Abstract Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any ...proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis.
The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the ...diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate
(
and a X-linked region including
), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders.
Background
Concern has been raised regarding international discrepancies in perioperative mortality after repair of ruptured abdominal aortic aneurysm (rAAA). The variation in in‐hospital mortality ...is difficult to interpret, owing to international differences in discharge strategies. This study compared 90‐day and 5‐year mortality in patients who had a rAAA in England and Sweden.
Methods
Patients undergoing rAAA repair were identified from English Hospital Episode Statistics and the Swedish Vascular Registry (Swedvasc) between 2003 and 2012. Ninety‐day and 5‐year mortality were compared after matching for age and sex. Within‐country analyses examined the impact of co‐morbidity, teaching hospital status or hospital annual caseload, adjusted with causal inference techniques.
Results
Some 12 467 patients underwent rAAA repair in England, of whom 83·2 per cent were men; the median (i.q.r.) age was 75 (70–80) years. A total of 2829 Swedish patients underwent rAAA repair, of whom 81·3 per cent were men; their median (i.q.r.) age was 75 (69–80) years. The 90‐day mortality rate was worse in England (44·0 per cent versus 33·4 per cent in Sweden; P < 0·001), as was 5‐year mortality (freedom from mortality 38·6 versus 46·3 per cent respectively; P < 0·001). In England, lower mortality was seen in teaching hospitals with larger bed capacity, higher annual caseloads and greater use of endovascular aneurysm repair (EVAR). In Sweden, lower mortality was associated with EVAR, high annual caseload, or surgery on weekdays compared with weekends.
Conclusion
Short‐ and long‐term mortality after rAAA repair was higher in England. In both countries, mortality was lowest in centres performing greater numbers of AAA repairs per annum, and more EVAR procedures.
English results worse
MaxPHOS is an active and robust P‐stereogenic ligand for asymmetric catalysis. The presence of an NH bridge between the two phosphine moieties allows the NH/PH tautomerism to take place. The ...neutral ligand, in which the NH form predominates, is an air‐sensitive compound. However, protonation of MaxPHOS leads to the stable PH form of the ligand, in which the overall positive charge is distributed on both P centers. This protonation turns the MaxPHOS⋅HBF4 salt 3 into an air‐stable compound both in the solid state and in solution. The salt 3 is also a convenient precursor for the preparation of rhodium(I) complexes by direct ligand exchange with the complex Rh(acac)(cod). Finally, the corresponding rhodium(I)‐MaxPHOS complex was tested in the asymmetric hydrogenation of a wide range of substrates. The complex proved to be a highly selective and robust system in these reactions.
A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) ...resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.
Niemann–Pick disease type C (NP-C) is an inherited neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Different clinical forms have been defined ...based on patient age at onset: perinatal, early-infantile (EI), late-infantile (Li), juvenile and adult. We evaluated the efficacy and tolerability of miglustat in 16 symptomatic NP-C patients, with comparative reference to one neurologically asymptomatic, untreated patient. All patients were categorized according to age at neurological disease onset, and were assessed using a standardized clinical assessment protocol: disability and cognitive function scales, positron emission tomography (PET), and biochemical markers. PET and disability scale evaluations indicated that cerebral hypometabolism and neurological symptoms were stabilized during treatment in juvenile-onset NP-C patients. EI and Li NP-C patients, who had higher disease severity at baseline (treatment start), showed increased disability scores and progressive cerebral hypometabolism during follow up. Similarly, while cognitive scale scores remained relatively stable in patients with juvenile NP-C, cognition deteriorated in EI and Li patients. Plasma chitotriosidase (ChT) activity was lower in the juvenile NP-C subgroup than in EI and Li patients, and generally increased in patients who discontinued treatment. Plasma CCL18/PARC and ChT activities indicated greater macrophagic activity in EI and Li patients
versus juveniles. Miglustat was generally well tolerated; frequent adverse events included diarrhea and flatulence, which were managed effectively by dietary modification and loperamide. Overall, miglustat appeared to stabilize neurological status in juvenile-onset NP-C patients, but therapeutic benefits appeared smaller among younger patients who were at a more advanced stage of disease at baseline.
