Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mφ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.
biodistribution of nanoparticles; cancer stem cell; eradication of cancer cells; macrophage; nanocarrier; phagocytosis; reprogramming of macrophages; ‘Trojan horses’; tumor-associated macrophage; tumor-supporting function
In systemic lupus erythematosus, acute kidney injury is usually associated with severe lupus nephritis and rarely associated with other glomerular diseases.
We recently encountered a patient with acute kidney injury that was associated with minimal change disease in systemic lupus erythematosus. A 26-year-old Chinese woman who had a history of systemic lupus erythematosus presented with nephrotic syndrome and acute kidney injury. She fulfilled four of the American College of Rheumatology criteria for the classification of systemic lupus erythematosus. However, a renal biopsy revealed that there were no glomerular abnormalities or deposition of immune complex. Her generalized edema disappeared, and her high serum creatinine level decreased to normal after prednisolone therapy.
Though the relationship between lupus and minimal change disease is still not defined, the possibility of systemic lupus erythematosus combined with minimal change disease must be differentiated in patients with lupus and severe proteinuria.
Acute kidney injury; Minimal change disease; Systemic lupus erythematosus
Emergence agitation is a frequent complication that can have serious consequences during recovery from general anesthesia. However, agitation has been poorly investigated in patients after craniotomy. In this prospective cohort study, adult patients were enrolled after elective craniotomy for brain tumor. The sedation-agitation scale was evaluated during the first 12 hours after surgery. Agitation developed in 35 of 123 patients (29%). Of the agitated patients, 28 (80%) were graded as very and dangerously agitated. By multivariate stepwise logistic regression analysis, independent predictors for agitation included male sex, history of long-term use of anti-depressant drugs or benzodiazepines, frontal approach of the operation, method and duration of anesthesia and presence of endotracheal intubation. Total intravenous anesthesia and balanced anesthesia with short duration were protective factors. Emergence agitation was associated with self-extubation (8.6% vs 0%, P = 0.005). Sedatives were administered more in agitated patients than non-agitated patients (85.7% vs 6.8%, P<0.001). In conclusion, emergence agitation was a frequent complication in patients after elective craniotomy for brain tumors. The clarification of risk factors could help to identify the high-risk patients, and then to facilitate the prevention and treatment of agitation. For patients undergoing craniotomy, greater attention should be paid to those receiving a frontal approach for craniotomy and those anesthetized under balanced anesthesia with long duration. More researches are warranted to elucidate whether total intravenous anesthesia could reduce the incidence of agitation after craniotomy.
The goal of this study is to evaluate the accuracy of patient-specific CT-based rapid prototype drill templates for C2 translaminar screw insertion.
Volumetric CT scanning was performed in 32 cadaveric cervical spines. Using computer software, the authors constructed drill templates that fit onto the posterior surface of the C2 vertebrae with drill guides to match the slope of the patient’s lamina. Thirty-two physical templates were created from the computer models using a rapid prototyping machine. The drill templates were used to guide drilling of the lamina and post-operative CT images were obtained. The entry point and direction of the planned and inserted screws were measured and compared.
Sixty-four C2 translaminar screws were placed without violating the cortical bone of a single lamina. The bilateral average transverse angle of intended and actual screw for C2TLS was 56.60 ± 2.22°, 56.38 ± 2.51°, 56.65 ± 2.24°, 56.39 ± 2.45°. The bilateral mean coronal angle of the planned and actual screw for C2TLS was 0°, 0°, −0.07 ± 0.32°, 0.12 ± 0.57°. The average displacement of the entry point of the superior and inferior C2TLS in the x, y, z axis was 0.27 ± 0.85, 0.49 ± 1.46, −0.28 ± 0.69, 0.43 ± 0.88, 0.38 ± 1.51, 0.23 ± 0.64 mm.
The small deviations seen are likely due to human error in the form of small variations in the surgical technique and use of software to design the prototype. This technology improves the safety profile of this fixation technique and should be further studied in clinical applications.
