Publications by authors named "Ming Lu"

882 Publications

Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer's Disease Dementia.

J Alzheimers Dis Rep 2021 Apr 29;5(1):321-336. Epub 2021 Apr 29.

Eli Lilly and Company, Indianapolis, IN, USA.

Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ) and Aβ concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer's disease (AD).

Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia.

Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline.

Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo.

Conclusion: LY3202626 tested at doses generating 70-90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.
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http://dx.doi.org/10.3233/ADR-210296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150257PMC
April 2021

Radiomics Analysis for Predicting Malignant Potential of Intraductal Papillary Mucinous Neoplasms of the Pancreas: Comparison of CT and MRI.

Acad Radiol 2021 Jun 7. Epub 2021 Jun 7.

Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Rd, Nanjing 210029, China. Electronic address:

Rationale And Objectives: To compare the performance of CT and MRI radiomics for predicting the malignant potential of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to investigate their value compared to the revised 2017 international consensus Fukuoka guidelines.

Materials And Methods: Sixty patients with surgically confirmed IPMNs (37 malignant and 23 benign) were included. Radiomics features were extracted from arterial and venous phase images of CT and T2-weighted images of MRI, respectively. Intraclass correlation coefficients for the radiomics features were calculated to assess the interobserver reproducibility. The least absolute shrinkage and selection operator algorithm was used for feature selection. Radiomics models were constructed based on selected features with logistic regression (LR) and support vector machine (SVM). A clinical and imaging model was constructed based on independent predictors of the revised 2017 Fukuoka guidelines determined in multivariate logistic regression with forward elimination.

Results: The reproducibility of MRI radiomics features was higher than that of CT radiomics features, regardless of arterial or venous phase features (all p < 0.001). MRI radiomics models achieved improved AUCs (0.879 with LR and 0.940 with SVM, respectively), than that of CT radiomics models (0.811 with LR and 0.864 with SVM, respectively). All radiomics models provided better predictive performance than the clinical and imaging model (AUC = 0.764).

Conclusion: The MRI radiomics models with higher reproducibility radiomics features performed better than CT radiomics models for predicting the malignant potential of IPMNs. The performance of radiomics models was superior to the clinical and imaging model based on Fukuoka guidelines.
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http://dx.doi.org/10.1016/j.acra.2021.04.013DOI Listing
June 2021

Clinicopathological features and lymph node and distant metastasis patterns in patients with gastroenteropancreatic mixed neuroendocrine-non-neuroendocrine neoplasm.

Cancer Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, China.

Objective: Owing to its rarity and heterogeneity, the biological behavior and optimal therapeutic management of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) have not been established. Herein, we aimed to evaluate the clinicopathological characteristics and metastatic patterns of MiNEN.

Methods: Continuous clinicopathological data of MiNEN patients treated at our hospital were retrospectively collected and analyzed.

Results: This study had enrolled 169 patients since January 2010 to January 2020. Pathological components were assessed in 129 patients with MiNEN (76.3%), and a focal (non-)neuroendocrine component was observed in 40 patients (23.7%; <30% of the tumor). Among the enrolled patients, 80 underwent surgical removal of the primary tumor and lymph nodes (LNs), and 34 with distant metastasis underwent biopsy of both primary tumor and metastatic lesions. In patients with LN metastasis, 68.8% (55/80) exhibited a pure component of either neuroendocrine (NE) or adenocarcinoma/squamous carcinoma (AS) in metastatic LNs, while 20% (16/80) showed different components in different LNs, and only 11.2% (9/80) exhibited both NE and AS components in the same LN. In patients with distant metastases, 26.5% (9/34) possessed coexisting NE and AS components in the distant metastases, 70.6% (24/34) were regarded as a pure NE component, and 2.9% (1/34) were comprised of a pure AS component.

Conclusion: Lymph node and distant metastases exhibited distinct metastatic patterns in patients with MiNEN. The major pathological component in regional LNs may have influenced the proportion of the two components within the primary tumor, but distant metastases were dominated by the NE component.
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http://dx.doi.org/10.1002/cam4.4031DOI Listing
June 2021

Individualized Nomogram for Predicting Survival in Patients with Brain Metastases After Stereotactic Radiosurgery Utilizing Driver Gene Mutations and Volumetric Surrogates.

Front Oncol 2021 13;11:659538. Epub 2021 May 13.

Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China.

It is well-known that genomic mutational analysis plays a significant role in patients with NSCLC for personalized treatment. Given the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS. Patients with BM and treated by SRS were eligible in this study. The primary endpoint was overall survival (OS). Cox regression models were used to identify independent prognostic factors. A survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. From January 2016 to December 2019, a total of 356 BM patients were eligible. The median OS was 17.7 months [95% confidence interval (CI) 15.5-19.9] and the actual OS at 1- and 2-years measured 63.2 and 37.6%, respectively. A nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, gene mutation status, and serum lactate dehydrogenase. The nomogram was validated in a separate cohort and demonstrated good calibration and good discriminative ability (C-index = 0.780, AUC = 0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced when compared with classical prognostic indices, including the Graded Prognostic Assessment (0.708), recursive partitioning analysis (0.587), and the SRS (0.536). Kaplan-Meier curves showed significant differences in OS among the stratified low-, median- and high-risk groups ( < 0.001). In conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry, and molecular biological surrogates. Although this nomogram should be validated by independent external study, it has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.
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http://dx.doi.org/10.3389/fonc.2021.659538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158152PMC
May 2021

Head-to-head comparison of the test performance of self-administered qualitative vs. laboratory-based quantitative fecal immunochemical tests in detecting colorectal neoplasm.

Chin Med J (Engl) 2021 May 19;134(11):1335-1344. Epub 2021 May 19.

Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Background: Fecal immunochemical tests (FITs) are the most widely used non-invasive tests in colorectal cancer (CRC) screening. However, evidence about the direct comparison of the test performance of the self-administered qualitative a laboratory-based quantitative FITs in a CRC screening setting is sparse.

