Publications by authors named "Dan Huang"

697 Publications

Classification of colon adenocarcinoma based on immunological characterizations: Implications for prognosis and immunotherapy.

Front Immunol 2022 27;13:934083. Epub 2022 Jul 27.

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Accurate immune molecular typing is pivotal for screening out patients with colon adenocarcinoma (COAD) who may benefit from immunotherapy and whose tumor microenvironment (TME) was needed for reprogramming to beneficial immune-mediated responses. However, little is known about the immune characteristic of COAD. Here, by calculating the enrichment score of immune characteristics in three online COAD datasets (TCGA-COAD, GSE39582, and GSE17538), we identified 17 prognostic-related immune characteristics that overlapped in at least two datasets. We determined that COADs could be stratified into three immune subtypes (IS1-IS3), based on consensus clustering of these 17 immune characteristics. Each of the three ISs was associated with distinct clinicopathological characteristics, genetic aberrations, tumor-infiltrating immune cell composition, immunophenotyping (immune "hot" and immune "cold"), and cytokine profiles, as well as different clinical outcomes and immunotherapy/therapeutic response. Patients with the IS1 tumor had high immune infiltration but immunosuppressive phenotype, IS3 tumor is an immune "hot" phenotype, whereas those with the IS2 tumor had an immune "cold" phenotype. We further verified the distinct immune phenotype of IS1 and IS3 by an in-house COAD cohort. We propose that the immune subtyping can be utilized to identify COAD patients who will be affected by the tumor immune microenvironment. Furthermore, the ISs may provide a guide for personalized cancer immunotherapy and for tumor prognosis.
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http://dx.doi.org/10.3389/fimmu.2022.934083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363576PMC
August 2022

Capabilities of hepatitis B surface antigen are divergent from hepatitis B virus DNA in delimiting natural history phases of chronic hepatitis B virus infection.

Front Immunol 2022 25;13:944097. Epub 2022 Jul 25.

Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Objective: Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA in the natural history of chronic HBV infection have not been rationally evaluated. This study aimed to re-characterize quantitative HBsAg and HBV DNA in the natural history phases.

Methods: A total of 595 and 651 hepatitis B e antigen (HBeAg)-positive patients and 485 and 705 HBeAg-negative patients were assigned to the early and late cohorts, respectively. Based on the 'S-shape' receiver operating characteristic (ROC) curves, the HBeAg-positive sub-cohorts with possibly high HBV replication (PHVR) and possibly low HBV replication (PLVR) and the HBeAg-negative sub-cohorts with possibly high HBsAg expression (PHSE) and possibly low HBsAg expression (PLSE) were designated.

Results: The areas under the ROC curve (AUCs) of HBsAg and HBV DNA in predicting HBeAg-positive significant hepatitis activity (SHA) in the early cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.655 and 0.541, 0.720 and 0.606, and 0.553 and 0.725, respectively; those in the late cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.646 and 0.501, 0.798 and 0.622, and 0.603 and 0.674, respectively. The AUCs of HBsAg and HBV DNA in predicting HBeAg-negative SHA in the early cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.508 and 0.745, 0.573 and 0.780, and 0.577 and 0.729, respectively; those in the late cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.503 and 0.761, 0.560 and 0.814, and 0.544 and 0.722, respectively. The sensitivity and specificity of HBsAg ≤4.602 log IU/ml in predicting HBeAg-positive SHA in the early cohort were 82.6% and 45.8%, respectively; those in the late cohort were 87.0% and 44.1%, respectively. The sensitivity and specificity of HBV DNA >3.301 log IU/ml in predicting HBeAg-negative SHA in the early cohort were 73.4% and 60.8%, respectively; those in the late cohort were 73.6% and 64.1%, respectively.

Conclusion: Quantitative HBsAg and HBV DNA are valuable, but their capabilities are divergent in delimiting the natural history phases.
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http://dx.doi.org/10.3389/fimmu.2022.944097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359073PMC
August 2022

Dual HER2 Targeted Therapy With Pyrotinib and Trastuzumab in Refractory HER2 Positive Metastatic Colorectal Cancer: A Result From HER2-FUSCC-G Study.

Clin Colorectal Cancer 2022 Jul 16. Epub 2022 Jul 16.

Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address:

Background: Dual-HER2 targeted therapy has led to a promising antitumor effect in HER2 positive cancers including gastrointestinal cancer. The present data focus on patients with HER2 positive colorectal cancer who received pyrotinib and trastuzumab after failure to standard second-line treatment.

Methods: Patients diagnosed of HER2 positive refractory or metastatic colorectal cancer were enrolled to receive trastuzumab in combination with pyrotinib as third-line and beyond therapy. Trastuzumab was given as a loading dose at 8 mg/kg followed by 6mg/kg once every 3 weeks, and oral pyrotinib as 400 mg per day until progression. ORR was set as the primary endpoint. PFS and OS were set as a secondary endpoints. This trial is registered with Clinical Trial.gov, NCT04960943, and is ongoing.

