High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in ...multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure.
We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts.
This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors.
Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.
•Clinicians often rely on original diagnostic samples for TMB analysis, and the impact of treatments on TMB remains unclear.•Chemotherapy was prone to be correlated with an increase of TMB in most cancer types.•Several actionable genes as well as some prognostic markers were significantly changed after chemotherapy.•Estimating TMB with the latest post-chemotherapy specimen would be a better option for response prediction of immunotherapy.
Remyelination represents an area of great therapeutic interest in multiple sclerosis but currently lacks a robust imaging marker. The purpose of this study was to use high-gradient diffusion MRI and ...macromolecular tissue volume imaging to obtain estimates of axonal volume fraction, myelin volume fraction, and the imaging g-ratio in patients with MS and healthy controls and to explore their relationship to neurologic disability in MS.
Thirty individuals with MS (23 relapsing-remitting MS, 7 progressive MS) and 19 age-matched healthy controls were scanned on a 3T MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Macromolecular tissue volume imaging was performed to quantify the myelin volume fraction. Diffusion data were fitted to a 3-compartment model of white matter using a spheric mean approach to yield estimates of axonal volume fraction. The imaging g-ratio was calculated from the ratio of myelin volume fraction and axonal volume fraction. Imaging metrics were compared between groups using 2-sided
tests with a Bonferroni correction.
The mean g-ratio was significantly elevated in lesions compared with normal-appearing WM (0.74 vs 0.67,
< .001). Axonal volume fraction (0.17 vs 0.23,
< .001) and myelin volume fraction (0.17 vs 0.25,
< .001) were significantly lower in lesions than normal-appearing WM. Myelin volume fraction was lower in normal-appearing WM compared with that in healthy controls (0.25 vs 0.27,
= .009). Disability, as measured by the Expanded Disability Status Scale, was significantly associated with myelin volume fraction (β = -40.5,
= .001) and axonal volume fraction (β = -41.0,
= .016) in normal-appearing WM.
The imaging g-ratio may serve as a biomarker for the relative degree of axonal and myelin loss in MS.
The Hong Kong Government released a Reference Framework (RF-HT) for Hypertension Care for Adults in Primary Care Settings since 2010. No studies have evaluated its adoption by primary care physicians ...(PCPs) since its release.
We aimed to evaluate the level of PCPs' adoption of the RF-HT and the potential barriers of its use in family practice.
A cross-sectional study was conducted by a self-administered validated survey among all PCPs in Hong Kong through various means.
We assessed the level of and factors associated with its adoption by multivariate logistic regression modelling.
A total of 3,857 invitation episodes were sent to 2,297 PCPs in 2014-2015. We received 383 completed questionnaires. The average score of adoption was 3.43 out of 4.00, and 47.5% of PCPs highly adopted RF-HT in their daily consultations. Male practitioners (adjusted odds ratio aOR = 0.524, 95% CI = 0.290-0.948, p = 0.033) and PCPs of public sector (aOR = 0.524, 95% CI = 0.292-0.940, p = 0.030) were significantly less likely to adopt the RF-HT. PCPs with higher training completion or being academic fellow are more likely to adopt RF-HT than those who were "nil to basic training completion" (aOR = 0.479, 95% CI = 0.269-0.853, p = 0.012) or "higher trainee" (aOR = 0.302, 95% CI = 0.093-0.979, p = 0.046). Three most-supported suggestions on RF-HT improvement were simplification of RF-HT, provision of pocket version and promoting in patients.
Among PCP respondents, the adoption level of the RF-HT was high. These findings also highlighted some factors associated with its adoption that could inform targeted interventions for enhancing its use in clinical practice.
