Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient's genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer ...Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R
= 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.
•A simple but sensitive sensor is established for ligase and polynucleotide kinase (PNK) assay.•Exponential HRCA confers the sensor with high sensitivity and selectivity.•Label-free detection mode ...greatly simplifies the sensor design and reduces the cost.•The sensor was successfully used for ultrasensitive assay of T4 ligase and T4 PNK.•Such a sensing strategy can be easily extended to studies on enzyme inhibitors.
Ligase and polynucleotide kinase (PNK) play important roles in DNA repair process. In this work, a simple, convenient and ultrasensitive fluorescence biosensor for label-free detection of ligase and PNK was proposed on the basis of target-triggered hyper-branched rolling circle amplification (HRCA). In the presence of PNK and ligase, the 5′-OH end of a linear Padlock DNA strand could be phosphorylated by PNK and then be converted by ligase into a circular template to trigger subsequent exponential HRCA reaction, producing amounts of double-stranded DNA (dsDNA) fragments, accompanied by the significant fluorescence increase of dsDNA-intercalating dye–SYBR Green I (SG I). In the absence of ligase or PNK, however, HRCA primer and uncyclized Padlock strands were completely digested by exonucleases, thus providing a low background for the sensing system. Therefore, by recording the fluorescence change of SG I, ligase and PNK activity could be facilely determined. The proposed biosensor exhibited excellent detection sensitivity for ligase and PNK activity with the detection limits of 3.4 × 10−4 U/mL and 3.8 × 10−4 U/mL, respectively. Such a sensing strategy could be easily extended to studies on inhibitors of these two enzymes, thus might offer a promising tool in clinical molecular diagnostics and cancer therapy.
The proportion of individuals with depression has rapidly increased along with the growth of the global population. Depression has been the currently most prevalent mental health disorder. An ...effective depression recognition system is especially crucial for the early detection of potential depression risk. A depression-related dataset is also critical while evaluating the system for depression or potential depression risk detection. Due to the sensitive nature of clinical data, availability and scale of such datasets are scarce. To our knowledge, there are few extensively practical depression datasets for the Chinese population. In this study, we first create a large-scale dataset by asking subjects to perform five mood-elicitation tasks. After each task, subjects' audio and video are collected, including 3D information (depth information) of facial expressions via a Kinect. The constructed dataset is from a real environment, i.e., several psychiatric hospitals, and has a specific scale. Then we propose a novel approach for potential depression risk recognition based on two kinds of different deep belief network (DBN) models. One model extracts 2D appearance features from facial images collected by an optical camera, while the other model extracts 3D dynamic features from 3D facial points collected by a Kinect. The final decision result comes from the combination of the two models. Finally, we evaluate all proposed deep models on our built dataset. The experimental results demonstrate that (1) our proposed method is able to identify patients with potential depression risk; (2) the recognition performance of combined 2D and 3D features model outperforms using either 2D or 3D features model only; (3) the performance of depression recognition is higher in the positive and negative emotional stimulus, and females' recognition rate is generally higher than that for males. Meanwhile, we compare the performance with other methods on the same dataset. The experimental results show that our integrated 2D and 3D features DBN is more reasonable and universal than other methods, and the experimental paradigm designed for depression is reasonable and practical.
Previous studies have found that patients with subclinical interstitial lung disease (ILD) are highly susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy. In the ...present study we aimed to evaluate the incidence of and risk factors for RP after thoracic intensity-modulated radiation therapy in lung cancer patients with subclinical ILD.
We retrospectively analyzed data from lung cancer patients with subclinical ILD who were treated with thoracic intensity-modulated radiation therapy with a prescribed dose of ≥ 50 Gy in our institution between January 2016 and December 2017.