Methods: Based on a CRC screening trial (TARGET-C), we included 3144 pre-colonoscopy fecal samples, including 24 CRCs, 230 advanced adenomas, 622 non-advanced adenomas, and 2268 participants without significant findings at colonoscopy. Three self-administered qualitative FITs (Pupu tube) with positivity thresholds of 8.0, 14.4, or 20.8 μg hemoglobin (Hb)/g preset by the manufacturer and one laboratory-based quantitative FIT (OC-Sensor) with a positivity threshold of 20 μg Hb/g recommended by the manufacturer were tested by trained staff in the central laboratory. The diagnostic performance of the FITs for detecting colorectal neoplasms was compared in the different scenarios using the preset and adjusted thresholds (for the quantitative FIT).

Results: At the thresholds preset by the manufacturers, apart from the qualitative FIT-3, significantly higher sensitivities for detecting advanced adenoma were observed for the qualitative FIT-1 (33.9% [95% CI: 28.7-39.4%]) and qualitative FIT-2 (22.2% [95% CI: 17.7-27.2%]) compared to the quantitative FIT (11.7% [95% CI: 8.4-15.8%]), while at a cost of significantly lower specificities. However, such difference was not observed for detecting CRC. For scenarios of adjusting the positivity thresholds of the quantitative FIT to yield comparable specificity or comparable positivity rate to the three qualitative FITs accordingly, there were no significant differences in terms of sensitivity, specificity, positive/negative predictive values and positive/negative likelihood ratios for detecting CRC or advanced adenoma between the two types of FITs, which was further evidenced in ROC analysis.

Conclusions: Although the self-administered qualitative and the laboratory-based quantitative FITs had varied test performance at the positivity thresholds preset by the manufacturer, such heterogeneity could be overcome by adjusting thresholds to yield comparable specificities or positivity rates. Future CRC screening programs should select appropriate types of FITs and define the thresholds based on the targeted specificities and manageable positivity rates.
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http://dx.doi.org/10.1097/CM9.0000000000001524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183845PMC
May 2021

Genetic analysis of three maize husk traits by QTL mapping in a maize-teosinte population.

BMC Genomics 2021 May 26;22(1):386. Epub 2021 May 26.

Sanya institute of China Agricultural University, Sanya, 572025, China.

Background: The maize husk consists of numerous leafy layers and plays vital roles in protecting the ear from pathogen infection and dehydration. Teosinte, the wild ancestor of maize, has about three layers of small husk outer covering the ear. Although several quantitative trait loci (QTL) underlying husk morphology variation have been reported, the genetic basis of husk traits between teosinte and maize remains unclear.

Results: A linkage population including 191 BCF inbred lines generated from the maize line Mo17 and the teosinte line X26-4 was used to identify QTL associated with three husk traits: i.e., husk length (HL), husk width (HW) and the number of husk layers (HN). The best linear unbiased predictor (BLUP) depicted wide phenotypic variation and high heritability of all three traits. The HL exhibited greater correlation with HW than HN. A total of 4 QTLs were identified including 1, 1, 2, which are associated with HL, HW and HN, respectively. The proportion of phenotypic variation explained by these QTLs was 9.6, 8.9 and 8.1% for HL, HN and HW, respectively.

Conclusions: The QTLs identified in this study will pave a path to explore candidate genes regulating husk growth and development, and benefit the molecular breeding program based on molecular marker-assisted selection to cultivate maize varieties with an ideal husk morphology.
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http://dx.doi.org/10.1186/s12864-021-07723-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152318PMC
May 2021

[Clinical efficacy of different rehabilitation modes for lumbar degenerative diseases after operation].

Zhongguo Gu Shang 2021 May;34(5):406-16

The Fourth Medical Center of PLAGeneral Hospital, Beijing 100048, China.

Objective: To compare clinical effects of different postoperative rehabilitation modes on lumbar degenerative diseases, and explore influence of rehabilitation mode and other factors on postoperative effect.

Methods: From June 2013 to July 2016, totally 900 patients were admitted from nine tertiary hospitals in Beijing to perform single segment bone grafting and internal fixation due to lumbar degenerative diseases were prospectively analyzed. There were 428 males and 472 females, the age of patient over 18 years old, with an average of (51.42±12.41) years old;according to patients' subjective wishes and actual residence conditions, all patients were divided into three groups, named as observation group 1 (performed integrated rehabilitation approach and orthopedic treatment model intervention), observation group 2 (performed integrated rehabilitation approach and orthopedic treatment, classified rehabilitation model intervention), and control group(performed routine rehabilitation model intervention). Visual analogue scale(VAS), Oswestry Disability Index(ODI) and Japanese Orthopaedic Association (JOA) were used to evaluate postoperative efficacy among three groups at 24 weeks. Possible factors affecting the postoperative efficacy including age, age grouping, gender, body mass index (BMI), BMI grouping, education level, visiting hospital, payment method of medical expenses, preoperative complications, preoperative JOA score, clinical diagnosis, surgery section, operative method, intraoperative bleeding volume, postoperative complications and rehabilitation mode were listed as independent variables, and postoperative ODI score at 24 weeks as dependent variables. Univariate analysis was used to analyze relationship between influencing factors and postoperative efficacy. Multiple linear regression was used to analyze relationship between influencing factors, rehabilitation mode and postoperative ODI score at 24 weeks, in further to find out the main reasons which affect postoperative efficacy, and to analyze impact of rehabilitation mode on postoperative efficacy.

