miR-550a-5p promotes the proliferation and migration of hepatocellular carcinoma by targeting GNE via the Wnt/ß-catenin signaling pathway.

Liver cancer is one of the most common tumors with a high malignant degree in the world. Its diagnosis and treatment are very difficult and limited. More novel and powerful DAT strategies are urgently needed to break this situation. An increasing number of studies have shown that microRNAs (miRNAs) could be used not only as biomarkers for the diagnosis and prognosis of hepatocellular carcinoma (HCC) but also as important targets for molecular targeted therapy. However, the role of miR-550a-5p in HCC and its specific mechanism remain unclear. Here we proposed and verified the hypothesis that the miR-550a-5p could regulate the progression of HCC and was positively associated with poor prognosis. We found that decreased miR-550a-5p would inhibit the proliferation and migration of HCC cell lines (HCs) by performing relevant assays. Interestingly, knocking down GNE could reverse the above effect of miR-550a-5p on HCs. Meanwhile, the western blot results showed that the Wnt/ß-catenin signaling pathway was at least partly involved in the regulation of HCC by miR-550a-5p. In addition, we also found that miR-550a-5p could suppress the growth of HCC in vivo via a xenograft tumor model assay. All in all, we draw a conclusion that the miR-550a-5p/GNE axis functioned as an important role in promoting the progression of HCC via the Wnt/ß-catenin signaling pathway.

Individualized clinical management of patients at risk for Alzheimer's dementia.

INTRODUCTION: Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. RESULTS: One hundred seventy-four were assigned interventions (age 25-86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. DISCUSSION: Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.

Two novel heterozygous HTRA1 mutations in two pedigrees with cerebral small vessel disease families.

Heterozygous HTRA1 mutations, recently, have been reported as a cause of autosomal dominant hereditary cerebral small vessel disease (CSVD). We herein describe clinical and neuroimaging findings in two familial CSVD with two different heterozygous HTRA1 mutations. Detailed clinical and neuroimaging examination were conducted in probands and their available family members. A next-generation sequencing-based comprehensive gene panel was used to investigate their causative mutations. A novel heterozygous missense variant c.527T>C (p.V176A) and a novel heterozygous nonsense variant c.589C>T (p.R197X) in HTRA1 gene were detected in probands of family 1 and family 2, respectively. Co-segregation analysis in family 1 showed eight family members were mutation carriers. All alive male patients showed typical clinical and neuroimaging features of CSVD. All alive female mutation carriers were clinical or neuroimaging asymptomatic. Screening of HTRA1 should be considered in patients with familial CSVD. A male predominance may exist in patients with heterozygous HTRA1 mutations and need to be further investigated.

Association between dietary vitamin C and telomere length: A cross-sectional study.

Background: Currently, telomere length is known to reflect the replication potential and longevity of cells, and many studies have reported that telomere length is associated with age-related diseases and biological aging. Studies have also shown that vitamin C acts as an oxidant and free radical scavenger to protect cells from oxidative stress and telomere wear, thus achieving anti-aging effects. At present, there are few and incomplete studies on the relationship between vitamin C and telomere length, so this study aims to explore the relationship between vitamin C and telomere length. Methods: This study used cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) database from 1999 to 2002, a total of 7,094 participants were selected from all races in the United States. Male participants accounted for 48.2% and female participants accounted for 51.8%. The correlation between vitamin C and telomere length was assessed using a multiple linear regression model, and the effect of dietary vitamin C on telomere length was obtained after adjusting for confounding factors such as age, gender, race, body mass index (BMI), and poverty income ratio (PIR). Results: This cross-sectional study showed that vitamin C was positively correlated with telomere length, with greater dietary vitamin C intake associated with longer telomeres (ß = 0.03, 95% CI: 0.01-0.05, P = 0.003). Conclusion: This study shows that vitamin C intake is positively correlated with human telomere length, which is of guiding significance for our clinical guidance on people's health care, but our study need to be confirmed by more in-depth and comprehensive other research results.

[Change of plasma endothelin-1 concentrations in photodynamic induced rat anterior ischemic optic neuropathy model and drug modulation].