Rapid prototyping; Post–pre registration; Personalized drill template; Computer-assisted; C2 translaminar screws
To assess the endoscopic activity and Clinical activity after a one-year period of infliximab therapy and to evaluate the association between mucosal healing and need for retreatment after stopping infliximab in patients with Inflammatory bowel disease (IBD).
The data from 109 patients with Crohn’s disease (CD) and 107 patients with Ulcerative colitis (UC) received one-year infliximab were assessed. The primary endpoint of the study was the proportion of clinical remission, mucosal healing and full remission in IBD after the one-year period of maintenance infliximab therapy. The secondary endpoint was the frequency of relapses in the next year.
A total of 84.4% (92/109) CD patients and 81.3% (87/107) UC patients achieved clinical remission, 71.56% (78/109) of CD patients and 69.16% (74/107) of UC patients achieved mucosal healing, 56.88% (62/109) of CD patients and 54.21% (58/107) of UC patients achieved full remission at the end of the year of infliximab therapy. Infliximab therapy was restarted in the 10.19% (22/216) patients (13 CD, 9 UC) who achieved mucosal healing, and 13.89% (30/216) patients (18 CD, 12 UC) who achieved clinical remission and 6.48% (14/216) patients (8 CD, 6 UC) who achieved full remission had to be retreated within the next year. Neither clinical remission nor mucosal healing was associated with the time to restarting Infliximab therapy in IBD.
Mucosal healing did not predict sustained clinical remission in patients with IBD in whom the infliximab therapies had been stopped. And stopping or continuing infliximab therapy may be determined by assessing the IBD patient’s general condition and the clinical activity.
MRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-intermediate S. pneumoniae (PISP), and vancomycin-resistant enterococci (VRE). In this study, the in vivo efficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.
Objective. Technically primates and dogs represent ideal models to investigate diseases characterized by abnormal intracortical remodeling. High expenses and ethical issues, however, restrict the use of those animals in research. Rodent models have been used as alternatives instead, but their value is limited, if none, because these animals lack intracortical bone remodeling. This study aimed at investigating the effect of ovariectomy onto the stimulation of intracortical remodeling in rat mandibles. Materials and Methods. Sixteen 12-week-old Spraque-Dawly (SD) female rats were randomly assigned into two groups, receiving either ovariectomy or sham operation. All the rats were sacrificed 18 weeks postoperatively. The entire mandibles were harvested for microcomputed tomography (micro-CT) and histomorphometric assessments. Results. Micro-CT examination showed significantly decreased bone mineral density (0.95 ± 0.01 versus 1.01 ± 0.02 g/cm3, P < 0.001) and bone volume (65.78 ± 5.45 versus 87.41 ± 4.12%, P < 0.001) in ovariectomy group. Histomorphometric assessment detected a sixfold increased intracortical bone remodeling as well as an increased bone modeling in mandibles of ovariectomized rats. Conclusion. For the first time, to the authors' knowledge, it was detected that ovariectomy stimulates intracortical remodeling in rat mandibles. This animal model might be of use to study various bone diseases associated with an abnormal intracortical remodeling process.
Some studies of animal models of middle cerebral artery occlusion indicate that inflammation plays a key role in the pathogenesis of cerebral ischemia and secondary damage. Flurbiprofen has been suggested to alleviate cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanisms underlying the protective action are still incompletely understood. In this study we want to investigate the protective effect of flurbiprofen after transient middle cerebral artery occlusion (MCAO) in rats and the role of the NF-κB signaling pathway on this neuroprotective effect. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. Flurbiprofen was administrated via tail-vein injection at the onset of reperfusion. HE staining and Immunohistochemistry were carried out to detect the morphological changes in ischemic penumbra cortex. The expression of inflammatory cytokines genes (IL-1β, IL-6 and TNF-α) and the levels of p-NF-κB (p65) in ischemic penumbra cortex were measured by RT-PCR and western blot. Administration of flurbiprofen at the doses of 5 mg/kg and 10 mg/kg significantly attenuated cerebral ischemia/reperfusion injury, as shown by a reduction in the morphological changes and inhibition of pro-inflammatory cytokine expression in ischemic penumbra cortex. Moreover, our findings further demonstrated that the inhibition of NF-κB activity was involved in the neuroprotective effect of flurbiprofen on inflammatory responses. Flurbiprofen protects against cerebral injury by reducing expression of inflammatory cytokines genes and this effect may be partly due to the inhibition of NF-κB signaling pathway.