Results: Between February 2020 to December 2021, 16 patients including 14 with RAS wild-type status were enrolled in this cohort. ORR was 50.0% in the overall population, and 57.1% in RAS wild-type patients. At a median follow-up of 11.2 months, median PFS and OS were 7.53 and 16.8 months, respectively. The RAS/BRAF wild-type patients had prolonged survival (PFS: 7.53 vs. 1.63 months, P = .02; OS: NR vs.4.13 months, P = .001) compared with RAS/BRAF mutant patients. The most common treatment-emergent adverse event (TEAE) reported is diarrhea. Five (31.3%) patients reported grade 3 TEAEs, and no death was reported.

Conclusions: Trastuzumab in combination with pyrotinib demonstrated encouraging antitumor activity that translated to prolonged survival benefit in HER2 positive refractory or mCRC patients who are RAS wild-type with acceptable tolerance.
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http://dx.doi.org/10.1016/j.clcc.2022.07.003DOI Listing
July 2022

Histomorphological and molecular genetic characterization of different intratumoral regions and matched metastatic lymph nodes of colorectal cancer with heterogenous mismatch repair protein expression.

J Cancer Res Clin Oncol 2022 Aug 8. Epub 2022 Aug 8.

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Purpose: To better understand the clinicopathological characteristics and molecular alterations in different intratumoral components of colorectal cancer (CRC) with heterogeneity of mismatch repair (MMR) protein expression and microsatellite instability (MSI) status.

Methods: The histopathological features, MSI status, and other molecular alterations were analyzed in separately microdissected intratumoral regions and matched metastatic lymph nodes in four cases with intratumoral heterogenous MMR expression screened from 500 CRC patients, using PCR-based MSI testing, MLH1 promoter methylation, and targeted next-generation sequencing (NGS).

Results: High microsatellite instability (MSI-H) was identified in MLH1/PMS2-deficient regions in Cases 1 to 3 and in MSH2/MSH6-deficient regions in Case 4, while microsatellite stability (MSS) was detected in all the intratumoral regions and metastatic lymph nodes with proficient MMR expression (pMMR). Intratumoral heterogeneity of MLH1 promoter methylation and/or other common driving gene mutations of CRC, such as KRAS and PIK3CA mutations, was identified in all four CRCs. Further, three cases (75%) showed heterogeneous histomorphological features in intratumoral components and metastatic lymph nodes (Cases 1, 2, and 4), and the corresponding metastatic lymph nodes showed moderate differentiation with MSS/pMMR (Cases 2 and 3).

Conclusions: Intratumoral heterogeneous MSI status is highly correlated with intratumoral histomorphological heterogeneity, which is also an important clue for the intratumoral heterogeneity of drive gene mutations in CRC. Thus, it is essential to detect MMR protein expression and other gene mutations in metastases before treatment, especially for CRCs with intratumoral heterogenous MMR protein expression or heterogenous histomorphological features.
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http://dx.doi.org/10.1007/s00432-022-04261-1DOI Listing
August 2022

Detection of DNA copy number alterations by matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis of single nucleotide polymorphisms.

Clin Chem Lab Med 2022 Aug 8. Epub 2022 Aug 8.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.

Objectives: Copy number alterations (CNAs) are frequently found in malignant tissues. Different approaches have been used for CNA detection. However, it is not easy to detect a large panel of CNA targets in heterogenous tumors.

Methods: We have developed a CNAs detection approach through quantitatively analyzed allelic imbalance by allelotyping single nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Furthermore, the copy number changes were quantified by real-competitive PCR (rcPCR) to distinguish loss of heterozygosity (LOH) and genomic amplification. The approach was used to validate the CNA regions detected by next generation sequencing (NGS) in early-stage lung carcinoma.

Results: CNAs were detected in heterogeneous DNA samples where tumor DNA is present at only 10% through the SNP based allelotyping. In addition, two different types of CNAs (loss of heterozygosity and chromosome amplification) were able to be distinguished quantitatively by rcPCR. Validation on a total of 41 SNPs from the selected CNA regions showed that copy number changes did occur, and the tissues from early-stage lung carcinoma were distinguished from normal.

Conclusions: CNA detection by MALDI-TOF MS can be used for validating potentially interesting genomic regions identified from next generation sequencing, and for detecting CNAs in tumor tissues consisting of a mixture of neoplastic and normal cells.
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http://dx.doi.org/10.1515/cclm-2022-0511DOI Listing
August 2022

The prognosis outcomes of autologous fat transfer for breast reconstruction after breast cancer surgery: a systematic review and meta-analysis of cohort studies.

Gland Surg 2022 Jul;11(7):1180-1191

Department of Orthopedics, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Wuhan, China.

Background: Autologous fat transfer (AFT) is a minimally invasive technique that employs a patient's own fat to correct disfiguring sequelae for breast reconstruction in postoperative breast cancer patients. However, the results of studies on this topic were controversial. In order to explore the effect of AFT on breast reconstruction after breast cancer surgery, we included cohort studies and conducted a meta-analysis.

