Mucosal surfaces are protected by a highly viscoelastic and adhesive mucus layer that traps most foreign particles, including conventional drug and gene carriers. Trapped particles are eliminated on the order of seconds to hours by mucus clearance mechanisms, precluding sustained and targeted drug and nucleic acid delivery to mucosal tissues. We have previously shown that polymeric coatings that minimize adhesive interactions with mucus constituents lead to particles that rapidly penetrate human mucus secretions. Nevertheless, a particular challenge in formulating drug-loaded mucus penetrating particles (MPP) is that many commonly used surfactants are either mucoadhesive, or do not facilitate efficient drug encapsulation. We tested a novel surfactant molecule for particle formulation composed of Vitamin E conjugated to 5 kDa polyethylene glycol (VP5k). We show that VP5k-coated poly(lactide-co-glycolide) (PLGA) nanoparticles rapidly penetrate human cervicovaginal mucus, whereas PLGA nanoparticles coated with polyvinyl alcohol or Vitamin E conjugated to 1 kDa PEG were trapped. Importantly, VP5k facilitated high loading of paclitaxel, a frontline chemo drug, into PLGA MPP, with controlled release for at least 4 days and negligible burst release. Our results offer a promising new method for engineering biodegradable, drug-loaded MPP for sustained and targeted delivery of therapeutics at mucosal surfaces.
PEG; drug delivery; Vitamin E TPGS; mucin
Although the relationship between allergy and cancer has been investigated extensively, the role of allergy in head and neck cancer (HNC) appears less consistent. It is not clear whether allergies can independently influence the risk of HNC in the presence of known strong environmental risk factors, including consumption of alcohol, betel quid, and cigarette.
The current paper reports results from: 1) an original hospital-based case-control study, which included 252 incident cases of HNC and 236 controls frequency-matched to cases on sex and age; and 2) a meta-analysis combining the results of the current case-control study and 13 previously published studies (9 cohort studies with 727,569 subjects and 550 HNC outcomes and 5 case-control studies with 4,017 HNC cases and 10,928 controls).
In the original case-control study, we observed a strong inverse association between allergies and HNC [odds ratio = 0.41, 95% confidence interval (CI): 0.27–0.62]. The meta-analysis also indicated a statistically significant inverse association between HNC and allergies [meta-relative risk (RR) = 0.76, 95% CI: 0.63–0.91], particularly strong for allergic rhinitis (meta-RR = 0.55, 95% CI: 0.40–0.76). In addition, the inverse association between allergies and HNC was observed only among men (meta-RR = 0.67, 95% CI: 0.54–0.84) but not among women (meta-RR = 0.98, 95% CI: 0.81–1.18).
These findings suggest that immunity plays an influential role in the risk of HNC. Future studies investigating immune biomarkers, including cytokine profiles and genetic polymorphisms, are warranted to further delineate the relationship between allergies and HNC. Understanding the relationship between allergies and HNC may help devise effective strategies to reduce and treat HNC.
The transcription factor STAT3 has been previously reported to be associated with mitochondria. However, we have been unable to visualize an association of STAT3-GFP, STAT3-DsRed or STAT3-Flag with mitochondria in human Hep3B hepatocytes thus far even though an association of these molecules with other cytoplasmic organelles (endosomes) was readily demonstrable. We then addressed the broader question of a possible association of other STAT-family of proteins with mitochondria by first using immunolocalization assays in Hep3B and human pulmonary arterial endothelial and smooth muscle cells. Strong anti-STAT6-immunolocalization with mitochondria was apparent in fluorescence and electron microscopy assays of cells first washed with a digitonin-sucrose buffer to remove bulk soluble STAT proteins. In live-cell imaging studies, STAT6-GFP, but not N1-GFP, was observed to constitutively colocalize with MitoTracker- and tetramethylrhodamine ethyl ester (TMRE)-positive mitochondria, and with mitochondrial F1-ATPase when assayed by immunofluorescence after fixation. This association was Tyr-phosphorylation independent in that a STAT6 truncated protein (STAT61-459-GFP) which lacked the SH2 domain (517–632) and the cytokine-activated Y641 phosphorylation site also accumulated in MitoTracker-positive mitochondria. This was consistent with the unexpected discovery that anti-STAT6-immunofluoresence also associated with mitochondria in mouse embryo fibroblasts (MEFs) from both wild-type and the STAT6SH2-/SH2- mouse. MEFs from the latter mouse, which had been engineered in 1996 to be deleted in the STAT6 SH2 domain (amino acids 505–584) expressed an immune-specific ∼50 kDa protein detectable in whole cell and mitochondria-enriched fractions. Taken together, the present data provide the first definitive evidence of the association of any STAT-protein family member with mitochondria - that of STAT6.
