[Microfocal prostate cancer: a clinicopathological analysis of 206 cases].

Objective: To investigate the clinical and pathological features and prognosis of patients with microfocal prostate adenocarcinoma. Methods: Clinical and pathological data of the patients diagnosed with microfocal adenocarcinoma on prostate biopsy at the West China Hospital from 2013 to 2019 were collected. Microfocal adenocarcinoma was defined as follows: Gleason score of 3+3=6, total number of the cores ≥10, number of the positive cores ≤2, and proportion of the tumor in each positive core<50%. Clinicopathological parameters, treatment plans and follow-up data were collected. Pathological information of the biopsy and radical resection specimens was used to analyze the correlation between pathological parameters in the biopsy report and adverse pathological features of radical resection specimens, including increased Gleason score, capsule invasion, positive surgical margin and perineural invasion. Results: A total of 206 cases of microfocal adenocarcinoma were diagnosed on prostate biopsies from 2013 to 2019, accounting for 6.7% of all adenocarcinoma cases. There were 139 cases of 1 positive core and 67 cases of 2 positive cores. Patients with microfocal adenocarcinoma were younger than those with non-microfocal adenocarcinoma (69 years versus 71 years, P<0.001). Compared with patients with non-microfocal adenocarcinoma, the pre-biopsy total prostate specific antigen (tPSA) and free prostate specific antigen (fPSA) levels in patients with microfocal adenocarcinoma were both lower (11.2 µg/L2 versus 23.7 µg/L2; 1.4 µg/L2 versus 3.0 µg/L2, P<0.001), the fPSA/tPSA level was higher (12.9% versus 10.7%, P<0.05), the prostate volume was larger (38.9 mL versus 34.3 mL, P<0.05), and the PSA density was lower (0.3 µg/L2 versus 0.8 µg/L2, P<0.001). 130 patients underwent radical prostatectomy, 30 patients chose active monitoring, 31 patients chose endocrine or radiation therapy, and 15 patients were lost to follow-up. Three patients in the active surveillance group underwent radical prostatectomy for disease progression after 21-39 months observation. Biochemical relapses occurred in two patients in the radical prostatectomy group. The remaining patients have no disease progression or recurrence at present. Compared with radical prostatectomy specimens, Gleason score in the biopsy material was increased in 64/115 patients (55.7%). Among resection excision specimens, 14 cases (12.2%) had extraprostatic extension (EPE), 35 cases (30.4%) had perineural invasion, and 16 cases (13.9%) had a positive margin. Univariate and multivariate analyses showed that low fPSA/tPSA ratio and 2 positive cores were independent risk factors for Gleason score increase in the radical prostatectomy specimens. A low fPSA/tPSA ratio was an independent risk factor for perineural invasion. Low fPSA/tPSA ratio and low prostate volume were associated with a positive margin in radical prostatectomy specimens. Conclusions: In this study, patients diagnosed with microfocal adenocarcinoma on prostate biopsy account for a high proportion of the patients with increased Gleason score in the radical prostatectomy specimens, and there is a certain proportion of adverse pathological features in the radical specimens. Therefore, for the patients with only a small amount of low-grade adenocarcinoma found in biopsy, PSA levels and PSA density should be taken into consideration in treatment selection.

Photoemission Spectroscopic Evidence for the Dirac Nodal Line in the Monoclinic Semimetal SrAs_{3}.

Topological nodal-line semimetals with exotic quantum properties are characterized by symmetry-protected line-contact bulk band crossings in the momentum space. However, in most of identified topological nodal-line compounds, these topological nontrivial nodal lines are enclosed by complicated topological trivial states at the Fermi energy (E_{F}), which would perplex their identification and hinder further applications. Utilizing angle-resolved photoemission spectroscopy and first-principles calculations, we provide compelling evidence for the existence of Dirac nodal-line fermions in the monoclinic semimetal SrAs_{3}, which possesses a simple nodal loop in the vicinity of E_{F} without the distraction from complicated trivial Fermi surfaces. Our calculations revealed that two bands with opposite parities were inverted around Y near E_{F}, resulting in the single nodal loop at the Γ-Y-S plane with a negligible spin-orbit coupling effect. The band crossings were tracked experimentally and the complete nodal loop was identified quantitatively, which provide a critical experimental support for the existence of nodal-line fermions in the CaP_{3} family of materials. Hosting simple topological nontrivial bulk electronic states around E_{F} and without complication from the trivial states, SrAs_{3} is expected to be a potential platform for topological quantum state investigation and applications.