Methods: A literature search was conducted using PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published up to September 14, 2020. We identified the eligible studies based on the PICOS principles, populations (patients diagnosed with breast cancer), interventions (patients undergoing AFT after breast cancer surgery), controls (patients who did not receive AFT after breast cancer surgery), outcomes [local recurrence (LR) rate, regional recurrence (RRR) rate, locoregional recurrence (LRR) rate, distant metastasis rate, systemic recurrence (SR) rate, and total death rate], study design (cohort studies). The I statistic was conducted to estimate heterogeneity. Relative risks (RRs) with 95% confidence intervals (CIs) were presented to evaluate whether AFT compromises oncological safety in breast reconstruction. Funnel plots and Egger's test were adopted to assess publication bias. Quality assessment for the included studies using the Newcastle-Ottawa Scale (NOS).

Results: Twenty-two cohort studies involving 9,971 postoperative patients with breast cancer were identified, with 3,622 receiving AFT being the experimental group, and 6,349 not receiving AFT in the control group. The overall quality of the included studies was rated as high. No significant differences in the rate of LR (RR: 0.916, 95% CI: 0.704-1.192), RRR (RR: 1.175, 95% CI: 0.773-1.787), LRR (RR: 0.788, 95% CI: 0.617-1.006), distant metastasis (RR: 1.133, 95% CI: 0.906-1.417), and total deaths (RR: 0.753, 95% CI: 0.539-1.051) were observed between the experimental group and control group (P>0.05). However, the AFT group had a lower rate of SR (RR: 0.671, 95% CI: 0.491-0.915, P=0.012).

Conclusions: The AFT group did not increase the rate of LR, RRR, LRR, distant metastasis, and total deaths in postoperative patients, which may indicate that AFT can be performed safely in breast reconstruction after excision of breast tumor.
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http://dx.doi.org/10.21037/gs-22-297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346223PMC
July 2022

Corneal endothelial cell density and its correlation with birth weight, anthropometric parameters, and ocular biometric parameters in Chinese school children.

BMC Ophthalmol 2022 Aug 6;22(1):334. Epub 2022 Aug 6.

Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.

Background: To describe the distribution of corneal endothelial cell density (ECD), and to explore its correlation with birth weight (BW), anthropometric parameters, and ocular biometric parameters in Chinese school children.

Methods: In the population-based cross-sectional Nanjing Eye Study, children were measured for anthropometric information, for ECD by the noncontact specular microscope and for ocular biometric parameters by the optic low-coherent reflectometer. Data from right eyes were analyzed to illustrate the distribution of ECD and for determining correlated factors with ECD using univariate and multiple linear regression analysis. Comparisons among three different BW groups were performed using a one-way ANOVA analysis followed by the Bonferroni correction for pairwise comparisons.

Results: Of 1171 children, the mean (± standard deviation) ECD was 2875.34 ± 195.00 cells/mm. In the Multiple Linear Regression analysis, BW, gender and central corneal thickness were significantly associated with ECD. The ECD increased by 36.16 cells/mm with BW increasing by 1 kg (P = 0.001) and increased by 0.44 cells/mm for every additional 1 mm in central corneal thickness (P = 0.01). The ECD of girls was 54.41 cells/mm higher than boys (P < 0.001). Children born with low BW presented significantly lower ECD than those born with normal BW (P < 0.05) and high BW (P < 0.05). Age and axial length were not significantly associated with ECD (P = 0.06 and P = 0.21, respectively).

Conclusions: In Chinese school children aged 82 to 94 months, the ECD is positively correlated with BW and central corneal thickness, in which BW is a newly identified associated factor. It is like that gender plays an important role in ECD distribution while girls have relatively greater ECD than boys.
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http://dx.doi.org/10.1186/s12886-022-02561-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356483PMC
August 2022

Combined improved A* and greedy algorithm for path planning of multi-objective mobile robot.

Sci Rep 2022 Aug 2;12(1):13273. Epub 2022 Aug 2.

The School of Mechanical and Automotive Engineering, South China University of Technology, Guangzhou, 510641, Guangdong, China.

With the development of artificial intelligence, path planning of Autonomous Mobile Robot (AMR) has been a research hotspot in recent years. This paper proposes the improved A* algorithm combined with the greedy algorithm for a multi-objective path planning strategy. Firstly, the evaluation function is improved to make the convergence of A* algorithm faster. Secondly, the unnecessary nodes of the A* algorithm are removed, meanwhile only the necessary inflection points are retained for path planning. Thirdly, the improved A* algorithm combined with the greedy algorithm is applied to multi-objective point planning. Finally, path planning is performed for five target nodes in a warehouse environment to compare path lengths, turn angles and other parameters. The simulation results show that the proposed algorithm is smoother and the path length is reduced by about 5%. The results show that the proposed method can reduce a certain path length.
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http://dx.doi.org/10.1038/s41598-022-17684-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345932PMC
August 2022

Computational method using heterogeneous graph convolutional network model combined with reinforcement layer for MiRNA-disease association prediction.

BMC Bioinformatics 2022 Jul 25;23(1):299. Epub 2022 Jul 25.

School of Computer Science and Technology, China University of Mining and Technology, Xuzhou, 21116, Jiangsu, China.

Background: A large number of evidences from biological experiments have confirmed that miRNAs play an important role in the progression and development of various human complex diseases. However, the traditional experiment methods are expensive and time-consuming. Therefore, it is a challenging task that how to develop more accurate and efficient methods for predicting potential associations between miRNA and disease.