With the advancement of the magnetic resonance (MR) technology, the whole-body ultrahigh field MR system operated from 7 to 9.4 T becomes feasible for the routine patient imaging in clinical settings. The associated potentials and challenges from the perspectives of technology, physics, and biology as well as clinical application of the ultrahigh field MR systems are different from those systems operated at 3 T, 1.5 T, or lower field strength. In this article, we will present our initial experiences of brain tumor imaging using the 7 and 8 T whole-body MR systems at the Ohio State University Medical Center and provide a brief overview pertinent to the ultrahigh field clinical MR systems.
ultrahigh field whole-body MR; 7 and 8 Tesla clinical MR; brain tumor
The -493G/T polymorphism in the microsomal triglyceride transfer protein (MTP) gene is associated with lower serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and longevity in several populations, but the results are inconsistent in different racial/ethnic groups. The current study was to investigate the plausible association of MTP -493G/T polymorphism with serum lipid levels and longevity in Zhuang long-lived families residing in Bama area, a famous home of longevity in Guangxi, China.
The MTP -493G/T was genotyped by PCR-restriction fragment length polymorphism in 391 Bama Zhuang long-lived families (BLF, n = 1467, age 56.60 ± 29.43 years) and four control groups recruited from Bama and out-of-Bama area with or without a familial history of exceptional longevity: Bama non-long-lived families (BNLF, n = 586, age 44.81 ± 26.83 years), Bama non-Zhuang long-lived families (BNZLF, n = 444, age 52.09 ± 31.91 years), Pingguo long-lived families (PLF, n = 658, age 50.83 ± 30.30 years), and Pingguo non-long-lived families (PNLF, n = 539, age 38.74 ± 24.69 years). Correlation analyses between genotypes and serum lipid levels and longevity were then performed.
No particularly favorable lipoprotein and clinical phenotypes were seen in BLF as compared to general families in the same area. Instead, the levels of total cholesterol (TC), TG, LDL-C, and the prevalence of dyslipidemia were significantly higher in the three Bama families as compared to the two non-Bama families (P < 0.01 for all). There were no differences in the allelic and genotypic frequencies among the tested cohorts (P > 0.05 for all), but the TT genotype tended to enrich in the three long-lived cohorts from both areas. In addition, the individuals harboring TT genotype exhibited lower LDL-C and TC levels in the overall populations and Bama populations with a region- and sex-specific pattern. Multiple linear regression analyses unraveled that LDL-C levels were correlated with genotypes in Bama combined population, BNLF, and the total population (P < 0.05 for each) but not in Pingguo populations; TC and HDL-C levels were correlated with genotypes in Bama combined population and BLF, respectively (P < 0.05 for each).
MTP -493G/T polymorphism may play an important role in fashioning the serum lipid profiles of Bama populations, despite no direct association between MTP -493G/T and longevity was detected.
Epithelial to mesenchymal transition (EMT) promotes cellular motility, invasiveness and metastasis during embryonic development and tumorigenesis. Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of EMT. A lot of evidences suggest that this process is Smad3-dependent. Herein we showed that exposure of aspc-1 and panc-1 pancreatic cancer cells to TGF-β1 resulted in characteristic morphological alterations of EMT, and enhancement of cell motility and gemcitabine (Gem) resistance along with an up-regulation of EMT markers genes such as vimentin, N-cadherin, MMP2 and MMP9. Naringenin (Nar) down-regulated EMT markers expression in both mRNA and protein levels by inhibiting TGF-β1/Smad3 signal pathway in the pancreatic cancer cells. Consequently, Nar suppressed the cells migration and invasion and reversed their resistance to Gem.
Herpes simplex encephalitis is associated with substantial morbidity and mortality and may be related to timely diagnosis and treatment. While awaiting the results of testing, hospitalization and empiric treatment with acyclovir is recommended, though the direct and indirect costs associated with this management are substantial. We sought to examine children hospitalized for possible herpes simplex encephalitis, following clinical and laboratory assessment in the emergency department, and empiric treatment with acyclovir, in order to describe the proportion receiving a complete course of treatment; and to identify the clinical variables which are associated with receiving a complete course, as compared with an incomplete course of acyclovir.