Results: All patients were followed up for 24 weeks after operation. All incisions healed at stage I with stable internal fixation. (1)Evaluation of postoperative efficacy:① There were no statistical differences in preoperative VAS and ODI among three groups(>0.05), the degree of pain and dysfunction decreased among three groups after operation, and had differences in postoperative VAS and ODI among three groups (<0.05). There were no significant differences between observation group 1 and observation group 2(>0.05); while compared with observation group 1 and control group, observation group 2 and control group, there were significant differences (<0.05). ②The function among three groups were improved in varying degrees after operation. There was difference in JOA score among three groups before operation and 24 weeks after operation (<0.05). There were no difference in JOA score among three groups between observation group 1 and observation group 2 (>0.05);while compared with observation group 1 and control group, observation group 2 and control group, there were significant differences (<0.05). (2)Influencing factors at 24 weeks after operation:①Univariate analysis showed gender, age, age grouping, education level, preoperative complications, clinical diagnosis, operative section, operative method, preoperative JOA score and rehabilitation mode had statistical significance with postoperative ODI score at 24 weeks (<0.05). BMI, BMI grouping, payment method of medical expenses, visiting hospital, intraoperative bleeding volume, postoperative complications had no statistical significance with postoperative ODI score at 24 weeks (<0.05).②Multivariate analysis results showed gender, rehabilitation mode, age, preoperative JOA score entered the equation eventually, stepwise multiple linear equation obtained had statistical significance (=12.294, = 0.000). Among rehabilitation mode, standardized regression coefficient of the integrated rehabilitation approach and orthopedic treatment with classified rehabilitation model was absolute value of the largest (0.176), which had the greatest influence on postoperative curative effect. The degree of dysfunction in control group was higher than that in observation group 1 and observation group 2. Postoperative dysfunction was more severe in males than that of in females. Older age has higher degree of dysfunction after operation. Lower preoperative JOA score has higher degree of dysfunction after operation.

Conclusion: Preoperative JOA score, gender, age could predict postoperative clinical effects of lumbar degenerative diseases in varying degrees treated with single level bone graft fusion and internal fixation. Different rehabilitation modes could improve clinical effects. Intergrated rehabilitation orthopedic treatment model and integrated rehabilitation approach and orthopedic treatment with classifiedrehabilitation model are superior to conventional rehabilitation model in improving patients' postoperative function and relieving pain, which is worthy of promoting in clinical.
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http://dx.doi.org/10.12200/j.issn.1003-0034.2021.05.004DOI Listing
May 2021

Facile Electrochemical Microbiosensor Based on Self-Assembly of Ag Nanoparticles Coated on TiCT for Measurements of Chloride Ions in the PD Mouse Brain.

Anal Chem 2021 Jun 20;93(21):7647-7656. Epub 2021 May 20.

A Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, P. R. China.

Chloride ion (Cl), one of the most important anions in the brain, has been confirmed to participate in the pathological process of Parkinson's disease (PD). As such, the development of a reliable method for measurements of Cl is extremely appealing, especially for understanding the pathogenesis of PD. We herein designed a facile electrochemical microbiosensor (ECMB), based on self-assembly of Ag nanoparticles (Ag NPs) coated on TiCT. The uniform nanosized Ag NPs were reduced by TiCT by a simple dipping process, endowing the ECMB with excellent specificity toward Cl detection and remarkably reproducible preparation process. Meanwhile, electro-oxidized graphene oxide was introduced as an inner reference, thus avoiding the environmental interference of the complicated brain systems to increase the determination accuracy. An extensive study revealed that the proposed ECMB would be a robust candidate for real-time monitoring of Cl in the PD mouse brain with high selectivity, accuracy, and reproducibility. Moreover, the availability and reliability toward Cl monitoring of the designed ECMB were well confirmed by comparing with the standard Volhard's method. Finally, by virtue of the successful employment of the developed detecting platform in the measurement of Cl in the PD mouse brain, systematic analysis and comparison of the average levels of Cl in the three regions including cortex, striatum, and hippocampus of brains from normal and PD model mice have been achieved.
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http://dx.doi.org/10.1021/acs.analchem.1c00342DOI Listing
June 2021

Let-7b-3p inhibits tumor growth and metastasis by targeting the BRF2-mediated MAPK/ERK pathway in human lung adenocarcinoma.

Transl Lung Cancer Res 2021 Apr;10(4):1841-1856

Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Background: Lung cancer is a malignant tumor with the highest morbidity and mortality rates worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Overall, current treatments of LUAD are not satisfactory; therefore, novel targets need to be explored. Let-7b-3p is an important member of the let-7 family of microRNAs (miRNAs), and has not been studied separately in LUAD. This study aimed to investigate the role and molecular mechanism of let-7b-3p in LUAD.

Methods: Herein, let-7b-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence hybridization (FISH) assays. MTT, colony formation assay, flow cytometry analysis, wound-healing, Transwell and experiments were conducted to assess let-7b-3p's function in LUAD. The downstream target TFIIB-related factor 2 (BRF2) was predicted using bioinformatics analyses and confirmed by dual-luciferase reporter assay and rescue experiments. Additionally, BRF2 was found to affect the MAPK/ERK pathway through transcriptome sequencing analysis and western blot (WB) assay.

Results: Let-7b-3p is downregulated in LUAD cells and tissue samples and low let-7b-3p expression is correlated with a poor prognosis in LUAD patients. Let-7b-3p suppresses the proliferation and metastasis of LUAD cells both and by directly targeting the BRF2-mediated MAPK/ERK pathway.

Conclusions: Let-7b-3p inhibits the development of LUAD and is an ideal novel therapeutic target for the treatment of LUAD.
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http://dx.doi.org/10.21037/tlcr-21-299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107730PMC
April 2021

Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.

Theranostics 2021 27;11(13):6560-6572. Epub 2021 Apr 27.

Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200040, China.

Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.
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http://dx.doi.org/10.7150/thno.55609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120208PMC
April 2021

Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress.

J Bioenerg Biomembr 2021 May 10. Epub 2021 May 10.

Department of Gynaecology, ZIBO Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255036, Shandong, China.

