PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients.

PURPOSE: Clinical trials showing programmed death (PD)-1-PD-ligand 1 (L1) axis as a promising therapeutic target in melanoma and non-small cell lung cancers have made the pathway a focus of recent attention. However, the data regarding PD-L1/PD-1 in breast cancer are inconsistent. Given the heterogeneity of breast cancers, the clinical relevance of PD-L1 and PD-1 tumor infiltrating lymphocytes (TIL) may vary according to subtypes of breast cancer. We aim to investigate PD-L1 expression in a large cohort of breast cancers and analyze its clinico-pathological as well as outcome relationship according to molecular subtypes. Also, we evaluate the relationship of PD-1 TIL and PD-L1 expression with patients' survival, particularly for breast cancers with high TIL. METHODS AND RESULTS: Immunohistochemical analysis of PD-L1 on tissue arrays for 1091 breast cancer patients and PD-1 TIL on 97 whole sections was performed. Associations of PD-L1 with luminal cancers (p < 0.001) and features associated with that subtype [lower histologic grade, absence of necrosis, ER, PR, and AR expression (p < 0.001)] were observed. However, in HER2+ breast cancers, PD-L1 was an independent poor prognostic indicator (DFS: HR = 1.866, p = 0.001; OS: HR = 1.517, p = 0.036). Interestingly, HER2+ cancers showed a lower PD-1 TIL level compared to the other high TIL cases (p = 0.011). Cases with low PD-TIL but high PD-L1 expression showed the worst survival. This could be indicative of an active immune suppression by PD-L1 expression. CONCLUSIONS: Our data showed the relevance of PD-L1 expression in HER2+ breast cancer. A combined evaluation of PD-L1 and PD-1 TIL in the prognosis of breast cancer might also be of value in treatment prediction.

Rectangular Co3O4 with micro-/nanoarchitectures: charge-driven PDDA-assisted synthesis and excellent lithium storage performance.

For the first time, two dimensional (2D) rectangular Co3O4 with micro-/nanoarchitectures is successfully synthesized by a facile hydrothermal treatment with the assistance of poly(diallyldimethylammonium chloride) (PDDA). Owing to the strong electrostatic interaction, positively charged PDDA molecules are considered as structure directing agents and play a crucial role in the formation of the unique 2D rectangular structure. Material characterization suggests that rectangular Co3O4 is typically endowed with a side length of 3-5 µm and a thickness of around 85 nm, and is composed of numerous interconnected nanocrystals about 15 nm in size. The interconnected nanocrystals provide few trap numbers for the electron transport process and contribute to the mesoporous structure with an average pore size of 18 nm. Thus, the distinctive micro-/nanoarchitectures effectively address the formidable challenges of Co3O4-based anode materials, highly favourable for enhancing lithium ion diffusion, improving electron transport pathways and alleviating volume variation during charge-discharge processes. When rectangular Co3O4 (FST-1) is evaluated as anode material for lithium ion batteries, a high reversible capacity of 1076.9 mA h g(-1) and an excellent first cycle Coulombic efficiency of 88.6% are achieved at a current density of 500 mA g(-1), thus delivering a capacity retention of nearly 100% after 100 cycles. Moreover, when tested at current densities as high as 1000 mA g(-1) and 2000 mA g(-1) for 100 cycles, lithium storage capacities can still be retained at 1020.2 mA h g(-1) and 616.4 mA h g(-1), respectively. Interestingly, by simply varying the reaction conditions or types of positively charged polymers, the polyelectrolyte-assisted hydrothermal route can be successfully extended to synthesize other novel micro-/nanoarchitectures, such as straw-tied-like and urchin-like structures, demonstrating great potential in developing next-generation anode materials for high performance lithium ion batteries.

Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.

Comparison of tape stripping with the human skin blanching assay for the bioequivalence assessment of topical clobetasol propionate formulations.