Eighty-seven consecutive lung cancer patients with subclinical ILD were selected for the study. The median follow-up period was 14.0 months. The cumulative incidence of grades ≥ 2 and ≥ 3 RP at one year was 51.0% and 20.9%, respectively. In the multivariate analysis, a mean lung dose ≥ 12 Gy was a significant risk factor for grade ≥ 2 RP (p = 0.049). Chemotherapy with gemcitabine in the past, V5 ≥ 50%, and subclinical ILD involving ≥ 25% of the lung volume were significantly associated with grade ≥ 3 RP (p = 0.046, p = 0.040, and p = 0.024, respectively).
Mean lung dose is a significant risk factor for grade ≥ 2 RP. Lung cancer patients who have received chemotherapy with gemcitabine in the past, V5 ≥ 50%, and those with subclinical ILD involving ≥ 25% of lung volume have an increased risk of grade ≥ 3 RP in lung cancer patients with subclinical ILD.
In this work, a highly efficient pesticide residue screening and quantification method was established using ultrahigh-performance liquid chromatography–tandem quadrupole time-of-flight mass ...spectrometry based on in-source fragmentation. Over 400 pesticides were tested, among which 96 pesticides displayed in-source fragmentation. A novel concept of in-source fragment fraction was proposed to evaluate the extent of in-source fragmentation, which was found to be chemical structure- and source parameter-dependent. A high-resolution MS/MS library containing 403 pesticides and 126 fragments was created and was applied for library searching of pesticide residues in vegetables and fruits. The introduction of in-source fragments effectively circumvented misannotation and occurrence of false negatives. The quantification ability for the fragments was validated in terms of recovery, linearity, and limit of quantification and its superiority to the parent pesticides was established. Finally, the proposed method was applied for the analysis of real samples and proficiency test samples, and false negative results were successfully avoided in the analysis.
Droughts can severely reduce the productivity of agricultural lands and forests. The United States Department of Agriculture (USDA) Southeast Regional Climate Hub (SERCH) has launched the Lately ...Identified Geospecific Heightened Threat System (LIGHTS) to inform its users of potential water deficiency threats. The system identifies droughts and other climate anomalies such as extreme precipitation and heat stress. However, the LIGHTS model lacks input from soil moisture observations. This research aims to develop a simple and easy-to-interpret soil moisture and drought warning index—standardized soil moisture index (SSI)—by fusing the space-borne Soil Moisture Active Passive (SMAP) soil moisture data with the North American Land Data Assimilation System (NLDAS) Noah land surface model (LSM) output. Ground truth soil moisture data from the Soil Climate Analysis Network (SCAN) were collected for validation. As a result, the accuracy of using SMAP to monitor soil moisture content generally displayed a good statistical correlation with the SCAN data. The validation through the Palmer drought severity index (PDSI) and normalized difference water index (NDWI) suggested that SSI was effective and sensitive for short-term drought monitoring across large areas.
Radiation-induced lung injury (RILI) including radiation-induced pneumonitis and radiation-induced pulmonary fibrosis is a side effect of radiotherapy for thoracic tumors. Azithromycin is a macrolide ...with immunomodulatory properties and anti-inflammatory effects. The immunopathology of RILI that results from irradiation is robust pro-inflammatory responses with high levels of chemokine and cytokine expression. In some patients, pulmonary interstitial fibrosis results usually due to an overactive immune response. Growing clinical studies recently proposed that the anti-inflammatory and immunomodulatory effects of azithromycin may benefit patients with acute lung injury. It has been shown potential benefits for patients with RILI in preclinical studies. Azithromycin has a variety of immunomodulatory effect to improve the process of disease, including inhibition of pro-inflammatory cytokines production participating in the regulatory function of macrophages, changes in autophagy, and inhibition of neutrophil influx. We review the published evidence of mechanisms of azithromycin, and focus on the potential effect of azithromycin on the immune response to RILI.