Flurbiprofen; focal cerebral ischemia; inflammation; nuclear factor-κB
Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies.
We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients.
In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23–1.97; p < 0.001). In the metastatic setting, dual anti-HER2 therapy demonstrated significant benefits in both PFS (hazard ratio (HR), 0.71; 95% CI, 0.62–0.81; p < 0.001) and OS (HR, 0.68; 95% CI, 0.57–0.82; p < 0.001). Subgroup analyses indicated that the addition of chemotherapy to dual anti-HER2 therapy could greatly improve pCR in the neoadjuvant settings. However, in the metastatic setting, similar PFS and OS were found in patients receiving dual anti-HER2 therapy with or without chemotherapy. Dual anti-HER2 therapy was associated with more frequent adverse events than monotherapy, but no statistical differences were observed in cardiac toxicity.
This systematic review provides a summary of all the data currently available, and confirms the benefits and risks of dual anti-HER2 therapy for HER2-positive breast cancer.
anti-HER2 therapy; HER2-positive breast cancer; Systematic review
Characterization of genome-wide patterns of allelic variation and linkage disequilibrium can be used to detect reliable phenotype–genotype associations and signatures of molecular selection. However, the use of Sesamum indicum germplasm for breeding is limited by the lack of polymorphism data.
Here we describe the massively parallel resequencing of 29 sesame strains from 12 countries at a depth of ≥ 13-fold coverage for each of the samples tested. We detected an average of 127,347 SNPs, 17,961 small InDels, and 9,266 structural variants per sample. The population SNP rate, population diversity (π) and Watterson’s estimator of segregating sites (θw) were estimated at 8.6 × 10-3, 2.5 × 10-3 and 3.0 × 10-3 bp-1, respectively. Of these SNPs, 23.2% were located within coding regions. Polymorphism patterns were nonrandom among gene families, with genes mediating interactions with the biotic or abiotic environment exhibiting high levels of polymorphism. The linkage disequilibrium (LD) decay distance was estimated at 150 kb, with no distinct structure observed in the population. Phylogenetic relationships between each of the 29 sesame strains were consistent with the hypothesis of sesame originating on the Indian subcontinent. In addition, we proposed novel roles for adenylate isopentenyltransferase (ITP) genes in determining the number of flowers per leaf axil of sesame by mediating zeatin biosynthesis.
This study represents the first report of genome-wide patterns of genetic variation in sesame. The high LD distance and abundant polymorphisms described here increase our understanding of the forces shaping population-wide sequence variation in sesame and will be a valuable resource for future gene–phenotype and genome-wide association studies (GWAS).
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0225-3) contains supplementary material, which is available to authorized users.
Sesamum indicum; Resequencing; Variation; Linkage disequilibrium
The function of TRPV1 (transient receptor potential vanilloid subfamily, member 1) in the central nervous system is gradually elucidated. It has been recently proved to be expressed in nucleus accumbens (NAc), a region playing an essential role in mediating opioid craving and taking behaviors. Based on the general role of TRPV1 antagonist in blocking neural over-excitability by both pre- and post-synaptic mechanisms, TRPV1 antagonist capsazepine (CPZ) was tested for its ability to prohibit persistent opioid craving in rats. In the present study, we assessed the expression of TRPV1 in nucleus accumbens and investigated the effect of CPZ in bilateral nucleus accumbens on persistent morphine conditioned place preference (mCPP) in rats. We also evaluated the side-effect of CPZ on activity by comparing cross-beam times between groups. We found that morphine conditioned place preference increased the TRPV1 expression and CPZ attenuated morphine conditioned place preference in a dose-dependent and target–specific manner after both short- and long-term spontaneous withdrawal, reflected by the reduction of the increased time in morphine-paired side. CPZ (10 nM) could induce prolonged and stable inhibition of morphine conditioned place preference expression. More importantly, CPZ did not cause dysfunction of activity in the subjects tested, which indicates the inhibitory effect was not obtained at the sacrifice of regular movement. Collectively, these results indicated that injection of TRPV1 antagonist in nucleus accumbens is capable of attenuating persistent morphine conditioned place preference without affecting normal activity. Thus, TRPV1 antagonist is one of the promising therapeutic drugs for the treatment of opioid addiction.