Hospitalized children prescribed acyclovir were included in this case control study. Clinical, laboratory and diagnostic variables were abstracted for children prescribed a complete (≥ 14 days) or an incomplete course (<14 days) of acyclovir. Odds ratios and 95% confidence intervals were calculated.
289 children met eligibility criteria, 30 (10%) received a complete course and 259 (90%) received an incomplete course. A history of mucocutaneous herpes simplex virus infection (p < 0.01), Glasgow Coma Scale ≤ 13 (p = 0.02), focal neurologic findings (p = 0.001) and elevated cerebrospinal fluid white blood cell count (p = 0.05) were associated with a complete course of acyclovir.
Many children did not complete a full course of therapy. Unnecessary testing and treatment is burdensome to families and the health care system. Possible predictive variables include abnormal Glascow Coma Scale, focal neurologic findings and cerebrospinal fluid pleocytosis.
Acyclovir; Herpes encephalitis; Herpes simplex; Clinical features
Aggregation of amyloid-β peptides (Aβ) into fibrils is the key pathological feature of many neurodegenerative disorders. Typical drugs inhibit Aβ fibrillation by binding to monomers in 1:1 ratio and display low efficacy. Here, we report that model CdTe nanoparticles (NPs) can efficiently prevent fibrillation of Aβ associating with 100–330 monomers at once. The inhibition is based on the binding multiple Aβ oligomers rather than individual monomers. The oligomer route of inhibition is associated with strong van der Waals interactions characteristic for NPs and presents substantial advantages in the mitigation of toxicity of the misfolded peptides. Molar efficiency and the inhibition mechanism revealed by NPs are analogous to those found for proteins responsible for prevention of amyloid fibrillation in human body. Besides providing a stimulus for finding biocompatible NPs with similar capabilities, these data suggest that inorganic NPs can mimic some sophisticated biological functionalities of proteins.
amyloid beta-peptides; fibril; nanoparticles; inhibition; nanoscale assemblies
This study aimed to investigate the clinicopathological features and prognosis of operable breast cancers in young and elderly Chinese women.
Patients and Methods
This study included 209 patients aged ≤35 years and 213 patients aged ≥60 but <70 years, who received treatment between January 2000 and December 2004. The clinicopathological features, molecular subtypes, therapeutic strategies, and prognosis were evaluated.
Tumor size was of significant difference between the 2 groups (p = 0.018), with more T2 and T3 tumors in the young group and more lymph node involvement in young patients with stage T1 tumors (p = 0.033). There were more triple-negative and less luminal A tumors in the young group (p = 0.018). 47.1% of tumors were not detected by mammography in the young group as compared to 5.5% in the elderly group (p < 0.001). More patients received chemotherapy in the young group (p < 0.001) and preferred breast-conserving surgery (p = 0.031). The 6-year disease-free survival (DFS) was 80 and 66% in the elderly and the young group, respectively (p = 0.001), but no difference was seen in overall survival.
Compared with elderly women, young breast cancer patients have different clinicopathological features and molecular subtypes, and poorer DFS. Furthermore, the insidious onset of breast cancer in young women suggests that clinicians should pay more attention to young women with breast abnormalities.
Breast; cancer; Molecular subtypes; Prognostic features; Very young women; Elderly women
Intramuscular fat (IMF) content plays an important role in meat quality. Many genes involved in lipid and energy metabolism were identified as candidate genes for IMF deposition, since genetic polymorphisms within these genes were associated with IMF content. However, there is less information on the expression levels of these genes in the muscle tissue. This study aimed at investigating the expression levels of sterol regulating element binding protein-1c (SREBP-1c), diacylglycerol acyltransferase (DGAT-1), heart-fatty acids binding protein (H-FABP), leptin receptor (LEPR) and melanocortin 4 receptor (MC4R) genes and proteins in two divergent Banna mini-pig inbred lines (BMIL). A similar growth performance was found in both the fat and the lean BMIL. The fat meat and IMF content in the fat BMIL were significantly higher than in the lean BMIL, but the lean meat content was lower. The serum triacylglycerol (TAG) and free fatty acid (FFA) contents were significantly higher in the fat than in the lean BMIL. The expression levels of SREBP-1c, DGAT-1 and H-FABP genes and proteins in fat BMIL were increased compared to the lean BMIL. However, the expression levels of LEPR and MC4R genes and proteins were lower.