The robustness of T2 value as a trabecular structural index at multiple spatial resolutions of 7 Tesla MRI.

PURPOSE: To evaluate the robustness of MR transverse relaxation times of trabecular bone from spin-echo and gradient-echo acquisitions at multiple spatial resolutions of 7 T. METHODS: The effects of MRI resolutions to T2 and T2* of trabecular bone were numerically evaluated by Monte Carlo simulations. T2 , T2*, and trabecular structural indices from multislice multi-echo and UTE acquisitions were measured in defatted human distal femoral condyles on a 7 T scanner. Reference structural indices were extracted from high-resolution microcomputed tomography images. For bovine knee trabecular samples with intact bone marrow, T2 and T2* were measured by degrading spatial resolutions on a 7 T system. RESULTS: In the defatted trabecular experiment, both T2 and T2* values showed strong ( |r| > 0.80) correlations with trabecular spacing and number, at a high spatial resolution of 125 µm3 . The correlations for MR image-segmentation-derived structural indices were significantly degraded ( |r| < 0.50) at spatial resolutions of 250 and 500 µm3 . The correlations for T2* rapidly dropped ( |r| < 0.50) at a spatial resolution of 500 µm3 , whereas those for T2 remained consistently high ( |r| > 0.85). In the bovine trabecular experiments with intact marrow, low-resolution (approximately 1 mm3 , 2 minutes) T2 values did not shorten ( |r| > 0.95 with respect to approximately 0.4 mm3 , 11 minutes) and maintained consistent correlations ( |r| > 0.70) with respect to trabecular spacing (turbo spin echo, 22.5 minutes). CONCLUSION: T2 measurements of trabeculae at 7 T are robust with degrading spatial resolution and may be preferable in assessing trabecular spacing index with reduced scan time, when high-resolution 3D micro-MRI is difficult to obtain.

Ultrafast 3D spin-echo acquisition improves Gadolinium-enhanced MRI signal contrast enhancement.

Long scan times of 3D volumetric MR acquisitions usually necessitate ultrafast in vivo gradient-echo acquisitions, which are intrinsically susceptible to magnetic field inhomogeneities. This is especially problematic for contrast-enhanced (CE)-MRI applications, where non-negligible T2* effect of contrast agent deteriorates the positive signal contrast and limits the available range of MR acquisition parameters and injection doses. To overcome these shortcomings without degrading temporal resolution, ultrafast spin-echo acquisitions were implemented. Specifically, a multiplicative acceleration factor from multiple spin echoes (×32) and compressed sensing (CS) sampling (×8) allowed highly-accelerated 3D Multiple-Modulation-Multiple-Echo (MMME) acquisition. At the same time, the CE-MRI of kidney with Gd-DOTA showed significantly improved signal enhancement for CS-MMME acquisitions (×7) over that of corresponding FLASH acquisitions (×2). Increased positive contrast enhancement and highly accelerated acquisition of extended volume with reduced RF irradiations will be beneficial for oncological and nephrological applications, in which the accurate in vivo 3D quantification of contrast agent concentration is necessary with high temporal resolution.

Relative bioavailability of two 5-mg montelukast sodium chewable tablets: a single dose, randomized, open-label, 2-period crossover comparison in healthy korean adult male volunteers.

Montelukast sodium, cysteinyl leukotriene receptor 1 specific antagonist, has been marketed in Korea for the treatment of bronchial asthma and allergic rhinitis. The aim of this study was to compare the pharmacokinetics and relative bioavailability of a test and reference formulation of montelukast 5-mg chewable tablets in healthy Korean male volunteers to meet KFDA regulatory criteria for marketing of the new generic formulation. This study was designed as a single-dose, 2-treatment, and 2-period crossover trial with 32 healthy volunteers. Each subject was randomly assigned to receive the test (Dong-Kook Montelukast Sodium Chewable Tablet 5 mg®) or reference (Singulair Chewable Tablet 5 mg®) formulation. The tablet was chewed 20 times, and then swallowed with 240 mL of water. Plasma concentrations of montelukast up to 24 h after the dose were determined using a validated UPLC-MS/MS method, and the bioequivalence between the 2 formulations was assessed by statistical analysis of mean ratios of log-transformed AUC0-24 h and Cmax. No period or sequence effects were detected. The AUC0-24 h was 1 835 ng·h/mL for the test formulation, and 1 930 ng·h/mL for the reference formulation. The respective values of AUC0-∞ were 1 917 and 2 015 ng·h/mL. The Cmax of the test and reference products (247 and 283 ng/mL, respectively) reached at 2.25 and 2.72 h, respectively. Then, they gradually decreased with the mean terminal t1/2 of 5.25 and 5.30 h for the test and reference products, respectively. The 90% CIs for the ratio of log-transformed AUC0-24 h and Cmax for the test and reference formulations were 0.92-0.99 and 0.83-0.91, respectively. No adverse events were reported in this study. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these fasting healthy Korean male volunteers.