This study was conducted to investigate survival and prognostic factors for extrahepatic cholangiocarcinoma (ECC) following surgical resection and evaluate the effects of postoperative adjuvant therapy (AT) on overall survival (OS). We retrospectively collected clinical and pathological data between March, 2008 and December, 2013. The Kaplan-Meier method and the COX regression model were used to evaluate the OS and prognostic factors of 105 postoperative ECC patients, of whom 32 had received AT. The patients were stratified into seven risk subgroups and the survival rates were compared within each subgroup between patients who received AT and those who did not. The results demonstrated a median OS of 17.6 months, with 1- and 3-year survival rates of 67.9 and 19.5%, respectively, for the entire cohort. On univariate analysis, preoperative cholangitis, non-R0 surgical margins, poor differentiation grade, stage 3/4 and lymphatic metastasis were identified as adverse prognostic factors. AT was not significantly associated with improved OS. However, the subgroup analysis revealed that the effect of AT was significant only in the lymphatic metastasis group (median OS, 21.6 vs. 10.4 months; and 3-year OS, 16.6 vs. 0%, respectively; P=0.02). The survival curves of the AT and non-AT groups were significantly different only for node-positive patients. The COX regression model identified lymphatic metastasis, surgical margins and AT as independent prognostic factors for ECC. A negative resection margin may reduce the mortality rate following surgery by 47%. By contrast, lymph node metastasis was associated with a 2.18-fold higher mortality rate for ECC patients. Postoperative AT contributed to a 0.45-fold mortality rate compared to non-AT ECC patients. Therefore, we concluded that AT is a favorable prognostic factor for ECC patients and it may prolong the survival of patients with lymphatic metastasis. Our data suggest that postoperative AT should be recommended for node-positive ECC patients.
adjuvant therapy; extrahepatic cholangiocarcinoma; prognosis; survival
Primary malignant melanoma originating in the colon is an extremely rare disease. Herein, we report a case of primary melanoma of the ascending colon. The patient was a 57-year-old male who was admitted to our hospital for persistent abdominal pain and episodes of bloody stool, nausea and vomiting. A computed tomography scan revealed lower intestinal intussusception and enlarged lymph nodes in the abdominal cavity and retroperitoneum. During laparoscopic operation, multiple enlarged lymph nodes were found. Several segments of the proximal small intestine were incarcerated into the distal small intestine, forming an internal hernia and obstruction. The necrotic terminal ileum was invaginated into the ascending cecum. Subsequently, adhesive internal hernia reduction and palliative right hemicolectomy were performed. Pathologic examination of the excised specimen revealed a polypoid mass in the ascending colon. Histological examination showed epithelioid and spindle tumor cells with obvious cytoplasmic melanin deposition. Immunohistochemical staining revealed that the tumor cells were positive for S-100, HMB-45 and vimentin, confirming the diagnosis of melanoma. The patient history and a thorough postoperative investigation excluded the preexistence or coexistence of a primary lesion elsewhere in the skin, anus or oculus or at other sites. Thus, we consider our case to represent an aggressive primary colon melanoma presenting as ileocecal intussusception and intestinal obstruction.