OBJECTIVE: To investigate changes of plasma endothelin-1 (ET-1) concentration in photodynamic induced rat anterior ischemic optic neuropathy model (rAION) and evaluate the effects of compound anisodine hydrobromide (CA). METHODS: Eighty-five Sprague-Dawley (SD) male rats were randomly divided into a blank control group of 10 rats and a model group of 75 rats. rAION model was established in the model group by photodynamic induction. The model group was divided into a rAION simple group of 25 rats, a CA intervention group of 25 rats, and a normal saline (NS) control group of 25 rats. Beginning from the day that the rAION model was established, temporal subcutaneous injections (once daily for 3 days) of CA and NS were performed in the CA and the NS groups, respectively. The plasma ET-1 concentrations were detected by radioimmunoassay and analyzed at 1, 3, 5, 7 and 14 days. RESULTS: The means plasma ET-1 concentration of rAION simple group is (114.9±17.6) ng/L, higher than that of the control group (69.4±9.1) ng/L (t=14.92, P<0.01). In the rAION model group, the plasma ET-1 concentrations 1 to 5 days after the model was established were higher than that of 7 to 14 days. During observational periods, on the 1st, 5th, 7th and 14th day, there was no significant difference between the CA and NS groups (t=0.58, 2.07, 0.81 and 0.93, P>0.05), but on the 3rd day the level of plasma ET-1 concentration in the CA group was significantly lower than that of the NS group (t=4.72, P<0.05). CONCLUSIONS: Increase of plasma ET-1 concentrations may play an important role in the pathogenesis of photodynamic induced rAION model. CA can decrease the plasma ET-1 concentrations in rAION rats.

Odontoid calcification and crowned dens syndrome: data from a Chinese center.

OBJECTIVES: To assess the prevalence of calcification surrounding the odontoid process (odontoid calcification) with crowned dens syndrome (CDS) and without CDS (non-CDS) and investigate factors that may related to the onset of CDS. METHODS: Retrospective review of consecutive patients visited Sir Run Run Shaw Hospital between 1 January 2018 and 5 November 2019 who were identified to have odontoid calcification on cervical computed tomography (CT) images. Those who presented with an acute or subacute episode of cervico-occipital pain were defined as CDS, others were non-CDS. RESULTS: We diagnosed 69 cases of odontoid calcification among 2902 cervical CTs of 2556 patients (69/2556, 2.70%), 19 (19/2556, 0.74%) cases of which were CDS, 50 (50/2556, 1.96%) cases were non-CDS. Mean age was 71 (54-86) years old in odontoid calcification patients. The male-to-female ratio of patients with odontoid calcification was 27:42 (0.64). The prevalence of odontoid calcification was 69/1497 (6.14%) in individuals over 50 years old, The prevalence was 0.59% (4/679), 5.05% (26/515), 11.49% (27/235) and 20% (12/60) in patients aged 50-59, 60-69, 70-79 and 80-89 years old, respectively. Age and female gender were predictive factors of odontoid calcification. Lower hemoglobin (Hgb), red blood cell count (RBC), higher C-reactive protein (CRP), pain scale score were found in CDS patients comparing with non-CDS group. No difference of age, gender, hypertension, diabetes mellitus, smoking, alcohol history, creatinine, white blood cell count, mean corpuscular volume, uric acid, calcium was found between the two groups. CONCLUSIONS: Odontoid calcification is a common radiological entity in patients older than 50 years. Lower Hgb, RBC, higher CRP, pain scale score were found in CDS patients comparing with non-CDS.

Reversible Splenial Lesion Syndrome with Some Novel Causes and Clinical Manifestations.

Objective Reversible splenial lesion syndrome (RESLES) is a clinical radiological syndrome characterized by a reversible lesion of the splenium of the corpus callosum with a decreased apparent diffusion coefficient (ADC) value. The clinical manifestations of RESLES are diverse. Methods Fifteen cases of adult RESLES patients (10 males and 5 females) were retrospectively selected from the radiology system using the key word "corpus callosum" at a university-affiliated tertiary care hospital between May 1, 2015 and December 31, 2019. The possible precipitating factors, clinicoradiological findings and modified Rankin Scale (mRS) on follow-up were then analyzed. Results The patient ages ranged from 22 to 53 years old. The mean age was 34 years old. The most common neurological symptoms included headache (3/15), dizziness (3/15), first onset of seizure (3/15), paroxysmal blurred vision (2/15), vertigo (2/15), amnesia (2/15), and confused consciousness without seizure (2/15), followed by drowsiness (1/15), paresthesia (1/15), dysmetria (1/15) and dysarthria (1/15). The precipitating factors included infection, seizure, anti-epileptic treatment with levetiracetam, carbamazepine, valproate, hyperglycemia, hypoglycemia, cerebral venous sinus thrombosis, and rabies vaccine injection prior to the onset of RESLES. All cases were carefully followed up and had excellent prognoses. Conclusion RESLES manifests as variety of symptoms with less specificity and precipitating factors. Paroxysmal blurred vision may be a relatively specific symptom of RESLES. Levetiracetam, carbamazepine or valproate could be the cause of RESLES, exposure to the rabies vaccine could be another predisposing factors for RESLES as well. RESLES type 1 was therefore found to be highly "reversible" with an excellent prognosis.