Magnetic field anisotropy based MR tractography.

Non-invasive measurements of structural orientation provide unique information regarding the connectivity and functionality of fiber materials. In the present study, we use a capillary model to demonstrate that the direction of fiber structure can be obtained from susceptibility-induced magnetic field anisotropy. The interference pattern between internal and external magnetic field gradients carries the signature of the underlying anisotropic structure and can be measured by MRI-based water diffusion measurements. Through both numerical simulation and experiments, we found that this technique can determine the capillary orientation within 3°. Therefore, susceptibility-induced magnetic field anisotropy may be useful for an alternative tractography method when diffusion anisotropy is small at higher magnetic field strength without the need to rotate the subject inside the scanner.

Active microelectronic neurosensor arrays for implantable brain communication interfaces.

We have built a wireless implantable microelectronic device for transmitting cortical signals transcutaneously. The device is aimed at interfacing a cortical microelectrode array to an external computer for neural control applications. Our implantable microsystem enables 16-channel broadband neural recording in a nonhuman primate brain by converting these signals to a digital stream of infrared light pulses for transmission through the skin. The implantable unit employs a flexible polymer substrate onto which we have integrated ultra-low power amplification with analog multiplexing, an analog-to-digital converter, a low power digital controller chip, and infrared telemetry. The scalable 16-channel microsystem can employ any of several modalities of power supply, including radio frequency by induction, or infrared light via photovoltaic conversion. As of the time of this report, the implant has been tested as a subchronic unit in nonhuman primates ( approximately 1 month), yielding robust spike and broadband neural data on all available channels.

The MYCN oncogene is a direct target of miR-34a.

Loss of 1p36 heterozygosity commonly occurs with MYCN amplification in neuroblastoma tumors, and both are associated with an aggressive phenotype. Database searches identified five microRNAs that map to the commonly deleted region of 1p36 and we hypothesized that the loss of one or more of these microRNAs contributes to the malignant phenotype of MYCN-amplified tumors. By bioinformatic analysis, we identified that three out of the five microRNAs target MYCN and of these miR-34a caused the most significant suppression of cell growth through increased apoptosis and decreased DNA synthesis in neuroblastoma cell lines with MYCN amplification. Quantitative RT-PCR showed that neuroblastoma tumors with 1p36 loss expressed lower level of miR-34a than those with normal copies of 1p36. Furthermore, we demonstrated that MYCN is a direct target of miR-34a. Finally, using a series of mRNA expression profiling experiments, we identified other potential direct targets of miR-34a, and pathway analysis demonstrated that miR-34a suppresses cell-cycle genes and induces several neural-related genes. This study demonstrates one important regulatory role of miR-34a in cell growth and MYCN suppression in neuroblastoma.

OK-432 sclerotherapy of plunging ranula in 21 patients: it can be a substitute for surgery.

BACKGROUND AND PURPOSE: Although first-choice therapy for the ranula is surgery, this choice presents technical difficulties and frequent recurrences because of insufficient surgery. We evaluated the efficacy of OK-432 sclerosis of the plunging ranula as a substitute for surgery. METHODS: Twenty-one patients with plunging ranula were treated with intralesional injection of OK-432. The liquid content of the ranula was aspirated as much as possible, after which OK-432 solution was injected in the same volumes as that drawn out. Patients were followed on sonography or CT. RESULTS: Seven (33.3%) patients with plunging ranulas showed total shrinkage and resolution, and 4 (19%) patients showed near-total shrinkage (more than 90% of the volume). Four (19%) patients revealed marked shrinkage (more than 70% of the volume), and 3 (14.3%) patients showed partial shrinkage (less than 70% of the volume). Three (14.3%) patients showed recurrence after total shrinkage 1 month after injection. The overall recurrence rate after each injection was 47% (16 of 34 injections in 21 patients), but the recurrence rate after the last sclerotherapy was only 14%. There were no serious side effects except for fever lasting 2-3 days (12 patients) and swelling (10 patients) for 3-5 days. Mild odynophagia for 1-2 days was also noted in 7 patients, and there was 1 severe case of odynophagia. CONCLUSION: OK-432 sclerotherapy of plunging ranula is a safe and potentially curative procedure that may be used as a primary treatment for plunging ranula before considering surgery.