Plakophilin 1 (PKP1) is a member of the arm-repeat (armadillo) and plakophilin gene families and it is an essential component of the desmosomes. Although desmosomes have generally been associated ...with tumor suppressor functions, we have consistently observed that PKP1 is among the top overexpressed proteins in squamous cell lung cancer. To explore this paradox, we developed in vivo and in vitro functional models of PKP1 gain/loss in squamous cell lung cancer. CRISPR-Cas9 PKP1 knockout severely impaired cell proliferation, but it increased cell dissemination. In addition, PKP1 overexpression increased cell proliferation, cell survival, and in vivo xenograft engraftment. We further investigated the molecular mechanism of the mainly oncogenic function of PKP1 by combining transcriptomics, proteomics, and protein-nucleic acid interaction assays. Interestingly, we found that PKP1 enhances MYC translation in collaboration with the translation initiation complex by binding to the 5'-UTR of MYC mRNA. We propose PKP1 as an oncogene in SqCLC and a novel posttranscriptional regulator of MYC. PKP1 may be a valuable diagnostic biomarker and potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may indirectly target MYC, a primary anticancer target.
Quantum technologies promise major advances in different areas. From computation to sensing or telecommunications, quantum implementations could bring significant improvements to these fields, ...arousing the interest of researchers, companies, and governments. In particular, the deployment of Quantum Key Distribution (QKD) networks, which enable the secure dissemination of cryptographic keys to remote application entities following Quantum Mechanics Principles, appears to be one of the most attractive and relevant use cases. Quantum devices and equipment are still in a development phase, making their availability low and their price high, hindering the deployment of physical QKD networks and, therefore, the research and experimentation activities related to this field. In this context, this paper focuses on providing research stakeholders with an open-access testbed where it is feasible to emulate the deployment of QKD networks, thus enabling the execution of experiments and trials, where even potential network attacks can be analyzed, without the quantum physical equipment requirement, nor compromising the integrity of an already built QKD network. The designed solution allows users to automatically deploy, configure, and run a digital twin environment of a QKD network, offering cost-effectiveness and great flexibility in the study of the integration of quantum communications in the current network infrastructures. This solution is aligned with the European Telecommunications Standard Institute (ETSI) standardized application interface for QKD, and is built upon open-source technologies. The feasibility of this solution has been validated throughout several functional trials carried out in the 5G Telefónica Open Network Innovation Centre (5TONIC), verifying the service performance in terms of speed and discarded qubits when generating the quantum keys.
Due to the inherent sensitivity of human embryonic stem cells (hESCs) to manipulations, the recovery and survival of hESCs after fluorescence-activated cell sorting (FACS) can be low. Additionally, a ...well characterized and robust methodology for performing FACS on hESCs using multiple-cell surface markers has not been described. The p160-Rho-associated coiled kinase (ROCK) inhibitor, Y-27632, previously has been identified as enhancing survival of hESCs upon single-cell dissociation, as well as enhancing recovery from cryopreservation. Here we examined the application of Y-27632 to hESCs after FACS to improve survival in both feeder-dependent and feeder-independent growth conditions.
HESCs were sorted using markers for SSEA-3, TRA-1-81, and SSEA-1. Cells were plated after sorting for 24 hours in either the presence or the absence of Y-27632. In both feeder-dependent and feeder-independent conditions, cell survival was greater when Y-27632 was applied to the hESCs after sort. Specifically, treatment of cells with Y-27632 improved post-sort recovery up to four fold. To determine the long-term effects of sorting with and without the application of Y-27632, hESCs were further analyzed. Specifically, hESCs sorted with and without the addition of Y-27632 retained normal morphology, expressed hESC-specific markers as measured by immunocytochemistry and flow cytometry, and maintained a stable karyotype. In addition, the hESCs could differentiate into three germ layers in vitro and in vivo in both feeder-dependent and feeder-independent growth conditions.
The application of Y-27632 to hESCs after cell sorting improves cell recovery with no observed effect on pluripotency, and enables the consistent recovery of hESCs by FACS using multiple surface markers. This improved methodology for cell sorting of hESCs will aid many applications such as removal of hESCs from secondary cell types, identification and isolation of stem cell subpopulations, and generation of single cell clones. Finally, these results demonstrate an additional application of ROCK inhibition to hESC research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this Letter we show that the extraordinary optical transmission phenomenon found before in 2D hole arrays is already present in a linear chain of subwavelength holes, which can be considered as ...the basic geometrical unit showing this property. In order to study this problem, we have developed a new theoretical framework, able to analyze the optical properties of finite collections of subwavelength apertures and/or dimples (of any shape and placed in arbitrary positions) drilled in a metallic film.
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