[Targeted epidural blood patch: an effective treatment for spontaneous intracranial hypotension].

OBJECTIVE: To report the authors' own experience in the treatment of spontaneous intracranial hypotension (SIH) with targeted epidural blood patch after locating the CSF leaks with CT myelography (CTM) and to discuss the mechanism and value of this method. METHODS: Six patients with SIH (3 males and 3 females aged 33-66 years) were included. All patients met the diagnostic criteria of 2nd edition of International Classification of Headache Disorders (2004). CT myelography revealed the CSF leak sites in all 6 patients. Autologous blood mixed with Omnipaque (300 mg/ml) was injected after selective puncture at the leak site indicated by CTM. RESULTS: All patients responded well to the treatment and achieved a complete resolution of symptoms. Nerve root irritation occurred in 2 patients. Three patients suffered from a temporary back pain. CONCLUSION: With the location of leak sites by CTM, targeted epidural blood patch is an effective way to treat spontaneous intracranial hypotension.

The effect of PEG-5K grafting level and particle size on tumor accumulation and cellular uptake.

PEG-modified gold nanoparticles (PEG-modified GNs) with diameters of 40 nm and 70 nm were prepared to elucidate the effect of extent of PEG (M.W. 5000) grafting and particle size on tumor accumulation and cellular uptake. Flow cytometry reveals that cellular uptake is strongly related to the size of PEG-modified GNs, rather than the extent of PEG-5K grafting level. Cytotoxicity analysis based on the intracellular release of drugs showed that the 70 nm PEG-modified GNs have the higher cytotoxicity, beccause of their greater cellular uptake. Also, particle size, rather than PEG-5K grafting level affects tumor accumulation. However, PEG-5K grafting level significantly affects the accumulation of particles in the liver and spleen. This finding is important in determining the proper PEG-5K grafting level and particle size for designing nano-medicines.

The accumulation of dual pH and temperature responsive micelles in tumors.

An optimized, biodegradable, dual temperature- and pH-responsive micelle system conjugated with functional group Cy5.5 was prepared in order to enhance tumor accumulation. The Dynamic light scattering (DLS) measurements showed that these diblock copolymers form micelle in PBS buffer with a size of around 50 nm by heating of an aqueous polymer solution from below to above the cloud point (CP). Anticancer drug, doxorubicin was incorporated into the inner core of micelle by hot shock protocol. The size and stability of the micelle were controlled by the copolymer composition and is fine tuned to extracellular pH of tumor. The mechanism then caused pH change and at body temperature which induce doxorubicin release from micelles and have strong effects on the viability of HeLa, ZR-75-1, MCF-7 and H661 cancer cells. Our in vivo results revealed a clear distribution of Doxorubicin-loaded mixed micelle (Dox-micelle) and efficiency targeting tumor site with particles increasing size in the tumor interstitial space, and the particles could not diffuse throughout the tumor matrix. In vivo tumor growth inhibition showed that Dox-micelle exhibited excellent antitumor activity and a high rate of anticancer drug in cancer cells by this strategy.

Multifunctional hollow nanoparticles based on graft-diblock copolymers for doxorubicin delivery.

This article reports a flexible hollow nanoparticles, self-assembling from poly(N-vinylimidazole-co-N-vinylpyrrolidone)-g-poly(d,l-lactide) graft copolymers and methoxyl/functionalized-PEG-PLA diblock copolymers, as an anticancer drug doxorubicin (Dox) carrier for cancer targeting, imaging, and cancer therapy. This multifunctional hollow nanoparticle exhibited a specific on-off switch drug release behavior, owning to the pH-sensitive structure of imidazole, to release Dox in acidic surroundings (intracellular endosomes) and to capsulate Dox in neutral surroundings (blood circulation or extracellular matrix). Imaging by SPECT/CT shows that nanoparticle conjugated with folic acids ensures a high intratumoral accumulation due to the folate-binding protein (FBP)-binding effect. In vivo tumor growth inhibition shows that nanoparticles exhibited excellent antitumor activity and a high rate of apoptosis in cancer cells. After 80-day treatment course of nanoparticles, it did not appreciably cause heart, liver and kidney damage by inactive Dox or polymeric materials. The results indicate that the flexible carriers with an on-off switched drug release may be allowed to accurately deliver to targeted tumors for cancer therapy.

