Sensitive detection of BRAF V600E mutation by Amplification Refractory Mutation System (ARMS)-PCR

BACKGROUND: BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid. These mutations provide potentially valuable diagnostic, prognostic and treatment response prediction markers. A sensitive, specific, low-cost assay to detect these mutations is needed. RESULTS: To detect BRAF V600E mutation in formalin-fixed, paraffin-embedded (FFPE) tissue, we developed a method using Amplification Refractory Mutation System (ARMS)-PCR. This method was designed to amplify three products in a single reaction tube: a 200 bp common product serving as an amplification control, a 144 bp BRAF V600E specific product, and a 97 bp wild-type (wt) specific product. The sensitivity of this method was determined to be as low as 0.5% for the BRAF V600E allele in a wild-type background. This method was successfully validated in 72 thyroid tumors. It detected V600E mutation in 22 out of 33 (67%) of the conventional papillary thyroid carcinoma (PTC), 8 out of 12 (75%) of the tall-cell variant of PTC, whereas none of the 10 follicular variant of PTC showed BRAF V600E mutation. In addition, none of the 14 follicular adenomas and 3 follicular carcinomas had BRAF V600E mutation. As a comparison method, direct dideoxy sequencing found only 27 out of 30 (90%) mutations detected by ARMS-PCR method, suggesting that this ARMS-PCR method has higher sensitivity. CONCLUSIONS: Our ARMS-PCR method provides a new tool for rapid detection of BRAF V600E mutation. Our results indicate that ARMS-PCR is more sensitive than automated dideoxy sequencing in detecting low BRAF V600E allele burdens in FFPE tumor specimen. The strategy of this ARMS-PCR design may be adapted for early detection of point mutations of a variety of biomarker genes

Prognosis signature for predicting the survival and immunotherapy response in esophageal carcinoma based on cellular senescence-related genes

BackgroundCellular senescence occurs throughout life and can play beneficial roles in a variety of physiological processes, including embryonic development, tissue repair, and tumor suppression. However, the relationship between cellular senescence-related genes (CSRGs) and immunotherapy in esophageal carcinoma (ECa) remains poorly defined.MethodsThe data set used in the analysis was retrieved from TCGA (Research Resource Identifier (RRID): SCR_003193), GEO (RRID: SCR_005012), and CellAge databases. Data processing, statistical analysis, and diagram formation were conducted in R software (RRID: SCR_001905) and GraphPad Prism (RRID: SCR_002798). Based on CSRGs, we used the TCGA database to construct a prognostic signature for ECa and then validated it in the GEO database. The predictive efficiency of the signature was evaluated using receiver operating characteristic (ROC) curves, Cox regression analysis, nomogram, and calibration curves. According to the median risk score derived from CSRGs, patients with ECa were divided into high- and low-risk groups. Immune infiltration and immunotherapy were also analyzed between the two risk groups. Finally, the hub genes of the differences between the two risk groups were identified by the STRING (RRID: SCR_005223) database and Cytoscape (RRID: SCR_003032) software.ResultsA six-gene risk signature (DEK, RUNX1, SMARCA4, SREBF1, TERT, and TOP1) was constructed in the TCGA database. Patients in the high-risk group had a worse overall survival (OS) was disclosed by survival analysis. As expected, the signature presented equally prognostic significance in the GSE53624 cohort. Next, the Area Under ROC Curve (AUC=0.854) and multivariate Cox regression analysis (HR=3.381, 2.073-5.514, P<0.001) also proved that the risk signature has a high predictive ability. Furthermore, we can more accurately predict the prognosis of patients with ECa by nomogram constructed by risk score. The result of the TIDE algorithm showed that ECa patients in the high-risk group had a greater possibility of immune escape. At last, a total of ten hub genes (APOA1, MUC5AC, GC, APOA4, AMBP, FABP1, APOA2, SOX2, MUC8, MUC17) between two risk groups with the highest interaction degrees were identified. By further analysis, four hub genes (APOA4, AMBP, FABP1, and APOA2) were related to the survival differences of ECa.ConclusionsOur study reveals comprehensive clues that a novel signature based on CSRGs may provide reliable prognosis prediction and insight into new therapy for patients with ECa

Iris volume change with physiologic mydriasis to identify development of angle closure: the Zhongshan Angle Closure Prevention Trial