intramuscular fat (IMF); expression levels; Banna mini-pig inbred line (BMIL)
This study aimed to review and analyse the computed tomography (CT) imaging results of frequently encountered developmental anomalies of the inferior vena cava (IVC). The underlying clinical significance was evaluated with reference to the relevant literature. CT images of patients who received abdominal or thoracic scanning between July 2009 and September 2011 were reviewed. Developmental anomalies observed in the IVC were identified and categorised. Images of the cases with typical anomalies were presented and their developmental mechanism, as well as clinical significance, was discussed. The most frequently encountered IVC developmental anomalies include the left vena cava, double vena cava, azygos continuation of the IVC, left circumaortic renal vein, left retroaortic renal vein and retrocaval ureter. The embryogenesis of the IVC is a complex process that results in various congenital anomalies. The developmental anomalies of the IVC are distinguished using a CT scan and have significant implications on clinical perspective.
anomaly; inferior vena cava; embryogenesis; cross-sectional imaging; computed tomography; posterior nutcracker phenomenon
Multiple phosphorylation sites of Drp1 have been characterized for their functional importance. However, the functional consequence of GSK3beta-mediated phosphorylation of Drp1 remains unclear. In this report, we pinpointed 11 Serine/Threonine sites spanning from residue 634∼736 of the GED domain and robustly confirmed Drp1 Ser693 as a novel GSK3beta phosphorylation site. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions. After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Thereafter, we found that overexpressed S693D, but not S693A mutant, caused an elongated mitochondrial morphology which is similar to that of K38A, S637D and K679A mutants. Interestedly, using H89 and LiCl to inhibit PKA and GSK3beta signaling, respectively, it appears that a portion of the elongated mitochondria switched to a fragmented phenotype. In investigating the biofunctionality of phosphorylation sites within the GED domain, cells overexpressing Drp1 S693D and S637D, but not S693A, showed an acquired resistance to H2O2-induced mitochondrial fragmentation and ensuing apoptosis, which affected cytochrome c, capase-3, -7, and PARP, but not LC3B, Atg-5, Beclin-1 and Bcl2 expressions. These results also showed that the S693D group is more effective in protecting both non-neuronal and neuronal cells from apoptotic death than the S637D group. Altogether, our data suggest that GSK3beta-mediated phosphorylation at Ser693 of Drp1 may be associated with mitochondrial elongation via down-regulating apoptosis, but not autophagy upon H2O2 insult.
This investigation sought to optimize ultrasmall particles of iron oxide (USPIO) contrast agent dosage for visualizing cerebral microvasculature on an 8.0-Tesla ultra high field magnetic resonance imaging system.
Materials and Methods
USPIO contrast agent was intravenously administered to 3 groups of 4 rats at 1, 2, and 3 mg Fe/kg. Each animal was scanned before and after injection of USPIO using a high resolution T2*-weighted gradient recalled echo sequence with an in-plane resolution of 78 µm. The signal-to-noise ratio (SNR) and the number of microvessels visualized within the cortex and basal ganglia were calculated and compared before and after the administration of USPIO.
As the USPIO dose increased, microvascular conspicuity increased, and SNR decreased. A dosage of 2 mg Fe/kg improved microvascular visualization in both cortex and basal ganglion regions relative to 1 mg Fe/kg without significantly sacrificing SNR as was the case at 3 mg Fe/kg.
Two mg Fe/kg USPIO is an optimal dose when imaging normal rat cerebral microvasculature using GRE T2*-weighted MR imaging at a field strength of 8 T.
USPIO; magnetic resonance imaging; brain; microvasculature
IgM provides a first line of defense during microbial infections. Serum IgM levels are detected routinely in clinical practice. And IgM is a genetically complex trait. We conducted a two-stage genome-wide association study (GWAS) to identify genetic variants affecting serum IgM levels in a Chinese population of 3495, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Our data show that a common single nucleotide polymorphism (SNP), rs11552708 located in the TNFSF13 gene was significantly associated with IgM levels (p = 5.00×10−7 in first stage, p = 1.34×10−3 in second stage, and p = 4.22×10−9 when combined). Besides, smoking was identified to be associated with IgM levels in both stages (P<0.05), but there was no significant interaction between smoking and the identified SNP (P>0.05). It is suggested that TNFSF13 may be a susceptibility gene affecting serum IgM levels in Chinese male population.