PURPOSE: A draft guidance on tape stripping for assessing the bioavailability/bioequivalence of topical formulations was issued by the United States Food and Drug Administration in 1998 but has since been withdrawn. This was due to problems associated with the method and also inconsistencies and variability in the resulting data. The purpose of this study was to re-visit the tape stripping technique, incorporate refinements to reduce variability and validate the method using bioequivalence data obtained from the assessment of a topical corticosteroid cream containing 0.05% clobetasol propionate using the human skin-blanching assay. METHODS: A pilot tape stripping study was conducted to establish the variability of the formulations.The bioequivalence of two different commercially available clobetasol propionate cream formulations and a clobetasol propionate ointment formulation were subsequently investigated using the tape stripping method. RESULTS: The data from the pilot tape stripping study correlated well with data from the human skin-blanching assay. A subsequent pivotal tape stripping study confirmed bioequivalence between the two cream formulations whereas bio-inequivalence was demonstrated between the cream and ointment formulations. CONCLUSIONS: These studies show that the results from tape stripping concur with data from the human skin blanching assay and demonstrate the potential of a well-controlled tape stripping study as an option for the assessment of bioequivalence of topical corticosteroid formulations.

Bioequivalence assessment of topical clobetasol propionate products using visual and chromametric assessment of skin blanching.

PURPOSE: The assessment of the degree of skin blanching following the application of a formulation containing a topical corticosteroid has been established as a surrogate method for the determination of bioequivalence. In this study, both visual and chromametric assessments have been carried out on two topical creams containing clobetasol propionate (0.05%) and the results from both methods are compared. METHODS: Human subjects (volunteers) were screened using a cream containing 0.05%clobetasol propionate, in order to identify appropriate subjects for inclusion in the study. The study was implemented according to the FDA guidance using both visual and chromameter assessment techniques. Blanching responses were assessed visually by three trained, independent observers and instrumentally using a Chromameter. An ED50 of 36 min was used as the dose duration based upon data previously obtained from a pilot study using the same topical corticosteroid reference product. A visual rating scale of 0-4 and the a-scale readings from the chromameter were used. RESULTS: The visual and chromameter blanching profiles showed similar blanching responses with good correspondence. The 90% confidence intervals for the data from both methods were calculated using Locke's method. When only the data obtained from 23 subjects who were identified as"detectors" (as per FDA guidance) were used, the products fell within the bioequivalence acceptance range of 80-125% using the visual assessment method (99.3-111.6%) whereas the data using a chromameter (86.5-129.3%) were just outside the acceptance limits. However, when all subjects (n=34) were included in the calculations, both the visual (97.9-109.2) and chromameter (90.2-120.7) data fell within the bioequivalence acceptance range. CONCLUSIONS: Whereas visual data indicated bioequivalence using either data from "detectors" or data from all subjects, the chromameter data from "detectors" only indicated bioinequivalence but inclusion of all subject data fell within the acceptance range to be declared bioequivalent.

Attribute clustering for grouping, selection, and classification of gene expression data.

This paper presents an attribute clustering method which is able to group genes based on their interdependence so as to mine meaningful patterns from the gene expression data. It can be used for gene grouping, selection, and classification. The partitioning of a relational table into attribute subgroups allows a small number of attributes within or across the groups to be selected for analysis. By clustering attributes, the search dimension of a data mining algorithm is reduced. The reduction of search dimension is especially important to data mining in gene expression data because such data typically consist of a huge number of genes (attributes) and a small number of gene expression profiles (tuples). Most data mining algorithms are typically developed and optimized to scale to the number of tuples instead of the number of attributes. The situation becomes even worse when the number of attributes overwhelms the number of tuples, in which case, the likelihood of reporting patterns that are actually irrelevant due to chances becomes rather high. It is for the aforementioned reasons that gene grouping and selection are important preprocessing steps for many data mining algorithms to be effective when applied to gene expression data. This paper defines the problem of attribute clustering and introduces a methodology to solving it. Our proposed method groups interdependent attributes into clusters by optimizing a criterion function derived from an information measure that reflects the interdependence between attributes. By applying our algorithm to gene expression data, meaningful clusters of genes are discovered. The grouping of genes based on attribute interdependence within group helps to capture different aspects of gene association patterns in each group. Significant genes selected from each group then contain useful information for gene expression classification and identification. To evaluate the performance of the proposed approach, we applied it to two well-known gene expression data sets and compared our results with those obtained by other methods. Our experiments show that the proposed method is able to find the meaningful clusters of genes. By selecting a subset of genes which have high multiple-interdependence with others within clusters, significant classification information can be obtained. Thus, a small pool of selected genes can be used to build classifiers with very high classification rate. From the pool, gene expressions of different categories can be identified.

Discovering high-order patterns of gene expression levels.