A methodology based on the "anterior chamber of rabbit eyes" model for noninvasively determining the biocompatibility of biomaterials in an immune privileged site.

In this study, a novel methodology based on the anterior chamber of rabbit eyes model was developed to evaluate the in vivo biocompatibility of biomaterials in an immune privileged site. The 7-mm-diameter membrane implants made from either a biological tissue material (amniotic membrane, AM group) or a biomedical polymeric material (gelatin, GM group) were inserted in rabbit anterior chamber for 36 months and characterized by biomicroscopic examinations, intraocular pressure measurements, and corneal thickness measurements. The noninvasive ophthalmic parameters were scored to provide a quantitative grading system. In this animal model, both AM and GM implants were visible in an ocular immune privileged site during clinical observations. The implants of the AM group appeared as soft tissue patches and have undergone a slow dissolution process resulting in a partial reduction of their size. Additionally, the AM implants did not induce any foreign body reaction or change in ocular tissue response for the studied period. By contrast, in the GM groups, significant corneal edema, elevated intraocular pressure, and increased corneal thickness were noted in the early postoperative phase (within 3 days), but resolved rapidly with in vivo dissolution of the gelatin. The results from the ocular grading system showed that both implants had good long-term biocompatibility in an ocular immune privileged site for up to 3 years. It is concluded that the anterior chamber of rabbit eyes model is an efficient method for noninvasively determining the immune privileged tissue/biomaterial interactions.

Carbodiimide cross-linked hyaluronic acid hydrogels as cell sheet delivery vehicles: characterization and interaction with corneal endothelial cells.

It was reported that cell-adhesive gelatin discs have been successfully used as delivery vehicles for intraocular grafting of bioengineered corneal endothelial cell sheets. Development of alternative biomaterials to bovine-based gelatin vehicles can potentially eliminate the risk of bovine spongiform encephalopathy. In the present work, to investigate whether it was appropriate for use as cell sheet delivery vehicles, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) cross-linked hyaluronic acid (HA) hydrogels were studied by determinations of morphological characteristic, mechanical and thermal property, water content, in vitro degradability and cytocompatibility. Glutaraldehyde (GTA) cross-linked HA samples were used for comparison. It was found that HA discs after cross-linking significantly increased its tensile stress but reduced its tensile strain, water uptake and enzymatic degradability. The results of differential scanning calorimetry demonstrated that cross-linking could lead to the alteration of polymer structure. In addition, the EDC-cross-linked HA discs had a smoother surface structure, a faster degradation rate and a relatively lower cytotoxicity as compared to the GTA cross-linked counterparts. It is concluded that EDC can be successfully applied for HA cross-linking to fabricate structurally stable, mechanically reinforced, readily deformable, transparent and cytocompatible HA hydrogel discs with the potential to be applied as delivery vehicles for corneal endothelial cell therapy.

Effect of charge and molecular weight on the functionality of gelatin carriers for corneal endothelial cell therapy.

Cell transplantation strategies usually involve the use of supporting carrier materials because of the soft and fragile nature of these grafts. In this work, a cell-adhesive gelatin hydrogel carrier was fabricated to deliver cultivated human corneal endothelial cell (HCEC) sheets, which were harvested from thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm)-grafted culture surfaces. The carrier disks, consisting of gelatins with a different isoelectric point (IEP = 5.0 and 9.0) and a molecular weight (MW) ranging from 3 to 100 kDa, were subjected to 16.6 kGy gamma irradiation for sterilization. The effect of IEP and MW of the raw gelatins (i.e., before irradiation) on the functionality of sterilized disks was studied by determinations of mechanical property, water content, dissolution degree, and cytocompatibility. Irrespective of the IEP of raw gelatin, hydrogel disks prepared with high MW (100 kDa) exhibited a greater tensile strength, lower water content, and slower dissolution rate than those made of low MW gelatin (8 and 3 kDa). From the investigation of cellular responses to the disks, the negatively charged gelatin (IEP = 5.0) groups were more cytocompatible when compared with their positively charged counterparts (IEP = 9.0) at the same MW (100 kDa). Additionally, in the negatively charged gelatin groups, only a slight increase in pro-inflammatory cytokine expression was observed with increasing MW of gelatin from 3 to 100 kDa. It is concluded that the gamma-sterilized hydrogel disks made from raw gelatins (IEP = 5.0, MW = 100 kDa) with appropriate dissolution degree and acceptable cytocompatibility are capable of providing stable mechanical support, making these carriers promising candidates for intraocular delivery of cultivated HCEC sheets.