Infectious agents have been shown to contribute to the development of lymphoid malignancies. The different distribution of lymphoid malignancies in Asian and Western populations suggests possibly different etiologies in Asian populations. Herpes zoster infection, commonly seen in immunocompromised persons, has been reported to be associated with lymphoid malignancies in retrospective case–control studies from Western populations, but the results are controversial and large-scale prospective studies from Asian populations are lacking.
A nationwide population-based matched-controlled prospective study on Taiwanese patients was performed using the National Health Insurance Research Database from 1996 to 2007. Herpes zoster and malignancies were defined by compatible ICD-9-CM (International Classification of Disease, 9th Revision, Clinical Modification) codes. Patients who had been diagnosed with any malignancies before herpes zoster, with known viral infections including human immunodeficiency virus, and duration from herpes zoster to diagnosis of malignancies less than 6 months were excluded.
Of 42,498 patients with herpes zoster prior to the diagnosis of any malignancies, the cumulative incidence for lymphoid malignancies was 0.11% (n = 48), compared with 0.06% (n = 106) in 169,983 age- and gender-matched controls (univariate hazard ratio (HR): 1.82, 95%CI: 1.29-2.55). The most common lymphoid malignancy was non-Hodgkin’s lymphoma (60.4%, n = 29), followed by multiple myeloma (27.1%, n = 13). Risk for developing lymphoid malignancies is significantly higher in herpes zoster patients (log rank P = 0.005). After adjusting for presence of any comorbidities in Charlson comorbidity index, time-dependent covariate for herpes group, and income category using Cox proportional hazard regressions, herpes zoster patients had an increased risk of developing lymphoid malignancies (adjusted HR: 1.68, 95%CI: 1.35-2.42, P = 0.0026), but did not have an increased risk of developing non-lymphoid malignancies (adjusted HR: 1.00, 95%CI: 0.91-1.05, P = 0.872).
Preceding herpes zoster infection is an independent risk marker for subsequent lymphoid malignancies in Taiwanese subjects. Further studies are warranted for pathogenesis exploration and preventive strategies in Asian populations.
Herpes zoster; Lymphoma; Leukemia; Epidemiology; Taiwan
The agricultural application of raw animal manure introduces large amounts of dissolved organic matter (DOM) into soil and would increase transport of heavy metals such as Cu which are widely present in animal manure. The purpose of this research was to evaluate the evolution of DOM from pig and cattle manures during composting through excitation-emission matrix (EEM) fluorescence spectroscopy and the binding ability of DOM toward copper (Cu) ions with the aid of fluorescence quenching titration. The excitation-emission matrix spectra indicated that tyrosine-like, tryptophan-like, and soluble microbial byproduct-like fluorescence decreased significantly, while humic-like and fulvic-like fluorescence increased and became the main peaks in composted manure DOM. Fluorescence quenching titration showed that the complexing capacities of pig and cattle manure DOM decreased after composting. Correlation analysis confirmed that complexing capacity of DOM positively and significantly correlates with tyrosine-like and soluble microbial byproduct-like materials which mostly degraded after composting. These results would suggest that the ability of manure DOM to complex with Cu is inhibited as a result of reduced protein-like materials after composting.
Elevated blood pressure during hypertension has been associated with microvascular rarefaction defined by loss of microvessels. However, whether rarefaction is a result of impaired angiogenesis remains unclear. The objective of this study was to compare angiogenesis across the time course of mesenteric microvascular network remodeling in adult spontaneously hypertensive versus normotensive rats. Angiogenic responses in 15–16-week-old SHR and Wistar rats at 0, 3, 5, 10 or 25 days post 20 minute exteriorization of the mesentery were quantified. Consistent with the phenomenon of rarefaction, vascularized area in unstimulated SHR was decreased compared to Wistar. By 25 days, SHR vascular area had increased to the Wistar level and vascular length density and capillary sprouting were comparable. At 3 and 5 days, SHR and Wistar tissues displayed an increase in the capillary sprouting and vascular density relative to their unstimulated controls. At 10 days, capillary sprouting in the SHR remained elevated. The percent change in vascular density was elevated in the SHR compared to the Wistar group at 3 and 5 days and by 25 days the rate of change was more negative. Our results suggest that SHR networks undergo an increased rate of growth followed by an increased rate of pruning.