Results: In the study, we developed a computational model that combined heterogeneous graph convolutional network with enhanced layer for miRNA-disease association prediction (HGCNELMDA). The major improvement of our method lies in through restarting the random walk optimized the original features of nodes and adding a reinforcement layer to the hidden layer of graph convolutional network retained similar information between nodes in the feature space. In addition, the proposed approach recalculated the influence of neighborhood nodes on target nodes by introducing the attention mechanism. The reliable performance of the HGCNELMDA was certified by the AUC of 93.47% in global leave-one-out cross-validation (LOOCV), and the average AUCs of 93.01% in fivefold cross-validation. Meanwhile, we compared the HGCNELMDA with the state‑of‑the‑art methods. Comparative results indicated that o the HGCNELMDA is very promising and may provide a cost‑effective alternative for miRNA-disease association prediction. Moreover, we applied HGCNELMDA to 3 different case studies to predict potential miRNAs related to lung cancer, prostate cancer, and pancreatic cancer. Results showed that 48, 50, and 50 of the top 50 predicted miRNAs were supported by experimental association evidence. Therefore, the HGCNELMDA is a reliable method for predicting disease-related miRNAs.

Conclusions: The results of the HGCNELMDA method in the LOOCV (leave-one-out cross validation, LOOCV) and 5-cross validations were 93.47% and 93.01%, respectively. Compared with other typical methods, the performance of HGCNELMDA is higher. Three cases of lung cancer, prostate cancer, and pancreatic cancer were studied. Among the predicted top 50 candidate miRNAs, 48, 50, and 50 were verified in the biological database HDMMV2.0. Therefore; this further confirms the feasibility and effectiveness of our method. Therefore, this further confirms the feasibility and effectiveness of our method. To facilitate extensive studies for future disease-related miRNAs research, we developed a freely available web server called HGCNELMDA is available at http://124.221.62.44:8080/HGCNELMDA.jsp .
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http://dx.doi.org/10.1186/s12859-022-04843-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316361PMC
July 2022

Effects and mechanism of antifreeze peptides from silver carp scales on the freeze-thaw stability of frozen surimi.

Food Chem 2022 Jul 16;396:133717. Epub 2022 Jul 16.

College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China. Electronic address:

The objective of this work was to investigate the cryoprotective effects of antifreeze peptides obtained from silver carp scales (ScAFPs) on the freeze-thaw stability of surimi, and to explore the action mechanisms of ScAFPs on frozen surimi. The comprehensive analysis of ice crystal size, myofibril protein oxidation, water retention, surimi gel properties, and rheological properties of surimi after different freeze-thaw cycles were investigated. Results showed that frozen surimi treated with ScAFPs exhibited a higher Ca-ATPase activity, salt-soluble protein concentration and sulfhydryl group content, while lower surface hydrophobicity, carbonyl content and disulfide bond content. Moreover, the gel properties and water holding capacity of surimi and surimi gel were improved significantly by regulating the size of ice crystals during freeze-thaw process. These findings indicate that ScAFPs could serviced as a new food ingredient with anti-freezing function for frozen products.
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http://dx.doi.org/10.1016/j.foodchem.2022.133717DOI Listing
July 2022

DNA Repair Factor Poly(ADP-Ribose) Polymerase 1 Is a Proviral Factor in Hepatitis B Virus Covalently Closed Circular DNA Formation.

J Virol 2022 07 7;96(13):e0058522. Epub 2022 Jun 7.

State Key Laboratory of Virology, Wuhan Institute of Virologygrid.439104.b, Chinese Academy of Sciences, Wuhan, China.

The biogenesis of covalently closed circular DNA (cccDNA) from relaxed circular DNA (rcDNA) is essential for chronic hepatitis B virus (HBV) infection. Different host DNA repair proteins are involved in the conversion of rcDNA to cccDNA. Here, we reported that the DNA repair factor poly(ADP-ribose) polymerase 1 (PARP1) is engaged in HBV cccDNA formation. PARP1 depletion remarkably impaired HBV replication and cccDNA synthesis. Inhibition of PARP1 poly (ADP-ribosylation) activity by olaparib suppressed cccDNA synthesis both and . Specifically, the early stage of cccDNA reservoir establishment was more sensitive to olaparib, suggesting that PARP1 participated in cccDNA formation. Furthermore, PARP1 was activated by recognizing the rcDNA-like lesions directly and combined with other DNA repair proteins. The results presented proposed that the DNA damage-sensing protein PARP1 and poly(ADP-ribosylation) modification play a key role in cccDNA formation, which might be the target for developing the anti-HBV drug. The biogenesis and eradication of HBV cccDNA have been a research priority in recent years. In this study, we identified the DNA repair factor PARP1 as a host factor required for the HBV cccDNA formation. HBV infection caused PARylation through PARP1 in Huh7-NTCP cells, primary human hepatocytes, and human-liver chimeric mice. We found that PARP1 could directly bind to the rcDNA lesions and was activated, PARylating other DNA repair proteins. We address the importance of PARP1-mediated PARylation in HBV cccDNA formation, which is a potential therapeutic target for chronic hepatitis B.
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http://dx.doi.org/10.1128/jvi.00585-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278152PMC
July 2022

Uterine tumours with myogenic differentiation harbouring SRF::RELA fusions.