Hydroporation as the mechanism of hydrodynamic delivery.

We have reported that a rapid tail vein injection of a large volume of plasmid DNA solution into a mouse results in high level of transgene expression in the liver. Gene transfer efficiency of this hydrodynamics-based procedure is determined by the combined effect of a large volume and high injection speed. Here, we show that the hydrodynamic injection induces a transient irregularity of heart function, a sharp increase in venous pressure, an enlargement of liver fenestrae, and enhancement of membrane permeability of the hepatocytes. At the cellular level, our results suggest that hepatic delivery by the hydrodynamic injection is accomplished by the generation of membrane pores in the hepatocytes.

Development of an integrated microelectrode/microelectronic device for brain implantable neuroengineering applications.

An ultra-low power analog CMOS chip and a silicon based microelectrode array have been fully integrated to a microminiaturized "neuroport" for brain implantable neuroengineering applications. The CMOS IC included preamplifier and multiplexing circuitry, and a hybrid flip-chip bonding technique was developed to fabricate a functional , encapsulated microminiaturized neuroprobe device. As a proof-of-concept demonstration, we have measured local field potentials from thalamocortical brain slices of rats, suggesting that the new neuroport can form a prime platform for the development of a microminiaturized neural interface to the brain in a single implantable unit.

Photovoltaic energy converter as a chipscale high efficiency power source for implanted active microelectronic devices.

We report the development of a microscale photovoltaic energy converter which has been designed and implemented to deliver power to CMOS-based microelectronic chips. The design targets the delivery of voltages on the order of 3V with power levels in excess of 10 mW. The geometry of the prototype device, which has been fabricated and tested, is specifically designed for coupling to an optical fiber, to facilitate remote power delivery in implantable component environment.

Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.

Lower gastrointestinal bleeding due to cytomegalovirus ileal ulcers in an immunocompetent man.

Cytomegalovirus (CMV) infections are commonly reported in severely immunocompromised hosts and ulcers of the alimentary tract are frequently observed in systemic CMV infections. However, invasive and ulcerative disease of the gastrointestinal (GI) tract caused by CMV has also been reported in healthy adults. Many reports show that a CMV infection can produce localized ulcerations in the esophagus, stomach, small intestine, and colon in nonimmunocompromised individuals. The most common site of involvement by CMV infection in the GI tract is the colon followed by the upper GI tract and the least common site is the small intestine. Although GI bleeding is one of the major presenting symptoms of patients with CMV infections of the GI tract, lower GI bleeding due to CMV ileal ulcers in immunocompetent patients, to our knowledge, has not been reported in the English literature. Recently, we experienced a case of lower GI bleeding due to CMV ileal ulcers in a 57-year-old man who had no evidence of immunocompromise. This case suggests that small intestinal ulcers due to CMV infection should be included in the differential diagnosis of lower GI bleeding even in immunocompetent hosts.

Long-term expression of human alpha1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using a hydrodynamics-based procedure.

The liver is an important target organ for gene transfer due to its large capacity for synthesizing serum proteins and its involvement in numerous genetic and acquired diseases. Previously, we and others have shown that an efficient gene transfer to liver cells in vivo can be achieved by an intravenous injection of plasmid DNA using a hydrodynamics-based procedure. In this study, we systematically characterized the expression of transgene encoding a secretory protein in mouse. Using human alpha1-antitrypsin (hAAT) gene as a reporter, we demonstrate that the serum level of hAAT can reach as high as 0.5 mg/ml by a simple tail vein injection of 10-50 microg plasmid DNA into a mouse. The serum hAAT reaches the peak level 1 day after DNA injection and then declines during the following 2 to 4 weeks to 2-5 microg/ml, a level which persists for at least 6 months. Southern analysis of extracted DNA and RT-PCR analysis of RNA from the liver reveal that hAAT gene is active and present as episomal form after 6 months. These results suggest that the hydrodynamics-based transfection procedure provides a valuable tool for screening genes for therapeutic purposes in whole animals.

Structural basis of DOTMA for its high intravenous transfection activity in mouse.