Melanoma; Colon; Ileocecal intussusception; Metastasis; S-100; HMB-45; Vimentin
A geochemical study of Three Gorges Reservoir (TGR) sediments was carried out to analyze the concentrations, distribution, accumulation, and potential sources of the seldom monitored trace elements (SMTEs). The mean concentrations of Li, B, Be, Bi, V, Co, Ga, Sn, Sb, and Tl were 47.08, 2.47, 59.15, 0.50, 119.20, 17.83, 30.31, 3.25, 4.14, and 0.58 mg/kg, respectively. The concentrations of total SMTEs, together with their spatial distribution, showed that the SMTEs were mainly due to anthropogenic inputs in the region of TGR. The assessment by Geoaccumulation Index indicates that Tl, Be, V, Co, and Fe are at the unpolluted level; Bi, Li, Ga, and Sn were at the “uncontaminated to moderately contaminated” level. However, B was classified as “moderately contaminated” level and Sb was ranked as “strongly contaminated” level. The pollution level of the SMTEs is Sb > B > Bi > Li > Ga > Sn > Tl > Be > V > Co > Fe. The results of Correlation Analysis and Principal Component Analysis indicated Be, V, Co, Ga, Sn, Tl, Bi, and Fe in sediments have a natural source. B and Li were positively correlated with each other and mainly attributed into similar anthropogenic input. In addition, Sb has less relationship with other SMTEs, indicating that Sb has another kind of anthropogenic source.
Malignant gliomas represent the most common primary brain tumors. The prognosis of patients with malignant gliomas is poor in spite of current intensive therapy and novel therapeutic modalities are needed. Here we report that norcantharidin is effective in growth inhibition of glioma cell lines in vitro.
Glioma cell lines (U87 and C6) were treated with norcantharidin. The effects of norcantharidin on the proliferation and apoptosis of glioma cells were measured by 3-[4,5-dimethylthiazol-2-thiazolyl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry. Western blotting was employed to determine the signaling pathway changes.
The results showed that norcantharidin effectively inhibited cell growth and induced apoptosis in glioma cells, which was concurrent with inhibition of the expression of phospho-MEK and phospho-ERK. Furthermore, the expression anti-apoptotic proteins Bcl-2 and Mcl-1 significantly reduced, but no changes in Bcl-xL and Bax.
Our findings demonstrate that norcantharidin is effective for growth inhibition of glioma cell lines and suggest that norcantharidin may be a new therapeutic option for patients with glioma.
Glioma; Norcantharidin; MAPK; Apoptosis
Little research has examined the popular belief that individuals with an autism spectrum disorder (ASD) are more likely than the general population to gravitate toward science, technology, engineering, and mathematics (STEM) fields. This study analyzed data from the National Longitudinal Transition Study-2, a nationally representative sample of students with an ASD in special education. Findings suggest that students with an ASD had the highest STEM participation rates although their college enrollment rate was the third lowest among 11 disability categories and students in the general population. Disproportionate postsecondary enrollment and STEM participation by gender, family income, and mental functioning skills were found for young adults with an ASD. Educational policy implications are discussed.
autism spectrum disorder; postsecondary enrollment; college; major; science; technology; engineering; and mathematics (STEM); college; young adult
Voltage-gated K+ channel (VKC) plays important roles in biology procession, especially in nervous system. Different subfamilies of VKCs have different biological functions. Thus, knowing VKCs’ subfamilies has become a meaningful job because it can guide the direction for the disease diagnosis and drug design. However, the traditional wet-experimental methods were costly and time-consuming. It is highly desirable to develop an effective and powerful computational tool for identifying different subfamilies of VKCs. In this study, a predictor, called iVKC-OTC, has been developed by incorporating the optimized tripeptide composition (OTC) generated by feature selection technique into the general form of pseudo-amino acid composition to identify six subfamilies of VKCs. One of the remarkable advantages of introducing the optimized tripeptide composition is being able to avoid the notorious dimension disaster or over fitting problems in statistical predictions. It was observed on a benchmark dataset, by using a jackknife test, that the overall accuracy achieved by iVKC-OTC reaches to 96.77% in identifying the six subfamilies of VKCs, indicating that the new predictor is promising or at least may become a complementary tool to the existing methods in this area. It has not escaped our notice that the optimized tripeptide composition can also be used to investigate other protein classification problems.
voltage-gated potassium channel; subfamily; optimized tripeptide composition; support vector machine; feature selection
Autophagy is important for cells to degrade protein aggregates and organelles. Our preliminary study suggests that ischemia/reperfusion in rabbit hearts promoted autophagic myocardial injury, resulting in no-reflow phenomenon. In this study, we sought to further understand the mechanism and outcome of the upregulation of autophagy in ischemia/reperfusion.
