Background and Aims
Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC‐ICC (cHCC‐ICC), is essential for patients’ survival. This ...study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell‐free DNA (cfDNA) fragmentomic profiles.
Approach and Results
Whole‐genome sequencings (WGS) were performed using plasma cfDNA samples from 192 patients with PLC (159 HCC, 26 ICC, 7 cHCC‐ICC) and 170 noncancer controls (including 53 liver cirrhosis LC or HBV‐positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 patients with PLC 157 HCC, 26 ICC, 6 cHCC‐ICC, 164 noncancer controls including 51 LC/HBV). Our model showed excellent performance for cancer detection in the test cohort (AUC: 0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early‐stage PLC (I: 95.9%, II: 97.9%), small tumors (≤3 cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776).
Conclusions
Our model, outperforming previous reports at a lower cost by solely using low‐coverage WGS data, exhibits excellent clinical potential for ultrasensitive and affordable detection of PLC and its subtypes.
The relationship between fine particulate matter (PM
2.5
) and respiratory disease outcomes among children aged 0 to 14 years in Lanzhou, China, was evaluated. We utilized a generalized additive ...model linked by a quasi-Poisson distribution to examine the associations between PM
2.5
and paediatric respiratory outpatient visits for time lags of 0 up to 7 days, and stratified by gender, age, and season. Cases of respiratory disease in children were collected from 3 large hospitals for the years 2014–2017 and then linked with air pollutant concentrations from 4 air quality monitoring stations by date. We observed positive and significant associations between PM
2.5
and respiratory disease from the lag to lag 7, and from lag01 to lag07, with ER reaching the maximum value at lag07. For each 10 μg/m
3
increase in PM
2.5
(lag07), the associated increment in respiratory diseases was 2.83% (95% CI 1.80%–3.86%). Males were more sensitive to the adverse effects, and the association was more significant in spring (from March to May) and winter (from December to the next February). Overall, the child group (age 3–6 years) demonstrated a higher risk of respiratory disease after PM
2.5
exposure. The associations between ambient PM
2.5
and respiratory hospital outpatients among young children became partially attenuated after the adjustment for gaseous pollutants in subgroups. The exposure-response curves were positive and generally nonlinear but flatted at concentrations over 60 μg/m
3
. This research found a significant association between ambient PM
2.5
levels and hospital outpatient visits in child with respiratory diseases in Lanzhou, China.
For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before ...surgery. For patients with clinical complete response (cCR), a "Watch and Wait" (W&W) approach can be adopted to improve quality of life. However, W&W approach may increase the recurrence risk in patients who are judged to be cCR but have minimal residual disease (MRD). Magnetic resonance imaging (MRI) is a major tool to evaluate response to nCRT; however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.
There is limited evidence regarding the associations between air pollution and emergency hospital visits for upper respiratory tract infection (URTI) in the arid regions of northwest China. We ...collected daily emergency department (ED) visits for URTI from three hospitals in Lanzhou during January 2014 and December 2018, as well as daily air pollutants and meteorological factors. In the present study, generalized additive model with quasi-Poisson regression was used to evaluate the relationship between short-term exposure to ambient pollutants and daily emergency hospital visits for URTI in Lanzhou, China. Furthermore, subgroup analyses were conducted by gender (male and female), age (0–14, 15–64, and ≥ 65 years)), and season (cold season, warm season). The results of the single-pollutant model show that the associations of PM
2.5
, PM
10
, SO
2
, NO
2
, and CO with URTI ED visits were all statistically significant, whereas we observed insignificant associations of O
3
8h. The highest association of each pollutant with hospital emergency visits was observed with PM
2.5
(5.302% (95% CI: 3.202, 7.445)), PM
10
(0.808% (95% CI: 0.291, 1.328)), SO
2
(10.607% (95% CI: 5.819, 15.611)), and NO
2
(5.325% (95% CI: 2.379, 8.357)) at lag 07 for an increase of 10 ug/m
3
in concentrations of the pollutants. Percentage increase for each 1-mg/m
3
increase in CO was 20.799% (95% CI: 11.834, 30.482) at lag 07. In the stratification analyses, females were more susceptible to PM
2.5
and PM
10
, while males were more sensitive to the effects of SO
2
, NO
2
, and CO, and the higher association effect of four pollutants (PM
2.5
, SO
2
, NO
2
, and CO) on hospital visits for URTI among children (0–14 years). The associations appeared to be stronger in the cool season than in the warm season. This study suggests that short-term exposure to air pollution, especially to SO
2
and CO, was associated with increased risk of hospital emergency visits for URTI in Lanzhou, China. Relevant strategies and health interventions should be strengthened to reduce the air pollution level in the future.