AIMS: To assess dynamic change of iris area (Iarea) and volume (VOL) with physiologic pupil dilation for progression of primary angle closure suspects. METHODS: Participants underwent baseline examinations including gonioscopy and anterior segment OCT (AS-OCT) as part of the Zhongshan Angle Closure Prevention Trial. The AS-OCT images were obtained both in the dark and light. Progression was defined as development of primary angle closure or an acute angle closure attack. Static ocular biometrics and dynamic changes were compared between progressors and non-progressors and multivariable logistic regression was developed to assess risk factors for progression. RESULTS: A mean 16.8% decrease in Iarea and a mean 6.26% decrease in VOL occurred with pupil dilation, while 22.96% non-progressors and 40% progressors presented VOL increases with pupil dilation. Iarea in light and dark and VOL in light were significantly smaller in progressors. In a multivariable logistic model, older age (p=0.008), narrower horizontal angle opening distance (AOD) 250 µm from the scleral spur (AOD250, p=0.001), flatter iris curvature (IC, p=0.006) and lower loss of iris volume (ΔVOL, p=0.04) were significantly associated with progression. With receiver operating characteristic analysis, the area under the curve for ΔVOL alone was 0.621, while that for the combined index (age, AOD250, IC and ΔVOL) was 0.824. Eyes with elevated intraocular pressure had less VOL loss compared with progressors developing peripheral anterior synechiae alone (p=0.055 for ΔVOL adjusted for pupil enlargement). CONCLUSION: A smaller change in ΔVOL is an additive risk factor to identify eyes more likely to develop angle closure disease. TRIAL REGISTRATION NUMBER: ISRCTN45213099

Improving End-to-End Speech Processing by Efficient Text Data Utilization with Latent Synthesis

Training a high performance end-to-end speech (E2E) processing model requires an enormous amount of labeled speech data, especially in the era of data-centric artificial intelligence. However, labeled speech data are usually scarcer and more expensive for collection, compared to textual data. We propose Latent Synthesis (LaSyn), an efficient textual data utilization framework for E2E speech processing models. We train a latent synthesizer to convert textual data into an intermediate latent representation of a pre-trained speech model. These pseudo acoustic representations of textual data augment acoustic data for model training. We evaluate LaSyn on low-resource automatic speech recognition (ASR) and spoken language understanding (SLU) tasks. For ASR, LaSyn improves an E2E baseline trained on LibriSpeech train-clean-100, with relative word error rate reductions over 22.3% on different test sets. For SLU, LaSyn improves our E2E baseline by absolute 4.1% for intent classification accuracy and 3.8% for slot filling SLU-F1 on SLURP, and absolute 4.49% and 2.25% for exact match (EM) and EM-Tree accuracies on STOP respectively. With fewer parameters, the results of LaSyn are competitive to published state-of-the-art works. The results demonstrate the quality of the augmented training data.Comment: 15 pages, 8 figures, 8 tables, Accepted to EMNLP 2023 Finding

Prevalence and causes of blindness, visual impairment among different ethnical minority groups in Xinjiang Uygur autonomous region, China.

BACKGROUND: The aim of this cross-sectional study is to ascertain the prevalence and causes of blindness, visual impairment, uptake of cataract surgery among different ethnic groups in Xinjiang Uygur Autonomous Region, China. METHODS: Four thousand one hundred fifty people at 50 years and above from different minority ethnic groups were randomly selected for an eye examination. The four trained eye teams collected data using tumbling E visual chart, torch, portable slit lamp and direct ophthalmoscope in 2015. The World Health Organization's definition of blindness and visual impairment (VI) was used to classify patients in each ethnic group. Data were analyzed by different minority groups and were compared with Han Chinese. RESULTS: 3977 (95.8%) out of 4150 people were examined. The prevalence of blindness from the study population was 1.7% (95% confidence interval: 1.3-2.2%).There was no significant difference in prevalence of blindness between Han Chinese and people of Khazak and other minority ethnic groups, nor, between male and female. Cataract was the leading course (65.5%) of blindness and uncorrected refractive error was the most common cause of VI (36.3%) followed by myopic retinopathy. The most common barrier to cataract surgery was lack of awareness of service availability. CONCLUSIONS: This study documented a low blindness prevalence among people aged 50 years and over comparing to prevalence identified through studies of other regions in China. It still indicates blindness and un-operated cataract as the significant public health issue, with no evidence of eye health inequalities, but some inequities in accessing to cataract surgery amongst ethnic minority groups in Xinjiang

Aligning Large Language Models with Human: A Survey

Large Language Models (LLMs) trained on extensive textual corpora have emerged as leading solutions for a broad array of Natural Language Processing (NLP) tasks. Despite their notable performance, these models are prone to certain limitations such as misunderstanding human instructions, generating potentially biased content, or factually incorrect (hallucinated) information. Hence, aligning LLMs with human expectations has become an active area of interest within the research community. This survey presents a comprehensive overview of these alignment technologies, including the following aspects. (1) Data collection: the methods for effectively collecting high-quality instructions for LLM alignment, including the use of NLP benchmarks, human annotations, and leveraging strong LLMs. (2) Training methodologies: a detailed review of the prevailing training methods employed for LLM alignment. Our exploration encompasses Supervised Fine-tuning, both Online and Offline human preference training, along with parameter-efficient training mechanisms. (3) Model Evaluation: the methods for evaluating the effectiveness of these human-aligned LLMs, presenting a multifaceted approach towards their assessment. In conclusion, we collate and distill our findings, shedding light on several promising future research avenues in the field. This survey, therefore, serves as a valuable resource for anyone invested in understanding and advancing the alignment of LLMs to better suit human-oriented tasks and expectations. An associated GitHub link collecting the latest papers is available at https://github.com/GaryYufei/AlignLLMHumanSurvey.Comment: work in progres

