Purpose/Objective(s)Trimodality therapy (TMT), which consists of transurethral resection of bladder tumor (TURBT) followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. We characterized the genomic and transcriptomic landscape associated with response to TMT through whole exome sequencing (WES) and expression profiling.Materials/MethodsMIBC patients treated with TMT at a single institution were identified. DNA and RNA were extracted from available FFPE pre-treatment TURBT samples, and WES and transcriptome-wide expression profiling were performed. WES data were analyzed by standard mutation analysis pipelines with a common variant filter to account for lack of matched germline samples. Somatic mutations, insertion/deletions, and copy number variations were identified. Molecular subtypes and DNA damage response (DDR) pathway scores were derived from expression profiles. Responders (R) were defined as patients with complete response at post-treatment cystoscopy and no recurrence. Nonresponders (NR) were defined as patients with incomplete response at post-treatment cystoscopy, those who underwent salvage cystectomy, or those with regional/distant disease progression.ResultsPre-treatment TURBT FFPE samples from 77 selected TMT patients were successfully sequenced and passed quality control metrics, 68 of which had matched transcriptomic profiling. The median age of the cohort was 72.7 years; 23% were female. All patients had MIBC (87% T2, 13% T3/T4) and the majority were treated with concurrent cisplatin-based chemotherapy. Median follow-up was 42 months in alive patients. Thirty-nine patients were classified as NR, while 38 were R. Mean somatic tumor mutational burden among R and NR was 13.5 (range, 4.2-31.5) and 11.3 (range, 3.4-26.8) mutations/megabase, respectively (p=0.08). Exploratory analyses of DDR pathways revealed more patients classified as R had mutations in ERCC2 (n=7) as compared to NR (n=1), p=0.023. Six of these 8 patients with ERCC2 mutations received cisplatin-based chemotherapy; of the 2 that did not, 1 was NR. Samples with ERCC2 mutations had higher hallmark DNA repair scores (median 0.110 versus -0.310, p=0.02), suggesting dysregulation of DDR. ERCC2 mutant tumors were also enriched for GSC luminal subtype compared to ERCC2 wildtype (83% vs. 37% luminal; p=0.03). Patients with ERCC2 mutations had improved disease-specific survival (HR 0.17 (95%CI: 0.064-0.41), p=0.04). Consistent with these results, in vitro studies showed ERCC2 mutant bladder cancer cell lines are significantly more sensitive to cisplatin and radiation than isogenic ERCC2 wildtype cells.ConclusionOur data demonstrate that alterations in ERCC2, a crucial DDR gene, may be associated with improved response to TMT. These findings require validation in larger cohorts.

In this work, we continue our development of phase field model benchmark problems with the addition of a third set, complimenting our previously developed problems for diffusion, precipitation, dendritic growth and linear elasticity. These benchmark problems are being jointly developed by the Center for Hierarchical Materials Design (CHiMaD) and the National Institute of Standards and Technology (NIST) along with input from the phase field community. The first problem in this third set targets Stokes flow, with a particular emphasis on flow around an obstruction placed asymmetrically in the domain. While Stokes flow is not traditionally in the canon of phase field problems, it is a class of problems gaining importance in areas such as filtration and water purification. The second problem deals with coupled Cahn-Hilliard diffusion and electrostatic forces, which is an important area in energy storage and battery sciences. We present our own solutions and discuss sources of numerical errors for the Stokes problem as well as simple checks to avoid fundamental issues in the coupled diffusion-electrostatics problem. The latter problem contains some subtleties that we expand on in an Appendix.

Moiré superlattices in van der Waals (vdW) heterostructures have given rise to a number of emergent electronic phenomena due to the interplay between atomic structure and electron correlations. A lack of a simple way to characterize moiré superlattices has impeded progress in the field. In this work we outline a simple, room-temperature, ambient method to visualize real-space moiré superlattices with sub-5 nm spatial resolution in a variety of twisted vdW heterostructures including but not limited to conducting graphene, insulating boron nitride and semiconducting transition metal dichalcogenides. Our method utilizes piezoresponse force microscopy, an atomic force microscope modality which locally measures electromechanical surface deformation. We find that all moiré superlattices, regardless of whether the constituent layers have inversion symmetry, exhibit a mechanical response to out-of-plane electric fields. This response is closely tied to flexoelectricity wherein electric polarization and electromechanical response is induced through strain gradients present within moiré superlattices. Moiré superlattices of 2D materials thus represent an interlinked network of polarized domain walls in a non-polar background matrix.

目的:探讨急性髓细胞白血病(AML)免疫表型伴系表达与染色体核型异常的相关性.方法:选择2017年1月-2019年6月我院血液科初诊AML患者共131例,男69例,女62例,平均年龄58岁(年龄分布22～88岁),其中包括M1 6例,M2 68例,M3 15例,M4 30例,M5 10例,M6 1例,急性混合细胞白血病1例.结果:131例患者中伴系表达62例,其中伴淋系异常表达,依次为伴CD56+31例,CD7+15例,CD19+10例,CD2+、CD5-各1例,其中两种以上伴系表达19例.131例患者中有31例未见染色体核型异常分裂相改变,未列入统计,15例M3患者由于免疫分型及染色体的特殊性,也不列入统计,最终入组85例.采用x2检验统计分析发现,染色体异常患者更容易出现伴系表达,差异有统计学意义(x2 =3.994,P=0.045 7).结论:AML免疫表型伴淋系异常表达主要为CD56、CD7、CD19等,存在伴系表达的患者更容易出现染色体异常.CD56可能是重现性染色体异常出现的重要提示指标.

Little is known about the community structure of bacteria in the rhizosphere of canola during growth. This study was conducted to characterize the community structure of soil bacteria in relation to soluble-C dynamics in a Podzol during the growth of canola. Next generation sequencing of 16S rDNA characterized the main bacterial communities in a Podzol that was unplanted (soil alone), and planted to canola (Brassica napus) with and without N-fertilizer addition. PERMANOVA and ANOVA analysis showed that the number of operational taxonomic units and the relative abundance of bacteria were higher in canola rhizosphere than in soil alone for phyla, classes, orders and families. In soil alone and at the family level, communities of Acidobacteriaceae, Micrococcaceae, Nocardioidaceae, Intrasporangiaceae and Nitrosomonadaceae had the highest relative abundances (sequence reads ranged from 1,000 to 3,000). In the rhizosphere, communities of Sphingomonadaceae, Bacillaceae, Gaiellaceae, Micrococcaceae and Intrasporangiaceae presented the highest relative abundance (sequence reads ranged from ~8,000 to 23,000). The addition of N-fertilizer increased the relative abundance of bacteria in 5 families, decreased those in 39 and did not affect the communities in 56 other families. A two-way ANOVA showed that management, inclusive of canola and N-fertilizer, had the largest (87%) effect on the total relative abundance of soil bacteria and soluble-C content. Polynomial regression models of second order showed a close relation between the relative abundance of bacteria and soluble-C content during crop growth. We suggest that diffusional constraints depleted soluble-C in the vicinity of microbial communities to a growth limiting concentration more frequently in the soil alone than in canola rhizosphere.