Study of Layout Techniques in Dynamic Logic Circuitry for Single Event Effect Mitigation

Dynamic logic circuits are highly suitable for high-speed applications, considering the fact that they have a smaller area and faster transition. However, their application in space or other radiation-rich environments has been significantly inhibited by their susceptibility to radiation effects. This work begins with the basic operations of dynamic logic circuits, elaborates upon the physics underlying their radiation vulnerability, and evaluates three techniques that harden dynamic logic from the layout: drain extension, pulse quenching, and a proposed method. The drain extension method adds an extra drain to the sensitive node in order to improve charge sharing, the pulse quenching scheme utilizes charge sharing by duplicating a component that offsets the transient pulse, and the proposed technique takes advantage of both. Domino buffers designed using these three techniques, along with a conventional design as reference, were modeled and simulated using a 3D TCAD tool. Simulation results confirm a significant reduction of soft error rate in the proposed technique and suggest a greater reduction with angled incidence. A 130 nm chip containing designed buffer and register chains was fabricated and tested with heavy ion irradiation. According to the experiment results, the proposed design achieved 30% soft error rate reduction, with 19%, 20%, and 10% overhead in speed, power, and area, respectively

Comparison of micro-radiofrequency therapy and tolterodine for the treatment of newly diagnosed overactive bladder: A retrospective cohort study

PurposeThis study aimed to retrospectively compare the efficacy and safety of micro-radiofrequency (RF) therapy through the urethra vs. oral tolterodine tartrate in the treatment of newly diagnosed overactive bladder (OAB).Materials and methodsIn this study, 46 patients who were newly diagnosed with moderate-to-severe OAB were included; 23 of them underwent the micro-RF treatment procedure, and the other 23 patients took tolterodine. Bladder diaries were recorded 3 days before treatment and during the follow-up period on 1, 3, and 7 weeks after micro-RF therapy or oral tolterodine. Micturition parameters including daily voiding times, daily urge urinary incontinence (UI) episodes, daily urgency episodes, mean volume per micturition, post-void residual volume (PVR), maximum urine flow rate (Qmax), overactive bladder symptom score (OABSS), and quality of life (QoL) score were analyzed.ResultsAll 46 patients underwent either micro-RF or oral tolterodine treatment, as well as a complete follow-up. The incidence of adverse events in the micro-RF group was 8.7% (2/23), and that in the tolterodine group was 43.5% (10/23). The following two adverse events happened in the micro-RF group: an injury to the urethra during catheterization in a man and a urinary tract infection in a woman, both of which were relieved or disappeared after day 3. The adverse effects in the tolterodine group were mainly dry mouth (4/23), dysuria (5/23), and constipation (8/23), but none of the patients withdrew from the drug therapy. Compared to pre-therapy, all parameters of both groups, including daily voiding times, daily urgency episodes, mean volume per micturition, OABSS, and QoL score, demonstrated significant improvements during follow-up in 7 weeks after therapy, except for daily UI episodes in the tolterodine group, while the above parameters showed bigger improvements in the micro-RF group than in the tolterodine group. Besides, the general treatment efficacy of micro-RF was 73.9% (17/23), which was significantly better than tolterodine (10/23, 43.5%), and the difference was 30.4% [95% CI: 3.4–57.5%, p = 0.036].ConclusionIn this retrospective study, we found that micro-RF therapy is safe and more effective than oral tolterodine for newly diagnosed moderate-to-severe OAB in a short-term follow-up. Stronger evidence would be provided through a well-designed, prospective, randomized controlled trial

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice

Postdiagnosis BMI Change Is Associated with Non-Small Cell Lung Cancer Survival

Background: Body mass index (BMI) change after a lung cancer diagnosis has been associated with non-small cell lung cancer (NSCLC) survival. This study aimed to quantify the association based on a large-scale observational study. Methods: Included in the study were 7,547 patients with NSCLC with prospectively collected BMI data from Massachusetts General Hospital and Brigham and Women's Hospital/Dana-Farber Cancer Institute. Cox proportional hazards regression with time-dependent covariates was used to estimate effect of time-varying postdiagnosis BMI change rate (% per month) on overall survival (OS), stratified by clinical subgroups. Spline analysis was conducted to quantify the nonlinear association. A Mendelian Randomization (MR) analysis with a total of 3,495 patients further validated the association. Results: There was a J-shape association between postdiagnosis BMI change and OS among patients with NSCLC. Specifically, a moderate BMI decrease [0.5-2.0; HR = 2.45; 95% confidence interval (CI), 2.25-2.67] and large BMI decrease (≥2.0; HR = 4.65; 95% CI, 4.15-5.20) were strongly associated with worse OS, whereas moderate weight gain (0.5-2.0) reduced the risk for mortality (HR = 0.78; 95% CI, 0.68-0.89) and large weight gain (≥2.0) slightly increased the risk of mortality without reaching statistical significance (HR = 1.10; 95% CI, 0.86-1.42).MR analyses supported the potential causal roles of postdiagnosis BMI change in survival. Conclusions: This study indicates that BMI change after diagnosis was associated with mortality risk

The biogenesis and biological function of PIWI-interacting RNA in cancer

Abstract Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24–31 nucleotides), bind to PIWI proteins, and show 2′-O-methyl modification at the 3′-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment

Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer SurvivalResearch in context

Backgrounds: Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC. Methods: A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method. Results: We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223. Interpretation: This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation. Keywords: GWAS, Genetic variants, Gastric cancer, Surviva

Construction, evaluation, and AOP framework-based application of the EpPRS as a genetic surrogate for assessing environmental pollutants

Background: Environmental pollutant measurement is essential for accurate health risk assessment. However, the detection of humans’ internal exposure to pollutants is cost-intensive and consumes time and energy. Polygenic risk scores (PRSs) have been widely applied in genetic studies of complex trait diseases. It is important to construct a genetically relevant environmental surrogate for pollutant exposure and to explore its utility for disease prediction and risk assessment. Objectives: This study enrolled 714 individuals with complete genomic data and exposomic data on 22 plasma-persistent organic pollutants (POPs). Methods: We first conducted 22 POP genome-wide association studies (GWAS) and constructed the corresponding environmental pollutant-based PRS (EpPRS) by clumping and P value thresholding (C + T), lassosum, and PRS-CS methods. The best-fit EpPRS was chosen by its regression R2. An adverse outcome pathway (AOP) framework was developed to assess the effects of contaminants on candidate diseases. Furthermore, Mendelian randomization (MR) analysis was performed to explore the causal association between POPs and cancer risk. Results: The C + T method produced the best-performing EpPRSs for 7 PCBs and 4 PBDEs. EpPRSs replicated the correlations of environmental exposure measurements based on consistent patterns. The diagnostic performance of type 2 diabetes mellitus (T2DM) PRS was improved by the combined model of T2DM-EpPRS of PCB126/BDE153. Finally, the AKT1-mediated AOP framework illustrated that PCB126 and BDE153 may increase the risk of T2DM by decreasing AKT1 phosphorylation through the cGMP-PKG pathway and promoting abnormal glucose homeostasis. MR analysis showed that digestive system tumors, such as colorectal cancer and biliary tract cancer, are more sensitive to POP exposure. Conclusions: EpPRSs can serve as a proxy for assessing pollutant internal exposure. The application of the EpPRS to disease risk assessment can reveal the toxic pathway and mode of action linking exposure and disease in detail, providing a basis for the development of environmental pollutant control strategies