Histopathology 2022 Jul 19. Epub 2022 Jul 19.

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Aims: In 2017, a subset of cellular variants of myofibroma and myopericytoma with a smooth muscle-like immunophenotype and harbouring recurrent SRF::RELA gene fusions was reported. Although the anatomical distribution was found to be quite broad, no tumours with these gene fusions in the female reproductive system have been illustrated to date.

Methods And Results: Herein, we report the histological and immunophenotypical features of three uterine tumours with SRF::RELA gene fusions. Microscopically, all three tumours were composed of cellular oval to spindle cells arranged in intersecting fascicles with variable amounts of collagen and a rich capillary network. Mitotic figures were scant. Regarding immunohistochemistry, diffuse staining for desmin, oestrogen receptor and progesterone receptor was observed in all three cases. The first case exhibited focal staining for h-caldesmon, whereas the latter two cases had diffuse staining. Furthermore, SRF::RELA rearrangement was observed in all three cases by using next-generation sequencing (NGS). Follow-up, ranging from 11 to 15 months, was available for these three patients, all of whom were well without evidence of disease.

Conclusions: In conclusion, we reported a special group of uterine neoplasms with myogenic differentiation harbouring SRF::RELA rearrangement. Although the follow-up time was limited, morphological characteristics and other studies with follow-up data supported that this type of uterine neoplasm appeared to behave in a benign manner. Further studies with longer follow-up are needed to clarify the biological nature of this particular type of uterine tumour.
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http://dx.doi.org/10.1111/his.14724DOI Listing
July 2022

Decreased expression of claudin-18.2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer.

J Gastrointest Oncol 2022 Jun;13(3):1035-1045

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Alpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC.

Methods: We retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC.

Results: Our results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without.

Conclusions: This study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient's preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.
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http://dx.doi.org/10.21037/jgo-22-462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274048PMC
June 2022

Relationship between positive margin and residual/recurrence after excision of cervical intraepithelial neoplasia: a systematic review and meta-analysis.

Transl Cancer Res 2022 Jun;11(6):1762-1769

Department of Obstetrics and Gynecology, The Fifth People's Hospital of Hainan Province, Haikou, China.

Background: The relationship between endocervical and ectocervical margin status and residual or recurrence after cervical intraepithelial neoplasia (CIN) resection has been controversial. We investigated the relationship between the excision margins and residual/recurrence to assess indicators for the scope of resection and the risk of treatment failure by using meta-analysis.

Methods: Literature searches were performed in PubMed, Medline, Embase, Central, Wangfang and CNKI databases. Patients after CIN resection were grouped according to whether there was residual or recurrence, and the differences in exposure factors between the two groups were compared. Or they were grouped by exposure factor, and compare the differences in residual and recurrence rates under different grouping conditions. The observed outcome was postoperative residual or recurrence. The risk of bias in the literature was assessed using the Newcastle-Ottawa Scale (NOS). The chi-square test were used for heterogeneity. Subgroup explored the sources of heterogeneity. Publication bias was assessed using funnel plots and Egger's test.

Results: A total of 11 studies were included in this study, 8 studies were at low risk of bias and 3 studies were at high risk of bias. The 11 studies included 3065 patients, 774 patients with positive margins and 2,291 patients with negative margins. The rate of residual/recurrence after excision of CIN in patients with positive margins was significantly higher than in patients with negative margins [odds ratio (OR) =3.99, P<0.00001]. There was no heterogeneity among the studies (P=0.16), with publication bias (P<0.05). The residual/recurrence rate was significantly higher in patients with positive endocervical margins than in patients with negative endocervical margins (OR =2.59, P<0.00001). There was no heterogeneity among studies (P=0.78) and no publication bias (P<0.05). There was no significant difference in residual/recurrence rate between positive and negative ectocervical margins (OR =1.14, P=0.36). There was no heterogeneity among studies (P=0.32) and no publication bias (P<0.05).

Conclusions: Positive endocervical margins, but not external cervical margins, are risk factors for residual/recurrence of CIN after resection. Close attention to the status of the endocervical margins is recommended. More aggressive treatment and frequent follow-up are needed for patients with positive endocervical margins.
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http://dx.doi.org/10.21037/tcr-22-1466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9273651PMC
June 2022

Reduction of antibiotic resistance genes (ARGs) in swine manure-fertilized soil via fermentation broth from fruit and vegetable waste.

Environ Res 2022 Jul 8;214(Pt 1):113835. Epub 2022 Jul 8.