Summary
The widely used Streptococcus pyogenes Cas9 (SpCas9) requires NGG as a protospacer adjacent motif (PAM) for genome editing. Although SpCas9 is a powerful genome‐editing tool, its use has been ...limited on the targetable genomic locus lacking NGG PAM. The SpCas9 variants xCas9 and Cas9‐NG have been developed to recognize NG, GAA, and GAT PAMs in human cells. Here, we show that xCas9 cannot recognize NG PAMs in tomato, and Cas9‐NG can recognize some of our tested NG PAMs in the tomato and Arabidopsis genomes. In addition, we engineered SpCas9 (XNG‐Cas9) based on mutations from both xCas9 and Cas9‐NG, and found that XNG‐Cas9 can efficiently mutagenize endogenous target sites with NG, GAG, GAA, and GAT PAMs in the tomato or Arabidopsis genomes. The PAM compatibility of XNG‐Cas9 is the broadest reported to date among Cas9s (SpCas9 and Cas9‐NG) active in plant.
In this study, we engineered SpCas9 (XNGCas9) based on mutations from both xCas9 and Cas9‐NG, and found that Cas9‐NG can efficiently mutagenize endogenous target sites with NG, GAG GAA and GAT PAMs in tomato or Arabidopsis genomes. The PAM compatibility of XNG‐Cas9 is the broadest reported to date among Cas9s.
Until the advent of immune checkpoint inhibitors (ICIs), definitive radiotherapy (RT) concurrently with chemotherapy was recommended for unresectable, locally advanced non-small cell lung cancer ...(LA-NSCLC). The trimodality paradigm with consolidation ICIs following definitive concurrent chemoradiotherapy has been the standard of care since the PACIFIC trial. Preclinical evidence has demonstrated the role of RT in the cancer-immune cycle and the synergistic effect of RT combined with ICIs (iRT). However, RT exerts a double-edged effect on immunity and the combination strategy still could be optimized in many areas. In the context of LA-NSCLC, optimized RT modality, choice, timing, and duration of ICIs, care for oncogenic addicted tumors, patient selection, and novel combination strategies require further investigation. Targeting these blind spots, novel approaches are being investigated to cross the borders of PACIFIC. We discussed the development history of iRT and summarized the updated rationale for the synergistic effect. We then summarized the available research data on the efficacy and toxicity of iRT in LA-NSCLC for cross-trial comparisons to eliminate barriers. Progression during and after ICIs consolidation therapy has been regarded as a distinct resistance scenario from primary or secondary resistance to ICIs, the subsequent management of which has also been discussed. Finally, based on unmet needs, we probed into the challenges, strategies, and auspicious orientations to optimize iRT in LA-NSCLC. In this review, we focus on the underlying mechanisms and recent advances of iRT with an emphasis on future challenges and directions that warrant further investigation. Taken together, iRT is a proven and potential strategy in LA-NSCLC, with multiple promising approaches to further improve the efficacy. Video Abstract.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death, partly due to the high recurrence rates for patients with PDAC. Current postoperative surveillance methods, ...including monitoring of clinical symptoms, tumor markers, and CT imaging, lack sensitivity and specificity for minimal residual disease (MRD). We investigated whether the detection of circulating tumor DNA (ctDNA) could identify MRD and predict relapse in postoperative patients with PDAC. In this study, we performed panel-captured sequencing to detect somatic mutations. Matched tissue samples were obtained to verify mutation. A total of 27 patients and 65 plasma samples were included. Among the somatic mutations, KRAS and TP53 were the most recurrent genes in both tissue and plasma samples. The detectable rate of ctDNA increased with the stage of PDAC. The maximal variant allele fraction (VAF) of ctDNA had a positive correlation with tumor largest diameter (
p
= 0.0101). Patients with ctDNA-positive status postoperatively had a markedly reduced disease-free survival (DFS) compared to those with ctDNA-negative status (HR, 5.20;
p
= 0.019). Positive vascular invasion significantly influenced disease-free survival (DFS) (
p
= 0.036), and positive postoperative ctDNA status was an independent prognostic factor for DFS (HR = 3.60; 95% CI, 1.15–11.28;
p
= 0.028). Postoperative ctDNA detection provides strong evidence of MRD and identifies patients with a high risk of relapse. ctDNA detection is a promising approach for personalized patient management during postoperative follow-up.
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