We employed a simulated ischemia/reperfusion (sI/R) model in human umbilical vein endothelial cells (HUVECs) in vitro, in the presence or absence of antioxidants.
Our study confirms that sI/R induces autophagy in HUVECs as measured by increased expression of Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3), electron microscopic analysis, and special biofluorescent staining with monodansylcadaverine. This sI/R-induced autophagy was also accompanied by increased levels of p65 protein expression and cell death. In addition, we detected the accumulation of reactive oxygen species (ROS) after sI/R. Moreover, with the application of ROS scavengers that block the release of ROS, we were able to demonstrate that inhibition of autophagy increases cell survival.
The study suggests that ROS accumulation is involved in the sI/R-induced autophagic cell death in HUVECs.
Autophagy; Reactive Oxygen Species; Reperfusion Injury
A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers. In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5′-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 4 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.
Nanogel-drug conjugates; Gemcitabine; phosphorylated nucleoside analogs; oral drug administration; drug-resistant animal tumor xenografts
Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44
receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of
nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and
suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability
of poorly soluble drugs with previously reported activity against CSC, such as etoposide,
salinomycin, and curcumin. The small nanogel particles (diam. 20–40 nm) with a hydrophobic
core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a
sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly,
CHA-drug nanogels demonstrated 2–7 times higher cytotoxicity in CD44-expressing
drug-resistant human breast and pancreatic adenocarcinoma cells compared to free drugs and
non-modified HA-drug conjugates. These nanogels were efficiently internalized via CD44
receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring
by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more
efficient drug accumulation in cancer cells compared to non-modified HA-drug conjugates. CHA-drug
nanogels were able to penetrate multicellular cancer spheroids and displayed higher cytotoxic effect
in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion,
the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug
bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer
cells and multicellular spheroids.
nanogel; hyaluronic acid; CD44; drug conjugate; cancer spheroids; drug-resistant cancer cells
Bioengineered bone substitutes might represent alternatives to autologous bone grafts in medically compromised patients due to reduced operation time and comorbidity. Due to the lack of an inherent vascular system their dimension is limited to the size of critical bone size defect. To overcome this shortcoming, the experiment tried to create heterotopic bone around vessels. In vivo, a two-component fibrin and thrombin gel containing recombinant bone morphogenic protein (rhBMP-2) and transglutamate vascular endothelial growth factor (TG-VEGF) in different ratios, respectively, was injected into a dimensionally stable membrane tube, wrapped around the femoral vessel bundle in twelve New Zealand white rabbits. Sacrifice occurred eight weeks postoperatively. Microcomputed tomography of the specimens showed significantly increased bone volume in the rhBMP-2 to TG-VEGF ratio of 10 to 1 group. Histology showed new bone formation in close proximity to the vessel bundle. Immunohistochemistry detected increased angiogenesis within the newly formed bone in the rhBMP-2 to TG-VEGF ratios of 3 to 1 and 5 to 1. Heterotopic bone was engineered in vivo around vessels using different rhBMP-2 and TG-VEGF ratios in a fibrin matrix injected into a dimensionally stable membrane tube which prevented direct contact with skeletal muscles.
HIV-1 viral quantitation is essential for treatment monitoring. An in-house assay would decrease financial barriers to access.
Materials and Methods
A real-time competitive RT-PCR in house assay (Sing-IH) was developed in Singapore. Using HXB2 as reference, the assay's primers and probes were designed to generate a 183-bp product that overlaps a portion of the LTR region and gag region. A competitive internal control (IC) was included in each assay to monitor false negative results due to inhibition or human error. Clinical evaluation was performed on 249 HIV-1 positive patient samples in comparison with the commercially available Generic HIV Viral Load assay. Correlation and agreement of results were assessed for plasma HIV-1 quantification with both assays.
The assay has a lower limit of detection equivalent to 126 copies/mL of HIV-1 RNA and a linear range of detection from 100–1000000 copies/mL. Comparative analysis with reference to the Generic assay demonstrated good agreement between both assays with a mean difference of 0.22 log10 copies/mL and 98.8% of values within 1 log10 copies/mL range. Furthermore, the Sing-IH assay can quantify HIV-1 group M subtypes A–H and group N isolates adequately, making it highly suitable for our region, where subtype B and CRF01_AE predominate.