Eleven structural analogues of two known cationic lipids, N-[1-(2, 3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP) were synthesized and utilized to evaluate the structural characteristics of DOTMA for its high intravenous transfection activity. Using a CMV-driven expression system and luciferase gene as a reporter, the transfection activity of these analogues was evaluated in mice using tail vein injection. Results concerning the structure-activity relationship with regard to the influence of the backbone, relative position between head group and the hydrophobic chains on the backbone, linkage bonds, as well as the composition of the aliphatic chains revealed that cationic lipids which give a higher in vivo transfection activity share the following structural characteristics: (1) cationic head group and its neighboring aliphatic chain being in a 1,2-relationship on the backbone; (2) ether bond for bridging the aliphatic chains to the backbone; and (3) paired oleyl chains as the hydrophobic anchor. Cationic lipids without these structural features had lower in vivo transfection activity. These structural characteristics, however, did not significantly influence their in vitro transfection activity. The contribution that cationic lipids make to the overall in vivo transfection activity is likely to be determined by the structure of DNA/lipid complexes and by the outcome of the interaction between the DNA/lipid complexes and blood components upon intravenous administration.

Synthesis and characterization of aromatic ring-based cationic lipids for gene delivery in vitro and in vivo.

A new series of cationic lipids has been synthesized for gene delivery using 3,5-dihydroxybenzyl alcohol as the backbone and starting material. Using CMV driven expression system and luciferase gene as a reporter, we demonstrated that the transfection activity of these new lipids when formulated with Tween 80 as co-lipid is comparable to that of DOTAP, one of the most commonly used cationic lipids for transfection. Among the four different cell lines tested including murine melanoma BL-6 cells, human embryonic kidney 293 cells, HepG2 and HeLa cells, the highest transgene expression was seen in 293 cells. Results from in vivo experiments using mice as an animal model show that these cationic lipids preferentially transfect the cells in the lung upon tail vein administration. The cationic lipid, N,N,N-trimethyl-N-[3,5-bis(tetradecyloxy)benzyl] ammonium bromide 4c(di-C14:0) with two 14-hydrocarbon chains exhibits the best transfection activity. These results suggest that these new aromatic ring-based cationic lipids are useful transfection reagents for both in vitro and in vivo gene transfer studies.

Comparison of incidence of gastroesophageal reflux and regurgitation associated with timing of removal of the laryngeal mask airway: on appearance of signs of rejection versus after recovery of consciousness.

STUDY OBJECTIVES: To compare the incidence of gastroesophageal reflux and regurgitation associated with laryngeal mask airway (LMA) removal when signs of rejecting the LMA, such as swallowing, struggling, and restlessness, were observed and when the patient could open his or her mouth on command. DESIGN: Randomized clinical trial. SETTING: Operating room and recovery room of a tertiary care referral hospital. PATIENTS: 63 ASA physical status I and II adult patients scheduled for elective orthopedic surgery. INTERVENTIONS: Using a standardized general anesthetic technique, patients were allocated randomly to Group A (n = 34; LMA removed when signs of rejection, such as swallowing, struggling, and restlessness, were observed) or Group B (n = 29; LMA removed when the patient could open his or her mouth on command). MEASUREMENTS AND MAIN RESULTS: To detect gastroesophageal reflux throughout anesthesia, a pH monitoring probe was positioned in the lower esophagus on the day before surgery. To assess regurgitation during emergence, a gelatin capsule of methylene blue (50 mg) was swallowed prior to induction. At the end of anesthesia, episodes of reflux and regurgitation of gastric contents were analyzed/determined by pH below 4 and bluish staining of the pharynx and/or LMA, respectively. Physical events such as bucking, straining, and coughing during the arousal phase were recorded in both groups by an independent observer. The incidence of reflux (pH < 4) from the time of the appearance of rejection signs to LMA removal and the total incidence of reflux in Group B were significantly higher than in Group A (p < 0.05). Staining of the LMA and the pharynx by methylene blue was not observed in patients from either experimental group. The number of physical events in Group B during the arousal phase was significantly increased compared to Group A (p < 0.05). Considering all patients in Group A and Group B, physical events were associated with the occurrence of reflux (p < 0.05). Desaturation (SpO2 < 95%) and clinical evidence of aspiration of gastric contents did not occur in either group. CONCLUSION: Maintenance of the LMA until the patient can open his or her mouth on command increases the incidence of gastroesophageal reflux.