This paper reports the discovery of statistically significant association patterns of gene expression levels from microarray data. By association patterns, we mean certain gene expression intensity intervals having statistically significant associations among themselves and with the tissue classes, such as cancerous and normal tissues. We describe how the significance of the associations among gene expression levels can be evaluated using a statistical measure in an objective manner. If an association is found to be significant based on the measure, we say that it is statistically significant. Given a gene expression data set, we first cluster the entire gene pool comprising all the genes into groups by optimizing the correlation (or more precisely, interdependence) among the gene expression levels within gene groups. From each group, we select one or several genes that are most correlated with other genes within that group to form a smaller gene pool. This gene pool then constitutes the most representative genes from the original pool. Our pattern discovery algorithm is then used, for the first time, to discover the significant association patterns of gene expression levels among the genes from the small pool. With our method, it is more effective to discover and express the associations in terms of their intensity intervals. Hence, we discretize each gene expression levels into intervals maximizing the interdependence between the gene expression and the tissue classes. From this data set of gene expression intervals, we discover the association patterns representing statistically significant associations, some positively and some negatively, with different tissue classes. We apply our pattern discovery methodology to the colon-cancer microarray gene expression data set. It consists of 2000 genes and 62 samples taken from colon cancer or normal subjects. The statistically significant combinations of gene expression levels that repress or activate colon cancer are revealed in the colon-cancer data set. The discovered association patterns are ranked according to their statistical significance and displayed for interpretation and further analysis.

An evaluation of the implementation of a best practice guideline on tracheal suctioning in intensive care units.

Aim To minimise suctioning-induced complications in intensive care patients, it is crucial that nurses are able to perform the procedure safely and act in accord with research-based recommendations. This paper reports the process of developing, disseminating and implementing the best practice guideline and an evaluation of the process and outcomes of care during and following its implementation in intensive care units. Methods The study was divided into four phases: (i) to develop the best practice guideline and plan strategies for its dissemination and implementation; (ii) to audit the current practice of nurses in the tracheal suctioning of patients in intensive care units with an artificial airway; (iii) to disseminate and implement the best practice guideline; and (iv) to evaluate the process as well as outcome of care following its implementation in intensive care units. Results The pretest results indicate that gaps exist between actual nursing practice and recommendations based on research evidence. Most nurses performed the skills in accord with the best practice guideline, with 65% nurses scoring above the 70% level. The post-test audit results show that, overall, nurses demonstrated a good endotracheal suctioning technique, with 96% scoring above 75%, indicating an overall improvement in compliance with the guideline. A statistically significant difference was found between the pretest (73%) and post-test (89%) compliance scores (t = -7.67, P < 0.005). Conclusions This implementation project highlights the importance of using a rigorous and systematic process to ensure the formal testing of an intervention. Some essential principles in implementing evidence are necessary, such as involving relevant staff and having a range of strategies and clear processes for implementation.

Determination of two intact glucosinolates in vegetables and Chinese herbs.

A reversed-phase HPLC method was developed for analyzing sinigrin and gluconasturtiin in six vegetable and two Chinese herb samples. A gradient program and mobile phases using methanol and 0.05% trifluoroacetic acid containing 20 mM ammonium acetate allowed sufficient retention and separation of the glucosinolates in the sample extracts. Quadrupole time-of-flight tandem mass spectrometry in negative ion electrospray ionization was used to analyze the fractions collected from the HPLC elution to confirm the identification of the glucosinolates. The levels of sinigrin and gluconasturtiin in the vegetables and Chinese herbs were determined by using an external calibration method. Concentrations of gluconasturtiin in the Chinese herbs were more than 15 times higher than those of sinigrin. Detection limits were 18 nmol g(-1) for sinigrin and 4 nmol g(-1) for gluconasturtiin when 50 g of fresh vegetable was analyzed.

Molecular characterization of quinolone-resistant Neisseria gonorrhoeae in Hong Kong.

In Hong Kong, ParC changes among high-level quinolone-resistant Neisseria gonorrhoeae (QRNG) isolates at Ser-87-->Arg were associated with a higher level of resistance than a Ser-87-->Ile alteration. Two previously undescribed mutations in clinical isolates occurring in gyrA, conferring Ala-92-->Pro and Asp-95-->Tyr changes, were detected. Nine different outer membrane lipoprotein (Lip) repeat classes-11 to 19 repeats-were identified, with repeat lengths of 16 and 17 the most common, indicating considerable strain diversity.