With a significantly lower running cost compared to commercially available assays, the broadly sensitive Sing-IH assay could help to overcome the cost barriers and serve as a useful addition to the currently limited HIV viral load assay options for resource-limited settings.
To analyze the correlation of polymorphisms of toll-like receptor 7 (TLR7) (rs179009) and toll-like receptor 9 (TLR9) (rs187084) in hepatitis C virus (HCV) infections in the Han population.
Materials and Methods
The genotypes of TLR7IVS2-151 in HCV infection were detected by Sanger sequencing using polymerase chain reaction-restriction fragment length polymorphism to determine the TLR9 T-1486C single nucleotide polymorphisms (SNP) for all enrolled patients.
We found no significant difference between males with spontaneous clearance of HCV versus those chronically infected [χ2=2.71, p=0.10, odd ratios (OR)=0.58, 95% confidence interval (CI) 0.31-1.11]. However, significant differences were found for the distribution of TLR7 (rs179009) in females (χ2=9.46, p=0.01). In females, a significant difference was also found between chronic hepatitis C and those with spontaneous clearance of HCV in terms of TLR7 IVS2-151G/A allele frequencies (χ2=9.50, p=0.00, OR=0.46, 95% CI 0.28-0.75). In HCV-infected patients, no significant association was found between the frequency of TLR9 genotypes and alleles.
The site of TLR7 IVS2-151 (rs179009) G/A may be a factor for susceptibility of chronic HCV in the female Han population. TLR9T-1486C (rs18084) SNP may not play a major role in HCV infection. However, individual risk profiles for HCV infection did vary by sex and this relationship should be further investigated.
Hepatitis C virus; single nucleotide polymorphism; TLR7; TLR9
Majority of C1 fractures can be effectively treated conservatively by immobilization or traction unless there is an injury to the transverse ligament. Conservative treatment usually involves a long period of immobilization in a halo-vest. Surgical intervention generally involves fusion, eliminating the motion of the upper cervical spine. We describe the treatment of unstable Jefferson fractures designed to avoid these problems of both conservative and invasive methods.
Materials and Methods:
A retrospective review of 12 patients with unstable Jefferson fractures treated with transoral osteosynthesis of C1 between July 2008 and December 2011 was performed. A steel plate and C1 lateral mass screw fixation were used to repair the unstable Jefferson fractures. Our study group included eight males and four females with an average age of 33 years (range 23-62 years).
Patients were followed up for an average of 16 months after surgery. Range of motion of the cervical spine was by and large physiologic: Average flexion 35° (range 28-40°), average extension 42° (range 30-48°). Lateral bending to the right and left averaged 30° and 28° respectively (range 12-36° and 14-32° respectively). The average postoperative rotation of the atlantoaxial joint, evaluated by functional computed tomography scan was 60° (range 35-72°). Total average lateral displacement of the lateral masses was 7.0 mm before surgery (range 5-12 mm), which improved to 3.5 mm after surgery (range 1-6.5 mm). The total average difference of the atlanto-dens interval in flexion and extension after surgery was 1.0 mm (range 1-3 mm).
Transoral osteosynthesis of the anterior ring using C1 lateral mass screws is a viable option for treating unstable Jefferson fractures, which allows maintenance of rotation at the C1-C2 joint and restoration of congruency of the atlanto-occipital and atlantoaxial joints.
Jefferson fractures; osteosynthesis; transoral approach
The number of youth on the autism spectrum approaching young adulthood and attending college is growing. Very little is known about the subjective experience of these college students. Disability identification and self-efficacy are two subjective factors that are critical for the developmental and logistical tasks associated with emerging adulthood. This study uses data from the National Longitudinal Transition Study 2 to examine the prevalence and correlates of disability identification and self-efficacy among college students on the autism spectrum. Results indicate nearly one-third of these students do not report seeing themselves as disabled or having a special need. Black race was associated with lower likelihood of both disability identification and self-efficacy.