CELNet: Evidence Localization for Pathology Images using Weakly Supervised Learning

Despite deep convolutional neural networks boost the performance of image classification and segmentation in digital pathology analysis, they are usually weak in interpretability for clinical applications or require heavy annotations to achieve object localization. To overcome this problem, we propose a weakly supervised learning-based approach that can effectively learn to localize the discriminative evidence for a diagnostic label from weakly labeled training data. Experimental results show that our proposed method can reliably pinpoint the location of cancerous evidence supporting the decision of interest, while still achieving a competitive performance on glimpse-level and slide-level histopathologic cancer detection tasks.Comment: Accepted for MICCAI 201

Genetic Diversity of PCR-Positive, Culture-Negative and Culture-Positive Mycobacterium ulcerans Isolated from Buruli Ulcer Patients in Ghana.

Culture of Mycobacterium ulcerans from Buruli ulcer patients has very low sensitivity. Thus confirmation of M. ulcerans infection is primarily based on PCR directed against IS2404. In this study we compare the genotypes obtained by variable number of tandem repeat analysis of DNA from IS2404-PCR positive cultures with that obtained from IS2404 positive, culture-negative tissue. A significantly greater genetic heterogeneity was found among culture-negative samples compared with that found in cultured strains but a single genotype is over-represented in both sample sets. This study provides evidence that both the focal location of bacteria in a lesion as well as differences in the ability to culture a particular genotype may underlie the low sensitivity of culture. Though preliminary, data from this work also suggests that mycobacteria previously associated with fish disease (M. pseudoshottsii) may be pathogenic for humans

Time dependence of changes of two cartilage layers in anterior cruciate ligament insertion after resection on chondrocyte apoptosis and decrease in glycosaminoglycan

<p>Abstract</p> <p>Background</p> <p>The purpose of this study is to clarify the differences in time-dependent histological changes (chondrocyte apoptosis and glycosaminoglycan (GAG) layer thickness decrease) between uncalcified fibrocartilage (UF) and calcified fibrocartilage (CF) layers at the anterior cruciate ligament (ACL) insertion after ACL resection of rabbits.</p> <p>Methods</p> <p>Forty male Japanese white rabbits underwent ACL substance resection in the right knee (resection group) and same operation without resection in the left knee (sham group). Animals were sacrificed 1, 2, 4 and 6 weeks after surgery.</p> <p>Results</p> <p>In the UF layer, the apoptosis rate in the resection group was significantly higher than that in the sham group at 1 and 2 weeks. The GAG layer thicknesses of the UF layer in the resection group at 1, 2, 4 and 6 weeks were lower than those in the sham group. In the CF layer, the apoptosis rate in the resection group was significantly higher than that in the sham group at 2 and 4 weeks. The GAG layer thickness of the CF layer in the resection group was lower than that in the sham group only at 6 weeks.</p> <p>Conclusion</p> <p>The increase in chondrocyte apoptosis rate preceded the decrease in GAG layer thickness in both layers. In the UF layer, the increase in chondrocyte apoptosis rate and the decrease in GAG layer thickness preceded those in the CF layer. Using a surviving ligament and minimizing a debridement of ACL remnant during ACL reconstruction may be important to maintain cartilage layers of ACL insertion. An injured ACL should be repaired before degenerative changes of the insertion occur.</p

Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration

Nuclear distribution element-like 1 (Ndel1) plays pivotal roles in diverse biological processes and is implicated in the pathogenesis of multiple neurodevelopmental disorders. Ndel1 function by regulating microtubules and intermediate filaments; however, its functional link with the actin cytoskeleton is largely unknown. Here, we show that Ndel1 interacts with TRIO-associated repeat on actin (Tara), an actin-bundling protein, to regulate cell movement. In vitro wound healing and Boyden chamber assays revealed that Ndel1- or Tara-deficient cells were defective in cell migration. Moreover, Tara overexpression induced the accumulation of Ndel1 at the cell periphery and resulted in prominent co-localization with F-actin. This redistribution of Ndel1 was abolished by deletion of the Ndel1-interacting domain of Tara, suggesting that the altered peripheral localization of Ndel1 requires a physical interaction with Tara. Furthermore, co-expression of Ndel1 and Tara in SH-SY5Y cells caused a synergistic increase in F-actin levels and filopodia formation, suggesting that Tara facilitates cell movement by sequestering Ndel1 at peripheral structures to regulate actin remodeling. Thus, we demonstrated that Ndel1 interacts with Tara to regulate cell movement. These findings reveal a novel role of the Ndel1-Tara complex in actin reorganization during cell movement.1142Ysciescopu

Xylitol production is increased by expression of codon-optimized Neurospora crassa xylose reductase gene in Candida tropicalis

Xylose reductase (XR) is the first enzyme in d-xylose metabolism, catalyzing the reduction of d-xylose to xylitol. Formation of XR in the yeast Candida tropicalis is significantly repressed in cells grown on medium that contains glucose as carbon and energy source, because of the repressive effect of glucose. This is one reason why glucose is not a suitable co-substrate for cell growth in industrial xylitol production. XR from the ascomycete Neurospora crassa (NcXR) has high catalytic efficiency; however, NcXR is not expressed in C. tropicalis because of difference in codon usage between the two species. In this study, NcXR codons were changed to those preferred in C. tropicalis. This codon-optimized NcXR gene (termed NXRG) was placed under control of a constitutive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter derived from C. tropicalis, and integrated into the genome of xylitol dehydrogenase gene (XYL2)-disrupted C. tropicalis. High expression level of NXRG was confirmed by determining XR activity in cells grown on glucose medium. The resulting recombinant strain, LNG2, showed high XR activity (2.86 U (mg of protein)−1), whereas parent strain BSXDH-3 showed no activity. In xylitol fermentation using glucose as a co-substrate with xylose, LNG2 showed xylitol production rate 1.44 g L−1 h−1 and xylitol yield of 96% at 44 h, which were 73 and 62%, respectively, higher than corresponding values for BSXDH-3 (rate 0.83 g L−1 h−1; yield 59%)

Radiofrequency Heating of the Cornea: An Engineering Review of Electrodes and Applicators

This paper reviews the different applicators and electrodes employed to create localized heating in the cornea by means of the application of radiofrequency (RF) currents. Thermokeratoplasty (TKP) is probably the best known of these techniques and is based on the principle that heating corneal tissue (particularly the central part of the corneal tissue, i.e. the central stroma) causes collagen to shrink, and hence changes the corneal curvature. Firstly, we point out that TKP techniques are a complex challenge from the engineering point of view, due to the fact that it is necessary to create very localized heating in a precise location (central stroma), within a narrow temperature range (from 58 to 76ºC). Secondly, we describe the different applicator designs (i.e. RF electrodes) proposed and tested to date. This review is planned from a technical point of view, i.e. the technical developments are classified and described taking into consideration technical criteria, such as energy delivery mode (monopolar versus bipolar), thermal conditions (dry versus cooled electrodes), lesion pattern (focal versus circular lesions), and application placement (surface versus intrastromal)

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmaxand AUC of panobinostat, respectively. No substantial change in Tmaxor half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary

Integrating Communities of Practice in Technology Development Projects

Technology development projects usually benefit when knowledge and expertise are drawn from a variety of sources, including potential users. Orchestrating the involvement of people from disparate groups is a crucial task for project managers. It requires finding a balance between differentiation, when teams work in isolation, and integration, when groups come together to exchange knowledge. This article argues that a “community of practice” perspective can help project managers to achieve this balance, by drawing attention to the assumptions, interests, skills, and formal and tacit knowledge of the different groups involved. Successful integration can be achieved by ensuring that the developing technology is comprehensible to all the groups concerned, and making sure that it satisfies their various interests