The use of columnar structures in thermal barrier coatings (TBCs) enables producing materials with lower thermal conductivities that are also able to accommodate thermal expansion during temperature ...cycling events. However, open porosity leads to the failure of TBCs because of the rapid oxidation of the coating-substrate interface. Here we propose to create an oxidation-induced sealing process to mitigate any oxidation or potential chemical attack. This is achieved by pre-mixing the top surface with a carbide phase (TiC or SiC) that oxidizes in contact with air to seal the surface through volume expansion. Laser processing was used as a technique to fabricate YSZ-Al2O3-TiC or YSZ-Al2O3-SiC layers on 316 stainless steel substrates to understand the viability of this process as well as this coating design in creating self-healing thermal barrier coatings. Nanocomposite self-healing coatings and single-phase yttria-stabilized zirconia (YSZ) reference layers were produced using a laser fluence of 17.0 J/mm2 (800 W), 19.1 J/mm2 (900 W), and 25.5 J/mm2 (1200 W) to optimize process conditions. These coatings were subsequently annealed at 720 °C for 12 h to ensure complete oxidation of the TiC(SiC) phase in the former coating. X-ray diffraction and cross-sectional energy dispersive x-ray spectroscopy (EDS) elemental mapping confirmed the creation of the desired columnar structure to accommodate thermal stresses and that a post-annealing treatment was required to achieve complete oxidation of the TiC(SiC) phase. The migration of TiO2 phase to the crack site was demonstrated using cross-sectional scanning electron microscopy (SEM) in tandem with elemental mapping via energy dispersive spectroscopy. The suggested optimum laser fluence to create a viable self-healing composite was found to be 17.0 J/mm2 since higher values resulted in significant interdiffusion between the substrate and the coating as indicated by cross-sectional SEM/EDS. Laser processing was demonstrated to be a viable technique that has the potential to create a self-healing layer that seals YSZ-based underlayers from diffusion.
•YSZ-Al2O3-TiC(SiC) self-healing layers were produced using laser processing.•Optimum laser fluence was found to be 17.0 J/mm2.•Annealing at 720 °C for 12 h was needed to fully oxidize the carbide phase.•The newly formed oxide phase migrated to the crack site.
We introduce one kind of embedded dynamic-random-access-memory (eDRAM) array (16 kilo-bits) with peripheral circuits. Each cell in an array comprises 1-control-Fin-type-field-effect-transistor FinFET ...(T) and 1-storage-npn-diode (D). The latter can be implemented by a nFinFET with the floating gate electrode. This 1T1D eDRAM technology is fully integrated with the 16-nm FinFET process and can be continually shrunk to the 3-nm technology node. The size of the unit-cell is <inline-formula> <tex-math notation="LaTeX">0.0242~\mu \text{m}~^{\mathrm{ 2}} </tex-math></inline-formula>. This 1T1D eDRAM cell can be programmed by the Zener-tunneling mechanism with 0.8 V of a writing voltage in 8 ns; the reading can be accomplished in 7 ns at −0.2 V. <inline-formula> <tex-math notation="LaTeX">116~\mu \text{s} </tex-math></inline-formula> of data retention at 25°C (<inline-formula> <tex-math notation="LaTeX">101~\mu \text{s} </tex-math></inline-formula> at 75°C); <inline-formula> <tex-math notation="LaTeX">100~\mu \text{W} </tex-math></inline-formula> of the write power; <inline-formula> <tex-math notation="LaTeX">9.125~\mu \text{W} </tex-math></inline-formula> of the read power have been recorded as well. These experimental pieces of evidence suggest that our 1T1D embedded DRAM technology could replace the conventional 1-transistor-1-capacitance (1T1C) eDRAM one with better cost-efficiency and lower power in the advanced CMOS technology to 3-nm node.
Summary
Transcriptome analysis using a cDNA microarray was performed to identify differentially expressed genes that are correlated with hatchability, and a new PCR‐RFLP marker of high hatchability ...among the identified genes was observed. We used the cDNA microarray technique for gene expression profiling of the magnum epithelium of laying Tsaiya ducks, and several regulated genes associated with hatchability were found. The results of real‐time PCR and Western blotting analysis confirmed that the mRNA and protein levels of ovomucoid in the magnum epithelium of animals in the low‐hatchability group were significantly higher than the levels in the high‐hatchability group (P < 0.05). Primers TovF1 and TovR1, designed according to the ovomucoid EST sequence, were used to amplify genomic DNA samples of different individual Tsaiya ducks, and sequence analysis of the amplified DNA products showed deletion among the ducks from the low‐hatchability group. Primers TovF2 and TovR2 were used to perform PCR‐RFLP analysis on the amplified DNA products to classify the ducks into +/+, +/− and −/− genotypes. The animals of +/+ and +/− genotypes were identified as having significantly higher hatchability than those of the −/− genotype (P < 0.05). In contrast, no differences were observed between genotypes in terms of fertility, duration of fertility, egg weight or total number of eggs. Our results indicated that a novel PCR‐RFLP marker of high hatchability, an ovomucoid gene polymorphism, can be used as a genetic marker for marker‐assisted selection to improve hatchability in Tsaiya ducks.
