BackgroundTumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.MethodsEleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.ResultsStudy results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.ConclusionsIncreasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

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Enhancers play a crucial role in gene regulation but the participation of enhancer transcripts (i.e. enhancer RNA, eRNAs) in regulatory systems remains unclear. We provide a computational analysis on eRNAs using genome-wide data across 12 mouse tissues. The expression of genes targeted by transcribing enhancer is positively correlated with eRNA expression and significantly higher than expression of genes targeted by non-transcribing enhancers. This result implies eRNA transcription indicates a state of enhancer that further increases gene expression. This state of enhancer is tissue-specific, as the same enhancer differentially transcribes eRNAs across tissues. Therefore, the presence of eRNAs describes a tissue-specific state of enhancer that is generally associated with higher expressed target genes, surmising as to whether eRNAs have gene activation potential. We further found a large number of eRNAs contain regions in which sequences and secondary structures are similar to microRNAs. Interestingly, an increasing number of recent studies hypothesize that microRNAs may switch from their general repressive role to an activating role when targeting promoter sequences. Collectively, our results provide speculation that eRNAs may be associated with the selective activation of enhancer target genes.

Crystalline compounds built up of periodically ordered nanostructured inorganic semiconductor motifs and organic molecules are a new type of hybrid semiconducting materials that are of great fundamental importance and technological relevance. [1][2][3][4][5][6][7][8][9] The most appealing feature of these materials is that many favorable properties of each individual component are brought into the hybrid structure by incorporating two distinctly different components into a single crystal lattice. Integration and combination of exceptional transport properties and structural/thermal stability from the inorganic component and superb flexibility and processibility from the organic component can be expected. Additionally, the blending of the inorganic and organic modules in these crystalline hybrid structures takes place at the atomic level and through chemical bonds, and thus is free of the interface issues that are inevitably present in conventional hybrid composite materials. Furthermore, the formation of such hybrid crystals almost always leads to unique and remarkable new features that are not possible for the individual constituents. Some notable examples include organic-inorganic perovskite-like structures and related materials, [1][2][3][4] hybrid metal oxides, [5,6] and semiconductors composed of zinc blende and wurtzite frameworks. [7][8][9] The II/VI based hybrid semiconductor crystal structures (II: Group 12 elements and Mn; VI: Group 16 elements) are composed of one-dimensional (1D) chains or two-dimensional (2D) slabs of II/VI semiconductor fragments that are interconnected or separated by organic amine molecules to form periodic crystal lattices. They are of the general formula [MQ(L) x ] (M = Mn, Zn, Cd; Q = S, Se, Te; L = organic amine or diamine; and x = 0.5, 1). The most intriguing observations include extremely strong band-edge absorption (e.g. 10-20 times higher than bulk II/VI and GaAs) and exceedingly large band-gap tunability (0.1-2.0 eV) as a result of very strong structure-induced quantum confinement. [10][11][12] Although, according to theoretical calculations, [10] the organic spacers give rise to a very limited effect on the band-gap-related electronic and optical properties, they play a crucial role in the structural, mechanical, and thermal behaviors of these hybrid materials. Herein, we report five crystal structures of 3D-[ZnTe(L) 0.5 ] made of ZnTe single-atomic slabs and longchain diamines, as well as their structural phase transitions, mechanical properties, specific heat capacity, thermal diffusivity, and thermal conductivity. Our analysis shows that crystalline hybrid semiconductors of this type are much lighter and substantially more flexible than their inorganic counterparts. The incorporation of organic molecules into the semiconductor crystal lattices also leads to significantly reduced thermal conductivity that is most desirable for high performance thermoelectric materials with structural integrity. [13][14][15] All the compounds were synthesized by solvothermal reactions u...

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Purpose: To investigate the clinical features, visual acuity outcomes and the most appropriate intervention time in patients with retained lens fragments managed by pars plana vitrectomy. Methods: This was a retrospective review of the records of 78 patients who underwent pars plana vitrectomy for retained lens fragments at the Tri-Service General Hospital from January 1, 2000, to December 31, 2006. Results: The mean age of the patients was 70 years (range, 24–92 years). There were 40 men (51%) and 38 women (49%). The mean follow-up period after surgery was 13.8 months. Forty-five patients (58%) had vitrectomy within 1 day of phacoemulsification (group A), 22 (28%) within 1 week (group B) and 11 (14%) after more than 1 week (group C). No patients in group A developed complications, and 76% achieved a final visual acuity of 6/12 or better. In group B, all patients had elevated intraocular pressure, and 45% achieved a final visual acuity of 6/12 or better. In group C, all patients presented with corneal edema, moderate or severe uveitis, and elevated intraocular pressure. Of these patients, 27% had cystoid macular edema, 36% developed retinal detachment, and 27% had a final visual acuity of 6/12 or better. Conclusion: Pars plana vitrectomy performed immediately after cataract surgery for retained lens fragments is a viable option and may achieve a better visual outcome, with reduced risk of secondary glaucoma, retinal detachment or cystoid macular edema.

Purposes The aims of this study were to describe the bacterial isolates and treatment outcomes of endophthalmitis after cataract surgery at a referral centre in Northern Taiwan. Methods This was a retrospective, interventional, and observational series. Medical records were review of patients with clinical diagnosed, and/or culture-proven bacterial endophthalmitis at a tertiary referral centre in Northern Taiwan from January 2002 to December 2008. Treatment generally conformed to standard guidelines. Main outcome measurements were results of organism culture, antibiotic susceptibility of isolated bacteria, and visual acuity (VA) outcome. Results Thirty-four patients had positive cultures. A total of 55.9% of the culturepositive isolates were Gram negative and 44.1% were Gram positive. Pseudomonas aeruginosa was the most commonly isolated organism. Eighteen patients had final VA better than 5/200, and 41 had final VA worse than 5/200. In multiple linear regression analysis, female gender, presence of hypopyon, and worse baseline VA were significant independent predictors of worse visual outcome. Conclusions It was found that at a referral centre in Northern Taiwan, the majority of bacterial isolates were Gram negative in acute postoperative bacterial endophthalmitis after cataract surgery and P. aeruginosa was the most common bacterial isolate.