School of Environmental Science and Engineering, Zhejiang Gongshang University, Hangzhou, 310012, China; Zhejiang Provincial Key Laboratory of Solid Waste Treatment and Recycling, Hangzhou, 310012, China. Electronic address:

The issue of growing increase of antibiotic resistance genes (ARGs) in manure-fertilized soil needs urgently addressing. In this study, fermentation broth from fruit and vegetable waste was prepared to reduce ARG abundance in swine manure-fertilized soils. With a six-month field experiment, we found that swine manure-fertilized soil had significantly higher ARG abundance than soil applied with chemical fertilizer. As expected, the homemade fermentation broth significantly reduced ARG abundance in swine manure-fertilized soil, possibly through the decrease of abundance of Actinomyces, in which there was a 48.0%, 51.9%, and 66.7% decrease in the abundance of Nocardioides, Streptomyces, and Nonomuraea, respectively. With the bacteriostatic experiment, we observed that fermentation broth (5 mL/L) significantly inhibited the growth and metabolism in Actinomycetes spp. and Nocardioides sp., in terms of ATPase and PDH activity. These findings confirmed that the inhibition of Actinobacteria, some of the most dominant ARG hosts, was one of the main mechanisms responsible for the decrease in ARG abundance in fermentation broth-treated soil. This study provides field-scale evidence of a feasible strategy for controlling farmland ARG pollution, which is of utmost importance for soil health in the context of sustainable agriculture.
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http://dx.doi.org/10.1016/j.envres.2022.113835DOI Listing
July 2022

Estrogen Receptor β (ESR2) Transcriptome and Chromatin Binding in a Mantle Cell Lymphoma Tumor Model Reveal the Tumor-Suppressing Mechanisms of Estrogens.

Cancers (Basel) 2022 Jun 24;14(13). Epub 2022 Jun 24.

Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden.

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data have suggested a role for estrogens, particularly acting through estrogen receptor β (ESR2). To study the ESR2 effects on MCL progression, MCL cells sensitive and resistant to the Bruton tyrosine kinase inhibitor ibrutinib were grafted to mice and treated with the ESR2-selective agonist diarylpropionitrile (DPN). The results showed that the DPN treatment of mice grafted with both ibrutinib-sensitive and -resistant MCL tumors resulted in impaired tumor progression. To identify the signaling pathways involved in the impaired tumor progression following ESR2 agonist treatment, the transcriptome and ESR2 binding to target genes were investigated by genome-wide chromatin immunoprecipitation in Granta-519 MCL tumors. DPN-regulated genes were enriched in several biological processes that included cell-cell adhesion, endothelial-mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, downregulation of individual genes, such as SOX11 and MALAT1, that play a role in MCL progression was also observed. Furthermore, the data suggested an interplay between the lymphoma cells and the tumor microenvironment in response to the ESR2 agonist. In conclusion, the results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant MCL tumors.
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http://dx.doi.org/10.3390/cancers14133098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264873PMC
June 2022

The role of toll-like receptors (TLRs) in pan-cancer.

Ann Med 2022 12;54(1):1918-1937

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Toll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis.

Methods: The expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data.

Results: Our multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research.

Conclusion: TLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Key MessagesToll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified.In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed.TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers.
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http://dx.doi.org/10.1080/07853890.2022.2095664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272932PMC
December 2022

Spatial dynamics of prokaryotic microbial communities in sediments of the Yellow Sea: Assembly process, co-occurrence relationships, and environmental implications.

J Environ Manage 2022 Oct 4;319:115645. Epub 2022 Jul 4.

Key Laboratory of Soil Environment and Pollution Remediation, Institute of Soil Science, Chinese Academy of Sciences, Nanjing, 210008, PR China.

Marine sediment microorganisms play an important role in the biogeochemical cycle of elements and the transformation of exogenous pollutants; therefore, it is important to study the microbial assembly process and inter taxa associations. In this study, we investigated the profiles and assembly processes of microbial communities of sediments collected from 19 points in the Yellow Sea. As revealed by 16S rRNA sequencing, Proteobacteria (43.11%-65.54%) was the dominant phylum in marine sediment. Further, the physicochemical properties of sediments were significantly influenced by depth (P < 0.05), and the effects of homogeneous selection became greater with increasing depth. The microbial species located in marine sediment at 35°N had a significantly higher co-occurrence relationship (82.76%) than those at 34°N (57.99%) and 36°N (54.07%). Additionally, the microbial community structure of the sediments changed significantly at the genus level with strong fluctuations in the physicochemical properties. By contrast, the carbon, nitrogen, and sulfur associated functional gene diversity and abundance showed no clear variation among different locations, indicating the probable functional redundancy and a potential functional gene pool of the microbes in marine sediments. This study could provide new insights into the composition of microorganisms in sediments in the Yellow Sea, the driving force of microbial diversity, the assembly process, the modes of species' co-occurrence, and their ecological functions.
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http://dx.doi.org/10.1016/j.jenvman.2022.115645DOI Listing
October 2022

Hyperglycemia is associated with adverse prognosis in patients with pancreatic neuroendocrine neoplasms.

Endocrine 2022 Aug 5;77(2):262-271. Epub 2022 Jul 5.

Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Background: Although glucose has a well-recognized protumoral role and the pancreas is a critical organ in adjusting glucose metabolism, the clinical value of hyperglycemia in pancreatic neuroendocrine neoplasms (pNENs) remains largely unidentified.

Methods: A retrospective study including 335 patients with pathologically confirmed pNENs was conducted. A baseline fasting blood glucose concentration ≥5.6 mmol/L was defined as hyperglycemia (otherwise, normal). Survival and regression analyses were performed.