Hypoxia can promote the progression and metastasis of ovarian cancer, while the underlying mechanisms are still unclear. Hypoxia culture or CoCl2 induced-oxygen deprivation condition could promote SKOV3 cells to express cyclooxygenase-2 (COX2). Luciferase assay indicates that hypoxia-inducible factor 1α (HIF1α) could bind directly with the promoter region of COX2 to promote the transcription. COX2 over-expressed SKOV3 cells show up-regulated stemness-related markers expression, proinflammatory gene expression, and increased tumor sphere formation. The inflammatory molecules (interleukin-6, C-X-C motif chemokine ligand 12, interleukin-1B, interleukin-10, and C-C motif chemokine ligand 2) and COX2 expression show positive correlations in the Cancer Genome Atlas data. COX2 over-expression could promote SKOV3 cell proliferation in the subcutaneous tumor model and metastasis in the transfer model. In conclusion, hypoxia-induced HIF-1α mediated COX2 expression could promote the proliferation, inflammation, and metastasis of ovarian cancer.
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http://dx.doi.org/10.1007/s10863-021-09900-9DOI Listing
May 2021

Global, regional and national burden of anxiety disorders from 1990 to 2019: results from the Global Burden of Disease Study 2019.

Epidemiol Psychiatr Sci 2021 May 6;30:e36. Epub 2021 May 6.

Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.

Aims: Anxiety disorders are widespread across the world. A systematic understanding of the disease burden, temporal trend and risk factors of anxiety disorders provides the essential foundation for targeted public policies on mental health at the national, regional, and global levels.

Methods: The estimation of anxiety disorders in the Global Burden of Disease Study 2019 using systematic review was conducted to describe incidence, prevalence and disability-adjusted life years (DALYs) in 204 countries and regions from 1990 to 2019. We calculated the estimated annual percentage change (EAPC) to quantify the temporal trends in anxiety disorders burden by sex, region and age over the past 30 years and analysed the impact of epidemiological and demographic changes on anxiety disorders.

Results: Globally, 45.82 [95% uncertainty interval (UI): 37.14, 55.62] million incident cases of anxiety disorders, 301.39 million (95% UI: 252.63, 356.00) prevalent cases and 28.68 (95% UI: 19.86, 39.32) million DALYs were estimated in 2019. Although the overall age-standardised burden rate of anxiety disorders remained stable over the past three decades, the latest absolute number of anxiety disorders increased by 50% from 1990. We observed huge disparities in both age-standardised burden rate and changing trend of anxiety disorders in sex, country and age. In 2019, 7.07% of the global DALYs due to anxiety disorders were attributable to bullying victimisation, mainly among the population aged 5-39 years, and the proportion increased in almost all countries and territories compared with 1990.

Conclusion: Anxiety disorder is still the most common mental illness in the world and has a striking impact on the global burden of disease. Controlling potential risk factors, such as bullying, establishing effective mental health knowledge dissemination and diversifying intervention strategies adapted to specific characteristics will reduce the burden of anxiety disorders.
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http://dx.doi.org/10.1017/S2045796021000275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157816PMC
May 2021

AI-based pathology predicts origins for cancers of unknown primary.

Nature 2021 Jun 5;594(7861):106-110. Epub 2021 May 5.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Cancer of unknown primary (CUP) origin is an enigmatic group of diagnoses in which the primary anatomical site of tumour origin cannot be determined. This poses a considerable challenge, as modern therapeutics are predominantly specific to the primary tumour. Recent research has focused on using genomics and transcriptomics to identify the origin of a tumour. However, genomic testing is not always performed and lacks clinical penetration in low-resource settings. Here, to overcome these challenges, we present a deep-learning-based algorithm-Tumour Origin Assessment via Deep Learning (TOAD)-that can provide a differential diagnosis for the origin of the primary tumour using routinely acquired histology slides. We used whole-slide images of tumours with known primary origins to train a model that simultaneously identifies the tumour as primary or metastatic and predicts its site of origin. On our held-out test set of tumours with known primary origins, the model achieved a top-1 accuracy of 0.83 and a top-3 accuracy of 0.96, whereas on our external test set it achieved top-1 and top-3 accuracies of 0.80 and 0.93, respectively. We further curated a dataset of 317 cases of CUP for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 61% of cases and a top-3 agreement of 82%. TOAD can be used as an assistive tool to assign a differential diagnosis to complicated cases of metastatic tumours and CUPs and could be used in conjunction with or in lieu of ancillary tests and extensive diagnostic work-ups to reduce the occurrence of CUP.
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http://dx.doi.org/10.1038/s41586-021-03512-4DOI Listing
June 2021

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Gastric Cancer 2021 May 4. Epub 2021 May 4.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Hai-Dian District, Fu-Cheng Road 52, Beijing, 100142, China.

Purpose: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients And Methods: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical Trial Information: NCT02881190.
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http://dx.doi.org/10.1007/s10120-021-01168-7DOI Listing
May 2021

Clinical Outcomes of Hip Arthroscopy for Hip Labrum Calcification in Young and Middle-Aged Patients.

Orthop Surg 2021 May 4. Epub 2021 May 4.

Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China.

Objective: To investigate the methods and outcomes of hip arthroscopy for hip labrum calcification, and to discuss the clinical, imaging, and intraoperative findings of hip labrum calcification.

Methods: This is a therapeutic case series study. From January 2015 to June 2018, 15 patients who met the inclusion and exclusion criteria were followed up for at least 2 years for an analysis on the outcomes of arthroscopy in the treatment of hip labrum calcification and the clinical, imaging, and intraoperative findings of the patients. There were eight males and seven females, with an average age of 38.9 ± 8.8 years (range, 23-50 years). The visual analog scale (VAS), the modified Harris hip score (mHSS), and the international hip outcome tool (iHOT-12) were used to evaluate the outcomes of surgery.