Hypertension; Angiogenesis; Spontaneously Hypertensive Rat; Microcirculation; Mesentery
Ghost cell odontogenic carcinoma (GCOC) is an exceptionally rare and malignant odontogenic tumor with aggressive growth characteristics. We describe a case of GCOC which was considerably derived from a previously resected calcifying cystic odontogenic tumor (CCOT). Cellular atypia, mitotic activity, Ki-67 labeling index and matrix metalloprotease-9 positive expression rate were all increased in the currently resected specimen compared to the initial one. This is a rare case of malignant transformation of CCOT to GCOC with respect to its histopathological and immunohistochemical findings.
Ghost cell odontogenic carcinoma; Calcifying cystic odontogenic tumor
Stable dispersions of nanofibers are virtually unknown for synthetic polymers. They can complement analogous dispersions of inorganic components, such as nanoparticles, nanowires, nanosheets, etc as a fundamental component of a toolset for design of nanostructures and metamaterials via numerous solvent-based processing methods. As such, strong flexible polymeric nanofibers are very desirable for the effective utilization within composites of nanoscale inorganic components such as nanowires, carbon nanotubes, graphene, and others. Here stable dispersions of uniform high-aspect-ratio aramid nanofibers (ANFs) with diameters between 3 and 30 nm and up to 10 μm in length were successfully obtained. Unlike the traditional approaches based on polymerization of monomers, they are made by controlled dissolution of standard macroscale form of the aramid polymer, i.e. well known Kevlar threads, and revealed distinct morphological features similar to carbon nanotubes. ANFs are successfully processed into films using layer-by-layer (LBL) assembly as one of the potential methods of preparation of composites from ANFs. The resultant films are transparent and highly temperature resilient. They also display enhanced mechanical characteristics making ANF films highly desirable as protective coatings, ultrastrong membranes, as well as building blocks of other high performance materials in place of or in combination with carbon nanotubes.
nanofibers; transparent nanocomposites; layer-by-layer assembly; LBL; Kevlar; aramid fibers
Enterotoxigenic Escherichia coli (ETEC) F4ac is a major determinant of diarrhea and mortality in neonatal and young pigs. Susceptibility to ETEC F4ac is governed by the intestinal receptor specific for the bacterium and is inherited as a monogenic dominant trait. To identify the receptor gene (F4acR), we first mapped the locus to a 7.8-cM region on pig chromosome 13 using a genome scan with 194 microsatellite markers. A further scan with high density markers on chromosome 13 refined the locus to a 5.7-cM interval. Recombination breakpoint analysis defined the locus within a 2.3-Mb region. Further genome-wide mapping using 39,720 informative SNPs revealed that the most significant markers were proximal to the MUC13 gene in the 2.3-Mb region. Association studies in a collection of diverse outbred populations strongly supported that MUC13 is the most likely responsible gene. We characterized the porcine MUC13 gene that encodes two transcripts: MUC13A and MUC13B. Both transcripts have the characteristic PTS regions of mucins that are enriched in distinct tandem repeats. MUC13B is predicated to be heavily O-glycosylated, forming the binding site of the bacterium; while MUC13A does not have the O-glycosylation binding site. Concordantly, 127 independent pigs homozygous for MUC13A across diverse breeds are all resistant to ETEC F4ac, and all 718 susceptible animals from the broad breed panel carry at least one MUC13B allele. Altogether, we conclude that susceptibility towards ETEC F4ac is governed by the MUC13 gene in pigs. The finding has an immediate translation into breeding practice, as it allows us to establish an efficient and accurate diagnostic test for selecting against susceptible animals. Moreover, the finding improves our understanding of mucins that play crucial roles in defense against enteric pathogens. It revealed, for the first time, the direct interaction between MUC13 and enteric bacteria, which is poorly understood in mammals.
Kalanchoe tubiflora (KT) is a succulent plant native to Madagascar, and is commonly used as a medicinal agent in Southern Brazil. The underlying mechanisms of tumor suppression are largely unexplored.
Cell viability and wound-healing were analyzed by MTT assay and scratch assay respectively. Cell cycle profiles were analyzed by FACS. Mitotic defects were analyzed by indirect immunofluoresence images.
An n-Butanol-soluble fraction of KT (KT-NB) was able to inhibit cell proliferation. After a 48 h treatment with 6.75 μg/ml of KT, the cell viability was less than 50% of controls, and was further reduced to less than 10% at higher concentrations. KT-NB also induced an accumulation of cells in the G2/M phase of the cell cycle as well as an increased level of cells in the subG1 phase. Instead of disrupting the microtubule network of interphase cells, KT-NB reduced cell viability by inducing multipolar spindles and defects in chromosome alignment. KT-NB inhibits cell proliferation and reduces cell viability by two mechanisms that are exclusively involved with cell division: first by inducing multipolarity; second by disrupting chromosome alignment during metaphase.