Results: Compared with patients with normal glucose, patients with hyperglycemia (47.8%) had a higher proportion of preexisting diabetes mellitus (DM) (36.9% vs. 4.6%, p < 0.001), lymph node involvement (31.0% vs. 14.6%, p = 0.002), distant metastasis (34.4% vs. 22.9%, p = 0.019), and carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (16.6% vs. 7.2%, p = 0.009). Hyperglycemia was associated with CA19-9 ≥ 37 U/mL (Odds Ratio (OR) = 3.19, 95% CI: 1.11-9.17, p = 0.031), lymph node involvement (OR = 2.32, 95% CI: 1.02-5.28, p = 0.045), nonfunctional tumors (OR = 9.90, 95% CI: 2.11-46.34, p = 0.004), and preexisting diabetes (OR = 18.24, 95% CI: 4.06-81.95, p < 0.001). Hyperglycemia was an independent determinant for overall survival in the multivariate analysis (hazard ratio (HR) = 2.65, 95% CI: 1.31-5.34, p = 0.006).

Conclusion: Hyperglycemia is an independent predictor of overall survival and is associated with preexisting DM or lymphatic metastasis in patients with pNENs. Patients with hyperglycemia and resectable pNENs may benefit from radical resection with dissection of regional lymph nodes.
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http://dx.doi.org/10.1007/s12020-022-03100-0DOI Listing
August 2022

A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study.

BMC Cancer 2022 Jun 28;22(1):710. Epub 2022 Jun 28.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China.

Background: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC.

Methods: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy.

Discussion: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety.

Trial Registration: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-022-09786-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238164PMC
June 2022

A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study.

BMC Cancer 2022 Jun 28;22(1):710. Epub 2022 Jun 28.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China.

Background: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC.

Methods: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy.

Discussion: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety.

Trial Registration: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-022-09786-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238164PMC
June 2022

Outcomes associated with comorbid anxiety and depression among patients with stable COPD: A patient registry study in China.

J Affect Disord 2022 09 26;313:77-83. Epub 2022 Jun 26.

Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China. Electronic address:

Background: Anxiety and depression are common among patients with chronic obstructive pulmonary disease (COPD), but the associations between psychiatric symptoms and specific COPD outcomes are uncertain.

Methods: Associations of psychiatric symptoms (anxiety and depression) and COPD outcomes (COPD Assessment Test (CAT), modified Medical Research Council dyspnea scale (mMRC), number of acute exacerbations and percentage predicted forced expiratory volume in 1 second (FEV% predicted)) sets were performed by canonical correlation analysis in 876 patients with COPD.

Results: In primary analysis, we discovered a statistically significant relationship between symptoms of anxiety/depression and COPD outcomes sets (1 - Λ = 0.11; P < .001). Symptoms of anxiety/depression and four COPD outcomes sets shared 11 % of variance. CAT was the main driver of the relationship (r = -0.930; r = 0.8649) followed by mMRC (r = -0.632; r = 0.3994) and exacerbation history (r = -0.478; r = 0.2285); FEV% predicted did't make a significant contribution to the relationship (r = 0.134; r = 0.018). In secondary analysis, women were associated with a stronger correlation based on the shared variance between psychiatric symptoms and COPD outcomes sets (17.4 %) than men (9.8 %).

Limitations: Some confounding factors such as education level, income, didn't be included. There were considerably fewer women enrolled in this study than men.

Conclusion: Psychiatric symptoms were associated with COPD subjective outcomes, and more related to COPD outcomes in women.
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http://dx.doi.org/10.1016/j.jad.2022.06.059DOI Listing
September 2022

Overexpression of long noncoding RNA LINC00638 inhibits inflammation and oxidative stress in rheumatoid arthritis fibroblast-like synoviocytes by regulating the Nrf2/HO-1 pathway.

Immun Inflamm Dis 2022 07;10(7):e663

Graduate School, Anhui University of Traditional Chinese Medicine, Hefei, Anhui, China.

Background: Abnormal expression of long noncoding RNAs (lncRNAs) is involved in several autoimmune diseases including rheumatoid arthritis (RA). In this study, we intended to explore the expression of lncRNA LINC00638 in RA and its potential mechanism of action related to inflammation and oxidative stress.

Methods: The level of LINC00638 in the peripheral blood mononuclear cells (PBMCs) obtained from 45 RA patients and 30 normal controls was analyzed and its correlation with clinical indicators was investigated. In vitro, we used tumor necrosis factor-α to stimulate fibroblast-like synoviocytes (FLS) of RA patients for cell based experiments. Subsequently, the overexpressed plasmid and small interfering RNA of LINC00638 were designed. Furthermore, we further analyzed the potential effects of LINC00638 on the proliferation and migration of RA-FLS and the nuclear factor erythrocyte derived 2 related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.

Results: LINC00638 expression was found to be significantly decreased in PBMCs of RA patients, and it was negatively correlated with erythrocyte sedimentation rate, interleukin (IL)-17, reactive oxygen species (ROS), and disease activity scores for 28 joints (DAS28). Overexpression of LINC00638 activated the Nrf2/HO-1 pathway, markedly decreased the expressions of IL-6, IL-17, IL-23, ROS, as well as malondialdehyde, increased the total antioxidant capacity, and attenuated the proliferation and migration of RA-FLS, while silencing of LINC00638 reversed these manifestations.