Results: A total of 15 patients were followed up for at least 2 years (28.1 ± 2.9 months). The average calcified volume was 118.0 mm (range, 19.4-609.2 mm ) and calcified volume was related to the preoperative hip function score. Thirteen patients had pain in the groin area (86.7%). Labrum calcifications were located (according to the clock distribution) as follows: 14 patients were anterior and superior (11:00-3:00); 12 cases of femoroacetabular impingement (FAI) were observed during operation, including five cases of pincer type, two cases of cam type, and five cases of mixed type. VAS pain score means were 7.73 ± 1.28 before surgery, decreasing to 2.0 ± 0.89 and 1.73 ± 0.79 at 1 and 2 years post-surgery, respectively. mHSS scores were 57.40 ± 6.23 before surgery and 82.10 ± 4.76 and 83.18 ± 4.07, 1 and 2 years post-surgery, respectively; iHOT-12 mean score pre-surgery was 37.67 ± 4.85, increasing to 67.64 ± 5.30 and 72.18 ± 4.49, 1 and 2 years post-surgery, respectively. Compared with preoperative values, postoperative VAS, mHSS, and iHOT-12 scores were significantly improved (P < 0.01); iHOT-12 scores also significantly decreased from 1 to 2 years postoperatively (P = 0.034). No patient had complications.

Conclusion: Hip arthroscopy is an effective method for the treatment of hip labrum calcification. The size of calcification influenced preoperative symptoms and function. Long-term irritation from FAI may be one important cause of labrum calcification.
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http://dx.doi.org/10.1111/os.12998DOI Listing
May 2021

Tübingen hip flexion splint more successful than Pavlik harness for decentred hips after the age of three months.

Bone Joint J 2021 May;103-B(5):991-998

Department of Pediatric Orthopaedics, Beijing Jishuitan Hospital, Beijing, China.

Aims: The objective of this study was to evaluate the clinical and radiological outcomes of patients younger than six months of age with developmental dysplasia of the hip (DDH) managed by either a Pavlik harness or Tübingen hip flexion splint.

Methods: Records of 251 consecutive infants with a mean age of 89 days (SD 47), diagnosed with DDH between January 2015 and December 2018, were retrospectively reviewed. Inclusion criteria for patients with DDH were: younger than 180 days at the time of diagnosis; ultrasound Graf classification of IIc or greater; treatment by Pavlik harness or Tübingen splint; and no prior treatment history. All patients underwent hip ultrasound every seven days during the first three weeks of treatment and subsequently every three to four weeks until completion of treatment. If no signs of improvement were found after three weeks, the Pavlik harness or Tübingen splint was discontinued. Statistical analysis was performed.

Results: The study included 251 patients with Graf grades IIc to IV in 18 males and 233 females with DDH. Mean follow-up time was 22 months (SD 10). A total of 116 hips were graded as Graf IIc (39.1%), nine as grade D (3.0%), 100 as grade III (33.7%), and 72 as grade IV (24.2%). There were 109 patients (128 hips) in the Pavlik group and 142 patients (169 hips) in the Tübingen group (p = 0.227). The Tübingen group showed a 69.8% success rate in Graf III and Graf IV hips while the success rate was significantly lower in the Pavlik group, 53.9% (p = 0.033). For infants older than three months of age, the Tübingen group showed a 71.4% success rate, and the Pavlik group a 54.4% success rate (p = 0.047).

Conclusion: The Tübingen splint should be the preferred treatment option for children older than three months, and for those with severe forms of DDH such as Graf grade III and IV, who are younger than six months at time of diagnosis. The Tübingen hip flexion splint is a valid alternative to the Pavlik harness for older infants and those with more severe DDH. Cite this article:  2021;103-B(5):991-998.
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http://dx.doi.org/10.1302/0301-620X.103B5.BJJ-2020-1946.R1DOI Listing
May 2021

Oxygen-Enriched Metal-Organic Frameworks Based on 1-(Trinitromethyl)-1-1,2,4-Triazole-3-Carboxylic Acid and Their Thermal Decomposition and Effects on the Decomposition of Ammonium Perchlorate.

ACS Appl Mater Interfaces 2021 May 30;13(18):21516-21526. Epub 2021 Apr 30.

School of Chemical Engineering, Nanjing University of Science and Technology, Xiaolingwei 200, Nanjing 210094, PR China.

Energetic metal-organic frameworks (EMOFs) with a high oxygen content are currently a hot spot in the field of energetic materials research. In this article, two series of EMOFs with different ligands were obtained by reacting 1-(trinitromethyl)-1H-1,2,4-triazole-3-carboxylic acid (tntrza) with metal iodide and metal nitrate, respectively. Furthermore, their structure, thermal stability, thermal decomposition kinetics, and energy performance are fully characterized. The research results revealed that the synthesized EMOFs possess a wide range of density (ρ = 1.88∼2.595 g cm), oxygen balance (OB(CO) = -21.1∼ -4.3%), and acceptable energy performance ( = 7.73∼8.74 km s and = 28.1∼41.1 GPa). The difference in OB(CO) caused by the ligand structure and metal properties has a great impact on the distribution of gas-phase products after the decomposition of these EMOFs. Noteworthy, [Ag(tntrza)] is particularly prominent among these EMOFs, not only because of its excellent detonation performance ( = 8.74 km s and = 41.1 GPa) endowed by its extremely high density (ρ = 2.595 g cm) and oxygen balance (OB(CO) = -4.3%) but also because of its effective catalytic effect on the decomposition of ammonium perchlorate (AP). This article broadens the horizon for the study of oxygen-enriched EMOFs with catalytic effects and helps understand the mechanism of thermal decomposition of EMOFs with nitroform and dinitro groups.
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http://dx.doi.org/10.1021/acsami.1c03110DOI Listing
May 2021

Changes of Body Mass Index and Body Shape in relation to risk of Gastric Cancer: A population-based case-control study.