KT-NB reduced cell viability by exclusively affecting formation of the proper structure of the mitotic apparatus. This is the main idea of the new generation of anti-mitotic agents. All together, KT-NB has sufficient potential to warrant further investigation as a potential new anticancer agent candidate.
Kalanchoe tubiflora; Multipolar spindle; Anti-proliferation
No effective therapies currently exist for chronic rhinosinusitis (CRS), a persistent inflammatory condition characterized by the accumulation of highly viscoelastic mucus (CRSM) in the sinuses. Nanoparticle therapeutics offer promise for localized therapies for CRS, but must penetrate CRSM in order to avoid washout during sinus cleansing and to reach underlying epithelial cells. Prior research has not established whether nanoparticles can penetrate the tenacious CRSM barrier, or instead become trapped. Here, we first measured the diffusion rates of polystyrene nanoparticles and the same nanoparticles modified with muco-inert polyethylene glycol (PEG) coatings in fresh, minimally perturbed CRSM collected during endoscopic sinus surgery from CRS patients with and without nasal polyp. We found that uncoated polystyrene particles, previously shown to be mucoadhesive, were immobilized in all CRSM samples tested. In contrast, densely PEGylated particles as large as 200 nm were able to readily penetrate all CRSM samples from patients with CRS alone, and nearly half of CRSM samples from patients with nasal polyp. Based on the mobility of different sized PEGylated particles, we estimate the average pore size of fresh CRSM to be at least 150 ± 50 nm. Guided by these studies, we formulated mucus-penetrating particles (MPP) composed of PLGA and Pluronics, two materials with a long history of safety and use in humans. We showed that biodegradable MPP are capable of rapidly penetrating CRSM at average speeds up to only 20-fold slower than their theoretical speeds in water. Our findings strongly support the development of mucus-penetrating nanomedicines for the treatment of CRS.
Controlled production of reactive oxygen species leads to reversible oxidation of protein tyrosine phosphatases (PTPs) and has emerged as an important tier of regulation over phosphorylation-dependent signal transduction. We present a modified cysteinyl-labeling assay that detects reversible oxidation of members of each of the different PTP subclasses. Here, we describe the methods for enriching reversibly oxidized PTPs from complex protein extracts, illustrating the procedure in IMR90 fibroblasts.
Studies on the effects of tuberculosis on a patient’s quality of life (QOL) are scant. The objective of this study was to evaluate the psychometric properties of the Taiwan short version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire using patients with tuberculosis in Taiwan and healthy referents.
The Taiwanese short version of the WHOQOL-BREF was administered to patients with tuberculosis undergoing treatment and healthy referents from March 2007 to July 2007. Patients with tuberculosis (n = 140) and healthy referents (n = 130), matched by age, sex, and ethnicity, agreed to an interview. All participants lived in eastern Taiwan. Reliability assessments included internal consistency, whereas validity assessments included construct validity, convergent validity, and discriminant validity.
More than half of these patients and referents were men (70.7% and 66.2%, respectively), and their average ages were 50.1 and 47.9 years, respectively. Approximately 60% of patients and referents were aboriginal Taiwanese (60.7% and 61.1%, respectively). The proportion with low socioeconomic status was greater for these patients. The internal consistency reliability coefficients were .92 and .93 for the patients and healthy referents, respectively. Exploratory factor analysis on the healthy referents displayed a 4-domain model, which was compatible with the original WHOQOL-BREF 4-domain model. However, for the TB patient group, after deleting 3 items, both exploratory and confirmatory factor analysis revealed a 6-domain model.
Psychometric evaluation of the Taiwan short version of the WHOQOL-BREF indicates that it has adequate reliability for use in research with TB patients in Taiwan. However, the factor structure generated from this TB patient sample differed from the WHO’s original 4-factor model, which raised a validity concern to apply the Taiwan short version of the WHOQOL-BREF to Taiwanese TB patients. Future research recruiting another sample to revisit this validity issue must be conducted to determine the validity of the WHOQOL-BREF TW in patients with TB.
Quality of life; Patients with tuberculosis; Instrumentation; Validity; Reliability