy of everolimus, and their intensities change dynamically when cells are resistant to everolimus. Furthermore, mTOR resistance is not only consequence of the AKT/mTOR pathway but also through the LKB1 or MAPK/ERK pathway. The LKB1 and pho-GSK3ß may also be potential predictive markers for everolimus.

20.
Mater Sci Eng C Mater Biol Appl ; 103: 109824, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349464

RESUMO

Graphene quantum dots (GQDs) have good biocompatibility, high luminescence, and low photobleaching properties, which make them promising alternatives to fluorescent dyes for cell imaging. However, most of the reported GQDs lack targeted selectivity that limits their applications in biomedicine. To overcome the drawback, novel GQDs modified with polyethyleneimine (PEI) or (3-carboxyl) phenyl bromide phosphine (TPP) were originally synthesized via a facile, low-cost, environmentally friendly, and large-scale preparation method. The GQDs-PEI was synthesized by a simple hydrothermal process, and then TPP was conjugated to the GQDs-PEI via the amide linkage. The physicochemical, optical, biocompatible, and targeted imaging properties were evaluated systematically. The results indicated that the average sizes of the as-produced GQDs-PEI and GQDs-TPP were 3.75 and 3.25 nm, respectively. More significantly, the two composites had excellent optical property, low cytotoxicity and selective targeting and imaging properties for cell nucleus or mitochondria, suggesting their promising applications as the cell nucleus imaging or mitochondria imaging in vivo and in vitro for diagnosis and therapy of some related diseases.

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