J Cancer 2021 23;12(10):3089-3097. Epub 2021 Mar 23.

Fudan University Taizhou Institute of Health Sciences, Taizhou, China.

The results of previous studies are heterogeneous about the effect of body fatness on risk of gastric cancer (GC). Herein we investigated the effect of changes of BMI and body shape on risk of GC. A population-based case-control study enrolled 1989 controls and 937 GC cases. Logistic regression models were used to calculate odd ratios (s) and 95% confidence intervals (s) for BMI and body shape in association with GC risk, according to anatomical subsite, Laurén's classification, sex and () infection. Subjects with higher BMI or body shape 10 years before interview had a lower risk of GC regardless of anatomical subsite, Laurén's classification, and sex (all for trend <0.05). But the relative risk patterns were different by status. When checking the effect of changes of body fatness, in + stratum, the s (95% ) were 0.40 (0.17-0.93) for subjects who were underweight at age 20 but had increased BMI afterwards, and 0.48 (0.32-0.73) for those of body shape 1/2 at age 20 but increased body shape subsequently, compared to subjects with stable BMI or body shape. When subjects had a normal BMI or 3/4 body shape at age 20, weight loss nearly doubled the risk of GC, and weight gain would decrease the risk. The association between body fatness and GC risk might differ by time point of measurement and -infection status. Further, the influence of changes of body fatness might be different by baseline body fatness and -infection status.
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http://dx.doi.org/10.7150/jca.56149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040898PMC
March 2021

TSH activates macrophage inflammation by G13 and G15-dependent pathways.

Endocrinology 2021 Apr 14. Epub 2021 Apr 14.

Scientific Center, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China.

Thyroid-stimulating hormone (TSH) treatment activates IκB/NFκB (p65) and ERK, P38 in macrophages, but how these pathways are activated, and how they contribute to the pro-inflammatory effect of TSH on macrophages remain unknown. TSH receptor (TSHR) is coupled to four subfamilies of G proteins (Gs, Gi/o, Gq/11 and G12/13) for its downstream signalling. This study investigated the G protein subtypes responsible for the pro-inflammatory effect of TSH on macrophages. qPCR showed that Gi2, Gi3, Gas, Gq, G11, G12, G13, G15 are abundantly expressed by macrophages. The contribution of different G-protein pathways to the pro-inflammatory effect was studied by the corresponding inhibitors or siRNA interference. While TSH-induced IκB phosphorylation was not inhibited by Gs inhibitor NF449, Gi inhibitor pertussis toxin, Gq or G11 siRNA, it was blocked by phospholipase C inhibitor U73122 or G15 siRNA interference. TSH-induced ERK and P38 phosphorylation was blocked by G13 but not G12 siRNA interference. Interfering either G13 or G15 was able to block the pro-inflammatory effect of TSH on macrophages. The present study demonstrate that TSH activates macrophage inflammation by G13/ERK-P38/Rho GTPases and G15/PLC/PKCs/IκB pathways.
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http://dx.doi.org/10.1210/endocr/bqab077DOI Listing
April 2021

Circular RNA hsa-circ-000881 suppresses the progression of lung adenocarcinoma via a miR-665/PRICKLE2 axis.

Ann Transl Med 2021 Mar;9(6):498

Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Background: Circular RNA (circRNA) has become a new focus in the field of tumor biology research in recent years. Many circRNAs have been showed to play an important role in the progression of lung adenocarcinoma (LUAD). In this work, we studied the oncological role of hsa-circ-000881 in LUAD and attempted to explore the related mechanism.

Methods: The relative expressions of hsa-circ-000881, miR-665, and PRICKLE2 were detected by RT-qPCR or western blot. Functional assays were conducted to analyze the role of hsa-circ-000881 in the proliferation, migration, and invasion of LUAD cells. A luciferase reporter assay was performed to verify whether hsa-circ-000881, miR-665, and PRICKLE2 interact with each other.

Results: Circ-000881 was remarkably downregulated in LUAD. Overexpression of circ-000881 attenuated cell growth, migration, and invasion, whereas its knockdown enhanced the malignancy of LUAD cells. The results of luciferase reporter assay and bioinformatics analysis confirmed that circ-000881 served as a sponge for miR-665, and PRICKLE2 was a direct target of miR-665.Overexpression of miR-665 or silencing of PRICKLE2 abolished circ-000881-mediated inhibition of malignant tumor behavior in LUAD cells.

Conclusions: Circ-000881 has inhibitory effects on LUAD via a miR-665/PRICKLE2 axis, suggesting that circ-000881 may be an underlying therapeutic target for LUAD.
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http://dx.doi.org/10.21037/atm-21-844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039684PMC
March 2021

Trans-olecranon fracture-dislocation of the elbow in children.

Int Orthop 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatric Orthopedics, Beijing Jishuitan Hospital, Beijing, 100035, China.

Objectives: Trans-olecranon fracture-dislocations are rare in children. To our knowledge, only 12 cases have been described in children till now and the treatment strategy for this injury in children remains unclear. To provide a clear clinical description and more accurate treatment options, we retrospectively reviewed cases with this kind of injury in our institution.

Methods: From 2002 to 2019, eleven cases diagnosed with trans-olecranon fracture-dislocation of the elbow were identified, and their medical charts and radiographs were obtained. All patients underwent open reduction and internal fixation through a posterior approach. At the most recent follow-up visit, all patients were evaluated clinically using the Mayo Elbow Performance Score (MEPS).

Results: The mean follow-up was 22 months (range, 6-42 months). All injuries were unilateral, and there were nine males and two females. The mean age at injury was nine years (range, 4-13 years), and the mean time from injury to surgery was 16.6 days (range, 2-60 days). According to Tiemdjo classification, there was one case with type I injury, one case with type II, six cases with type III, and three cases with type IV. According to the MEPS criteria, the outcomes were excellent in five cases, good in two cases, fair in one case, and poor in three cases. Four patients were delayed cases, who underwent surgery two weeks after injury. The average operation time was significantly longer in four children sustaining delayed surgery (140 ± 43 min, vs. 50 ± 12 min, p < 0.001).