Until now, a number of epidemiological studies have focused on the association between ambient particulate matter pollution and chronic obstructive pulmonary disease (COPD), especially in developed ...countries. There are limited evidences on the association between short-term exposure to particulate matters (PM
2.5
, PM
C
, and PM
10
) and overall hospital outpatient visits for COPD at the same time in China. Thus, a time-series analysis on the short-term association between three subtypes of PM (PM
2.5
, PM
C
, and PM
10
) and daily hospital outpatients for COPD in Lanzhou, China was conducted, from 2014 to 2017.An over dispersed, generalized additive model was used to analyze the associations after controlling for time trend, weather conditions, day of the week, and holidays. Stratified analyses were also performed by age and gender. The results disclosed that a 10-μg/m
3
increase in PM
2.5
concentration at a lag of 0–7 days was associated with 1.190% (95% CI 0.176~2.215%). For PM
c
, therewere not statistically significant effects at any lag days, but we could find the greatest effect at lag07 that a 10-μg/m
3
increase in concentration was associated with 0.014% (95% CI − 0.065~0.093%). PM
10
also exerted a high effect for COPD (0.185% increase; 95% CI − 0.046~0.417%) when 6 days of exposures (lag6), however, no significance relationship could be found. For COPD among males, positive results were observed for PM
2.5
with lags of 0–7 days, a 10-μg/m
3
increase was 1.184% (95% CI 0.095~2.284%). The effect of PM
2.5
on females was also most significant at lag07, a 10-μg/m
3
increase was 1.254% (95% CI 0.053~2.469%). For those aged < 65 years old, PM
2.5
was not statistically significant at all lag days, but it reached the maximum at lag07, a 10-μg/m
3
increase was 0.978% (95% CI − 0.139~2.108%). For those aged 65 ≥ years old and older, PM
2.5
had a statistically significant lag effect at lag1, lag2, lag3, lag02, lag03, lag04, lag05, lag06, and lag07, and it was most significant at lag07; a 10-μg/m
3
increase was 1.906% (95% CI 0.553~3.277%). Short-term exposure to PM
2.5
was associated with increased risk of hospital visits for COPD. In particular, the elderly (aged ≥ 65 years old) and males were relatively more sensitive to PM
2.5
, and were affected right away after the PM
2.5
concentration went up.
Pleural effusion (PE) is commonly observed in advanced lung cancer and was suggested to contain both cell-free tumor DNA and tumor cells. Molecular profiling of PE represents a minimally invasive ...approach of detecting tumor driver mutations for clinical decision making, especially when tumor tissues are not available. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples to address the feasibility in clinical use.
Sixty-three metastatic lung cancer patients with (n=30, cohort 1) or without (n=33, cohort 2) matched tumor tissues were enrolled in this study. PE and plasma samples of each patient were collected simultaneously. Supernatant and cell precipitate of PE were processed separately to extract cfDNA (PE-cfDNA) and sediment DNA (sDNA). All samples were subjected to targeted next-generation sequencing (NGS) of 416 cancer-related genes.
PE supernatants contain more abundant tumor DNA than PE sediments and plasma samples, suggested by higher mutant allele frequencies (MAF) and elevated mutation detection rate in PE-cfDNA (98.4% vs. 90.5% in PE sDNA vs. 87% in plasma cfDNA). In Cohort 1 with matched tumor tissue, tumor mutational burden (TMB) of PE-cfDNA was similar as tumor tissues (6.4 vs. 5.6), but significantly higher than PE sDNA (median TMB: 3.3) and plasma cfDNA (median TMB: 3.4). Ninety-three percent (27 out of 29) of tissue-determined driver mutations were detected in PE-cfDNA, including alterations in
,
,
,
,
, and
, while only 62% were captured in plasma cfDNA. PE-cfDNA also has the highest detection rate of
driver mutations in the full cohort (71% vs. 68% in PE sDNA vs. 59% in plasma cfDNA). Mutation detection from cytological negative and hemorrhagic PE is challenging. Comparatively, PE-cfDNA demonstrated absolute superiority than PE sDNA in such a scenario, suggesting that it is an independent source of tumor DNA and therefore less influenced by the abundance of tumor cells.
Genomic profiling of PE-cfDNA offers an alternative, and potentially more meticulous approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. Our data further demonstrate that in hemorrhagic or cytologically negative PE samples, PE-cfDNA has higher mutation detection sensitivity than sDNA and plasma cfDNA, and therefore is a more reliable source for genetic testing.