Background and purpose
To investigate the risk of stroke development following a diagnosis of Bell's palsy in a nationwide follow‐up study.
Methods and materials
Information on Bell's palsy and other ...factors relevant for stroke was obtained for 433 218 eligible subjects without previous stroke who had ambulatory visit in 2004. Of those, 897 patients with Bell's palsy were identified. Over a median 2.9 years of follow‐up, 4581 incident strokes were identified. We estimated hazard ratios (HR) and 95% confidence intervals CI with Cox proportional hazard models adjusting for age, sex, co‐morbidities, and important risk factors. Standardized incidence ratio of stroke amongst patients with Bell's palsy was analyzed.
Results
Compared with non‐Bell's palsy patients, patients with Bell's palsy had a 2.02‐times (95% CI, 1.42–2.86) higher risk of stroke. The adjusted HR of developing stroke for patients with Bell's palsy treated with and without systemic steroid were 1.67 (95% CI, 0.69–4) and 2.10 (95%, 1.40–3.07), respectively.
Conclusions
Patients with Bell's palsy carry a higher risk of stroke than the general population. Our data suggest that these patients might benefit from a more intensive stroke prevention therapy and regular follow‐up after initial diagnosis.
Glutamate transporters regulate excitatory neurotransmission and prevent glutamate-mediated excitotoxicity in the CNS. To better study the cellular and temporal dynamics of the expression of these ...transporters, we generated bacterial artificial chromosome promoter Discosoma red glutamate-aspartate transporter (GLAST) and green fluorescent protein glutamate transporter-1 (GLT-1) reporter transgenic mice. Analysis of these mice revealed a differential activation of the transporter promoters not previously appreciated. GLT-1 promoter activity in the adult CNS is almost completely restricted to astrocytes, often and unexpectedly in a nonoverlapping pattern with GLAST. Spinal cord GLT-1 promoter reporter, protein density, and physiology were 10-fold lower than in brain, suggesting a possible mechanism for regional sensitivity seen in disease. The GLAST promoter is active in both radial glia and many astrocytes in the developing CNS but is downregulated in most astrocytes as the mice mature. In the adult CNS, the highest GLAST promoter activity was observed in radial glia, such as those located in the subgranular layer of the dentate gyrus. The continued expression of GLAST by these neural progenitors raises the possibility that GLAST may have an unanticipated role in regulating their behavior. In addition, GLAST promoter activation was observed in oligodendrocytes in white matter throughout many (e.g., spinal cord and corpus callosum), but not all (e.g., cerebellum), CNS fiber tracts. Overall, these studies of GLT-1 and GLAST promoter activity, protein expression, and glutamate uptake revealed a close correlation between transgenic reporter signals and uptake capacity, indicating that these mice provide the means to monitor the expression and regulation of glutamate transporters in situ.
Anterior cruciate ligament (ACL) reconstruction (ACLR) surgeries successfully restore anterior tibial translation but not tibial rotation. This study aimed to explore landing strategies focusing on ...the control of tibial rotation at landing when the ACL is most vulnerable. Three groups of male subjects (50 ACLRs, 26 basketball players, and 31 controls) participated in one‐leg forward hop tests for determining the tibial rotatory landing strategies adopted during the initial landing phase. The differences in knee kinematics and muscle activities between internal and external tibial rotatory (ITR, ETR) landing strategies were examined. A higher proportion of basketball players (34.6%) were found to adopt ITR strategies (controls: 6.5%), exhibiting significantly greater hopping distance and knee strength. After adjusting for hopping distance, subjects adopting ITR strategies were found to hop faster with straighter knees at foot contact and with greater ITR and less knee adduction angular displacement during the initial landing phase. However, significantly greater angular displacement in knee flexion, greater medial hamstring activities, and greater co‐contraction index of hamstrings and medial knee muscles were also found during initial landing. Our results support the importance of the recruitments of medial hamstrings or the local co‐contraction in assisting the rotatory control of the knee during initial landing for avoiding ACL injuries.
PDF