Conclusion: To our knowledge, this is the largest sample size reported to date. We recommend open reduction and internal fixation, using either plates or tension-band techniques, depending on the injury pattern. In addition, we emphasize that early operation could achieve good clinical outcomes.
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http://dx.doi.org/10.1007/s00264-021-05010-8DOI Listing
April 2021

MRI-based radiomics signature for pretreatment prediction of pathological response to neoadjuvant chemotherapy in osteosarcoma: a multicenter study.

Eur Radiol 2021 Mar 30. Epub 2021 Mar 30.

Department of Radiology, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics. Guangdong Province), 183 Zhongshan Da Dao Xi, Guangzhou, 510630, Guangdong, China.

Objective: To develop and validate a radiomics signature based on magnetic resonance imaging (MRI) from multicenter datasets for preoperative prediction of pathologic response to neoadjuvant chemotherapy (NAC) in patients with osteosarcoma.

Methods: We retrospectively enrolled 102 patients with histologically confirmed osteosarcoma who received chemotherapy before treatment from 4 hospitals (68 in the primary cohort and 34 in the external validation cohort). Quantitative imaging features were extracted from contrast-enhanced fat-suppressed T1-weighted images (CE FS T1WI). Four classification methods, i.e., the least absolute shrinkage and selection operator logistic regression (LASSO-LR), support vector machine (SVM), Gaussian process (GP), and Naive Bayes (NB) algorithm, were compared for feature selection and radiomics signature construction. The predictive performance of the radiomics signatures was assessed with the area under receiver operating characteristics curve (AUC), calibration curve, and decision curve analysis (DCA).

Results: Thirteen radiomics features selected based on the LASSO-LR classifier were adopted to construct the radiomics signature, which was significantly associated with the pathologic response. The prediction model achieved the best performance between good and poor responders with an AUC of 0.882 (95% CI, 0.837-0.918) in the primary cohort. Calibration curves showed good agreement. Similarly, findings were validated in the external validation cohort with good performance (AUC, 0.842 [95% CI, 0.793-0.883]) and good calibration. DCA analysis confirmed the clinical utility of the selected radiomics signature.

Conclusion: The constructed CE FS T1WI-radiomics signature with excellent performance could provide a potential tool to predict pathologic response to NAC in patients with osteosarcoma.

Key Points: • The radiomics signature based on multicenter contrast-enhanced MRI was useful to predict response to NAC. • The prediction model obtained with the LASSO-LR classifier achieved the best performance. • The baseline clinical characteristics were not associated with response to NAC.
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http://dx.doi.org/10.1007/s00330-021-07748-6DOI Listing
March 2021

Ischemic-hypoxic preconditioning enhances the mitochondrial function recovery of transplanted olfactory mucosa mesenchymal stem cells via miR-181a signaling in ischemic stroke.

Aging (Albany NY) 2021 04 4;13(8):11234-11256. Epub 2021 Apr 4.

The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410006, Hunan, P.R. China.

Cerebral ischemia/reperfusion injury causes a series of intricate cascade reactions in brain tissue causing apoptosis and proinflammatory programmed cell death known as pyroptosis of nerve cells. The dysfunction of target organelle mitochondria plays a key role in the process of neuronal apoptosis and pyroptosis. Mesenchymal stem cells (MSCs) have been widely used in the experimental or clinical treatment of various ischemic diseases, but the therapeutic efficacy of MSCs on cerebral ischemia-reperfusion injury need to be improved. We successfully cultured olfactory mucosa MSCs (OM-MSCs) to obtain a better source of seed cells. In this way, the therapeutic potential of OM-MSCs transplantation has been evaluated for ischemic stroke using an optimized culture scheme . Ischemic-hypoxic preconditioned OM-MSCs (IhOM-MSCs) were used to treat a neuron model of oxygen-glucose deprivation/reperfusion and the middle cerebral artery occlusion in rats. These results demonstrated that IhOM-MSCs mediated the upregulation of the downstream target genes GRP78 and Bcl-2 by miR-181a to protect mitochondrial function and inhibit apoptosis and pyroptosis of neurons in the ischemia/reperfusion injury model. Thus, IhOM-MSCs transplantation may be an effective therapy of ischemic stroke in the future.
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http://dx.doi.org/10.18632/aging.202807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109091PMC
April 2021

Tumor infiltrating lymphocyte signature is associated with single nucleotide polymorphisms and predicts survival in esophageal squamous cell carcinoma patients.

Aging (Albany NY) 2021 04 4;13(7):10369-10386. Epub 2021 Apr 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Purpose: Esophageal cancer is the sixth leading cause of cancer-related death worldwide, and is associated with a poor prognosis. Stromal tumor infiltrating lymphocytes (sTIL) and certain single nucleotide polymorphisms (SNPs) have been found to be predictive of patient survival. In this study, we explored the association between SNPs and sTIL regarding the predictability of disease-free survival in patients with esophageal squamous cell carcinoma (ESCC).

Materials And Methods: We collected 969 pathologically confirmed ESCC patients from 2010 to 2013 and genotyped 101 SNPs from 59 genes. The number of sTIL for each patient was determined using an automatic algorithm. A Kruskal-Wallis test was used to determine the association between genotype and sTIL. The genotypes and clinical factors related to survival were analyzed using a Kaplan-Meier curve, Cox proportional hazards model, and log-rank test.

Results: The median age of the patients was 67 (42-85 years), there was a median follow-up of 851.5 days and 586 patients died. The univariable analysis showed that 10 of the 101 SNPs were associated with sTIL. Six SNPs were also associated with disease-free survival. A multivariable analysis revealed that sTIL, rs1801131, rs25487, and rs8030672 were independent prognostic markers for ESCC patients. The model combining SNPs, clinical characteristics and sTIL outperformed the model with clinical characteristics alone for predicting outcomes in ESCC patients.