The Role of CD1d and MR1 Restricted T Cells in the Liver

The liver is one of the most important immunological organs that remains tolerogenic in homeostasis yet promotes rapid responses to pathogens in the presence of a systemic infection. The composition of leucocytes in the liver is highly distinct from that of the blood and other lymphoid organs, particularly with respect to enrichment of innate T cells, i.e., invariant NKT cells (iNKT cells) and Mucosal-Associated Invariant T cells (MAIT cells). In recent years, studies have revealed insights into their biology and potential roles in maintaining the immune-environment in the liver. As the primary liver-resident immune cells, they are emerging as significant players in the human immune system and are associated with an increasing number of clinical diseases. As such, innate T cells are promising targets for modifying host defense and inflammation of various liver diseases, including viral, autoimmune, and those of tumor origin. In this review, we emphasize and discuss some of the recent discoveries and advances in the biology of innate T cells, their recruitment and diversity in the liver, and their role in various liver diseases, postulating on their potential application in immunotherapy

Validation of handheld fundus camera with mydriasis for retinal imaging of diabetic retinopathy screening in China: a prospective comparison study.

OBJECTIVES: To investigate the clinical validity of using a handheld fundus camera to detect diabetic retinopathy (DR) in China. DESIGN AND SETTINGS: Prospective comparison study of the handheld fundus camera with a standard validated instrument in detection of DR in hospital and a community screening clinic in Guangdong Province, China. PARTICIPANTS: Participants aged 18 years and over with diabetes who were able to provide informed consent and agreed to attend the dilated eye examination with handheld tests and a standard desktop camera. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the proportion of those with referable DR (R2 and above) identified by the handheld fundus camera (the index test) compared with the standard camera. Secondary outcome was the comparison of proportion of gradable images obtained from each test. RESULTS: In this study, we examined 304 people (608 eyes) with each of the two cameras under mydriasis. The handheld camera detected 119 eyes (19.5%) with some level of DR, 81 (13.3%) of them were referable, while the standard camera detected 132 eyes (21.7%) with some level of DR and 83 (13.7%) were referable. It seems that the standard camera found more eyes with referable DR, although McNemar's test detected no significant difference between the two cameras.Of the 608 eyes with images obtained by desktop camera, 598 (98.4%) images were of sufficient quality for grading, 12 (1.9%) images were not gradable. By the handheld camera, 590 (97.0%) were gradable and 20 (3.2%) images were not gradable.The two cameras reached high agreement on diagnosis of retinopathy and maculopathy at all the levels of retinopathy. CONCLUSION: Although it could not take the place of standard desktop camera on clinic fundus examination, the handheld fundus camera showed promising role on preliminary DR screening at primary level in China. To ensure quality images, mydriasis is required

Changes in body weight and cardiovascular risk factors in a Chinese population with type 2 diabetes mellitus: a longitudinal study

IntroductionThe primary care management of blood glucose, blood pressure, lipid profiles, and body weight is important among patients with type 2 diabetes mellitus (T2DM) to prevent disease progression. Information on how weight changes would improve or deteriorate cardiovascular (CV) risk factors is warranted for making primary care recommendations. We aimed to investigate the changes in body weight and CV risk factors and to analyse their association in a Chinese population with T2DM.MethodsWe retrieved longitudinal data between 2020 and 2021 from 1,758 adult primary care patients enrolled in a diabetic retinopathy (DR) screening programme. Linear associations of changes in body weight with CV risk factors were explored. Multivariable logistic regression analysis was performed to examine associations between different weight change categories and the worsening of CV risk factors.ResultsThe mean age of all the participants was 63.71 years, and over half of participants were females. During a one-year follow-up period, 24.7% of patients had a weight loss of ≥3%, while 22.2% of patients had a weight gain of ≥3%. Patients who had a weight loss of ≥3% were more likely to prevent the worsening of haemoglobin A1c (HbA1c) and triglycerides, while those who had a weight gain of ≥3% tended to have worsened HbA1c, lipid profiles, and blood pressure.ConclusionResults from this real-world investigation suggested the concurrent need for weight loss intervention among patients who are overweight or obese and weight gain prevention among patients whose body weight falls within the normal range in the context of community-based diabetes management