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airway that represents a large global disease burden. Inflammation is a prominent feature of COPD and ...represents an important target for treatment. Toll‐like receptors (TLRs) are pattern recognition receptors that detect invading microorganisms and nonmicrobial endogenous molecules to trigger inflammatory responses during host defense and tissue repair. The TLR signaling pathway is closely linked to the pathogenesis of COPD. Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, is well known for its anti‐inflammatory activities. However, the molecular function of SFN in inhibition of COPD inflammation has yet to be fully elucidated. In this study, we investigated the effects of SFN on lipopolysaccharide (LPS)‐ or Pam3CysSerLys4 (Pam3CSK4)‐induced inflammation in monocyte‐derived macrophages (MDMs) from patients with COPD. MDMs from patients with COPD showed higher expression levels of TLR2, TLR4 and downstream myeloid differentiation factor 88 (MyD88) than healthy controls, along with increased secretion of interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α) (P < 0.05). Stimulation with TLR ligands (Pam3CSK4 and LPS) up‐regulated the levels of TLR2, TLR4 and MyD88 in MDMs from patients with COPD and induced the release of IL‐6 and TNF‐α (P < 0.05). Pretreatment of MDMs from patients with COPD with SFN significantly suppressed Pam3CSK4‐ or LPS‐induced TLR2, TLR4 and MyD88 expression, along with a reduction in the production of IL‐6 and TNF‐α (P < 0.05). Collectively, these data indicate that SFN exerts its anti‐inflammatory activity in COPD by modulating the TLR pathway. SFN may represent a potential therapeutic agent for the treatment of COPD.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airway, and toll‐like receptors play important roles in the regulation of inflammatory processes. In this study, we report that sulforaphane exerts anti‐inflammatory activity via the toll‐like receptor pathway in macrophages from patients with COPD. Sulforaphane may have potential as a new therapeutic approach for the anti‐inflammatory treatment of COPD.
Previous studies on liquid biopsy-based early detection of advanced colorectal adenoma (advCRA) or adenocarcinoma (CRC) were limited by low sensitivity. We performed a prospective study to establish ...an integrated model using fragmentomic profiles of plasma cell-free DNA (cfDNA) for accurately and cost-effectively detecting early-stage CRC and advCRA. The training cohort enrolled 310 participants, including 149 early-stage CRC patients, 46 advCRA patients and 115 healthy controls. Plasma cfDNA samples were prepared for whole-genome sequencing. An ensemble stacked model differentiating healthy controls from advCRA/early-stage CRC patients was trained using five machine learning models and five cfDNA fragmentomic features based on the training cohort. The model was subsequently validated using an independent test cohort (N = 311; including 149 early-stage CRC, 46 advCRA and 116 healthy controls). Our model showed an area under the curve (AUC) of 0.988 for differentiating advCRA/early-stage CRC patients from healthy individuals in an independent test cohort. The model performed even better for identifying early-stage CRC (AUC 0.990) compared to advCRA (AUC 0.982). At 94.8% specificity, the sensitivities for detecting advCRA and early-stage CRC reached 95.7% and 98.0% (0: 94.1%; I: 98.5%), respectively. Promisingly, the detection sensitivity has reached 100% and 97.6% in early-stage CRC patients with negative fecal occult or CEA blood test results, respectively. Finally, our model maintained promising performances (AUC: 0.982, 94.4% sensitivity at 94.8% specificity) even when sequencing depth was down-sampled to 1X. Our integrated predictive model demonstrated an unprecedented detection sensitivity for advCRA and early-stage CRC, shedding light on more accurate noninvasive CRC screening in clinical practice.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and ...neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the -187 to -2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation.
Recent findings indicate that air pollution contributes to the onset and advancement of chronic obstructive pulmonary disease (COPD). Nevertheless, there is insufficient research indicating that air ...pollution is linked to COPD in the region of inland northwest China. Daily hospital admission records for COPD, air pollutant levels, and meteorological factor information were collected in Jiuquan for this study between 1 January 2018 and 31 December 2019. We employed a distributed lag non-linear model (DLNM) integrated with the generalized additive model (GAM) to assess the association between air pollution and hospital admissions for COPD with single lag days from lag0 to lag7 and multiday moving average lag days from lag01 to lag07. For example, the pollutant concentration on the current day was lag0, and on the prior 7th day was lag7. The present and previous 7-day moving average pollutant concentration was lag07. Gender, age, and season-specific stratified analyses were also carried out. It is noteworthy that the delayed days exhibited a different pattern, and the magnitude of associations varied. For NO
and CO, obvious associations with hospitalizations for COPD were found at lag1, lag01-lag07, and lag03-lag07, with the biggest associations at lag05 and lag06 RR = 1.015 (95%CI: 1.008, 1.023) for NO
, RR = 2.049 (95%CI: 1.416, 2.966) for CO, while only SO
at lag02 was appreciably linked to hospitalizations for COPD 1.167 (95%CI: 1.009, 1.348). In contrast, short-term encounters with PM
, PM
, and O
were found to have no significant effects on COPD morbidity. The lag effects of NO
and CO were stronger than those of PM
and PM
. Males and those aged 65 years or older were more vulnerable to air pollution. When it came to the seasons, the impacts appeared to be more pronounced in the cold season. In conclusion, short-term encounters with NO
and CO were significantly correlated with COPD hospitalization in males and the elderly (≥65).
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