Conclusion: We discovered 10 SNPs associated with sTIL in ESCC and we built a model of sTIL, SNPs and clinical characteristics with improved prediction of survival in ESCC patients.
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http://dx.doi.org/10.18632/aging.202798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064198PMC
April 2021

A nomogram for screening esophageal squamous cell carcinoma based on environmental risk factors in a high-incidence area of China: a population-based case-control study.

BMC Cancer 2021 Mar 31;21(1):343. Epub 2021 Mar 31.

Fudan University Taizhou Institute of Health Sciences, Taizhou, China.

Background: Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors.

Methods: We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design.

Results: Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively).

Conclusions: An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.
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http://dx.doi.org/10.1186/s12885-021-08053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011400PMC
March 2021

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys.

Neuroimage Clin 2021 Mar 23;30:102633. Epub 2021 Mar 23.

Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, TN, USA. Electronic address:

Purpose: The sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at -1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions.

Methods: MRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTR). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREX) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites.

Results: The parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREX of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, -1.6 and -3.5 ppm RF offsets.

Conclusion: These results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREX correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.
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http://dx.doi.org/10.1016/j.nicl.2021.102633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039857PMC
March 2021

The gut microbiome in subclinical atherosclerosis: a population-based multi-phenotype analysis.

Rheumatology (Oxford) 2021 Mar 26. Epub 2021 Mar 26.

State Key Laboratory of Genetic Engineering and Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China.

Background: The altered microbiota, considered as quantitative traits, has also been identified to play pivotal roles in the host vascular physiology and might contribute to diseases. To understand the role of gut microbiota on vascular physiology in the sub-clinical elderly population and how lifestyles affect the composition of host gut microbiota to further impact the pathogenesis of vascular diseases.

Methods: Performed a population-based fecal metagenomic study over 569 elderly asymptomatic sub-clinical individuals in rural China. An association network was built based on clinical measurements and detailed epidemiologic questionnaires, including blood chemistry, arterial stiffness, carotid ultrasonography, and metagenomic datasets.

Results: Carotid arterial atherosclerosis indices, including intima-media thickness (IMT), were shown essentially in the network, and were significantly associated with living habits, socio-economic status, and diet. Using mediation analysis, we found that higher frequency of taking fresh fruits, fresh vegetables, and more exercise significantly reduces carotid arteries atherosclerosis in terms of IMT, PSV and EDV values the through the mediation of Alistepes, Oligella, and Prevotella. The gut microbes explained 16.5% of the mediation effect of lifestyles on the pathogenesis of carotid atherosclerosis. After adjusted, Faecalicatena (OR = 0.20∼0.30) was shown protective in the formation of carotid athersclerosis independently, while Libanicoccus (OR = 2.39∼2.43) were hazardous to carotid arterial IMTs. KEGG/KO analyses revealed a loss of anti-inflammation function in IMT subjects.

Conclusions: Our study provided a Chinese population-wide phenotype-metagenomic network, revealing association and mediation effect of gut microbiota on carotid artery atherosclerosis, hinting at a therapeutic and preventive potential of microbiota in vascular diseases.
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http://dx.doi.org/10.1093/rheumatology/keab309DOI Listing
March 2021

Secular trends in the incidence and survival of all leukemia types in the United States from 1975 to 2017.

J Cancer 2021 22;12(8):2326-2335. Epub 2021 Feb 22.

Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China.

Various studies have indicated that the prognosis of leukemia has been improved in recent years, but the secular trends of incidence and long-term survival of all leukemia have not been thoroughly examined. We estimated the leukemia incidence and 5-year survival rate along with the temporal trends by sex, race, age, and subtype in the United States over the past four decades using Surveillance, Epidemiology, and End Results (SEER) database. The overall incidence of leukemia steadily increased from 12.39/100 000 in 1975 to 14.65/100 000 in 2011, and then began to decline in recent years (13.73/100 000 in 2017), with average annual percent changes (APC) of 0.350 (<0.001). The 5-year relative survival rate of leukemia patients significantly improved from 33.2% in 1975 to 66.1% in 2012 (APC=1.980, <0.001). The main subtypes of leukemia, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia, increased in most age groups; conversely, the incidences of all other subtypes were gradually declined during the monitoring period. The incremental advancement in leukemia prognosis had been achieved in almost all histological subtypes, especially among young patients. Based on SEER data, the leukemia incidence increased gradually over the past decades, and then began to decline in recent years in the United States. The 5-year relative survival rate increased incrementally over time, especially among young patients. However, the huge disparities among different sexes, races, histological subtypes, and age groups, emphasize that precise causes control and innovative treatments need to be developed to reduce the incidence and improve the prognosis, especially among specific populations.
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http://dx.doi.org/10.7150/jca.52186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974881PMC
February 2021

Optimization of a quadrature birdcage coil for functional imaging of squirrel monkey brain at 9.4T.

Magn Reson Imaging 2021 Jun 17;79:45-51. Epub 2021 Mar 17.

Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

A quadrature transmit/receive birdcage coil was optimized for squirrel monkey functional imaging at the high field of 9.4 T. The coil length was chosen to gain maximum coil efficiency/signal-to-noise ratio (SNR) and meanwhile provide enough homogenous RF field in the whole brain area. Based on the numerical simulation results, a 16-rung high-pass birdcage coil with the optimal length of 9 cm was constructed and evaluated on phantom and in vivo experiments. Compared to a general-purpose non-optimized coil, it exhibits approximately 25% in vivo SNR improvement. In addition to the volume coil, details about how to design and construct the associated animal preparation system were provided.
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http://dx.doi.org/10.1016/j.mri.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107140PMC
June 2021