Conclusions: LINC00638 was found to be expressed at low levels in RA patients and was associated with immune inflammation, oxidative stress, and disease activity. Overexpression of LINC00638 can reduce the proliferation as well as migration of RA-FLS, and activate the Nrf2/HO-1 pathway to inhibit the inflammation and oxidative stress.
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http://dx.doi.org/10.1002/iid3.663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208282PMC
July 2022

Insights into microbial contamination in multi-type manure-amended soils: The profile of human bacterial pathogens, virulence factor genes and antibiotic resistance genes.

J Hazard Mater 2022 09 11;437:129356. Epub 2022 Jun 11.

School of Environmental Science and Engineering, Zhejiang Gongshang University, Hangzhou 310012, China; Zhejiang Provincial Key Laboratory of Solid Waste Treatment and Recycling, Hangzhou 310012, China. Electronic address:

Concerns regarding biological risk in environment have garnered increasing attention. Manure has been believed to be a significant source of antibiotic resistance genes (ARGs) in agricultural soil. Nevertheless, the profile of microbial contamination including ARGs, virulence factor genes (VFGs) and human bacterial pathogens (HBPs) in different manure-amended soils remain largely unknown. Here, we conducted the systematic metagenome-based study to explore changes in resistome, VFGs and HBPs in soils treated by frequently-used manures. The results revealed that many manure-borne ARGs, VFGs, and HBPs could be spreaded into soils, and their diversity and abundance were significantly different among chemical fertilizer, pig manure, chicken manure, cow dung and silkworm excrement application. A total of 157 potential HBPs accounting about 1.33% of total bacteria were detected. The main ARGs transferred from manures to soil conferred resistance to vancomycin and macrolide-lincosamide-streptogramin. The series analysis revealed positive co-occurrence patterns of ARGs-HBPs, VFGs-HBPs and ARGs-VFGs. Microbial contamination were more serious in pig manure and silkworm excrement sample than in the other samples, implying the usage of these two manures increased the risk of HBPs and dissemination of ARGs. This study confirmed the prevalence and discrepancy of resistome, VFGs and HBPs in different manure-amended soils.
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http://dx.doi.org/10.1016/j.jhazmat.2022.129356DOI Listing
September 2022

Metformin: A promising drug for human cancers.

Oncol Lett 2022 Jul 12;24(1):204. Epub 2022 May 12.

Institute of Precision Cancer Medicine and Pathology, Department of Pathology, Jinan University Medical College, Guangzhou, Guangdong 510630, P.R. China.

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and , and experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.
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http://dx.doi.org/10.3892/ol.2022.13325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178677PMC
July 2022

METTL3 Inhibits Antitumor Immunity by Targeting mA-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer.

Gastroenterology 2022 Jun 11. Epub 2022 Jun 11.

Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Background & Aims: N-Methyladenosine (mA) is the most prevalent RNA modification and recognized as an important epitranscriptomic mechanism in colorectal cancer (CRC). We aimed to exploit whether and how tumor-intrinsic mA modification driven by methyltransferase like 3 (METTL3) can dictate the immune landscape of CRC.

Methods: METTL3 knockout mice, CD34 humanized mice, and different syngeneic mice models were used. Immune cell composition and cytokine level were analyzed by flow cytometry and Cytokine 23-Plex immunoassay, respectively. MA sequencing and RNA sequencing were performed to identify downstream targets and pathways of METTL3. Human CRC specimens (n = 176) were used to evaluate correlation between METTL3 expression and myeloid-derived suppressor cell (MDSC) infiltration.

Results: We demonstrated that silencing of METTL3 in CRC cells reduced MDSC accumulation to sustain activation and proliferation of CD4 and CD8 T cells, and eventually suppressed CRC in ApcMettl3 mice, CD34 humanized mice, and syngeneic mice models. Mechanistically, METTL3 activated the mA-BHLHE41-CXCL1 axis by analysis of mA sequencing, RNA sequencing, and cytokine arrays. METTL3 promoted BHLHE41 expression in an mA-dependent manner, which subsequently induced CXCL1 transcription to enhance MDSC migration in vitro. However, the effect was negligible on BHLHE41 depletion, CXCL1 protein or CXCR2 inhibitor SB265610 administration, inferring that METTL3 promotes MDSC migration via BHLHE41-CXCL1/CXCR2. Consistently, depletion of MDSCs by anti-Gr1 antibody or SB265610 blocked the tumor-promoting effect of METTL3 in vivo. Importantly, targeting METTL3 by METTL3-single guide RNA or specific inhibitor potentiated the effect of anti-programmed cell death protein 1 treatment.

Conclusions: Our study identifies METTL3 as a potential therapeutic target for CRC immunotherapy whose inhibition reverses immune suppression through the mA-BHLHE41-CXCL1 axis. METTL3 inhibition plus anti-programmed cell death protein 1 treatment shows promising antitumor efficacy against CRC.
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http://dx.doi.org/10.1053/j.gastro.2022.06.024DOI Listing
June 2022

Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling.

Acta Pharmacol Sin 2022 Jun 8. Epub 2022 Jun 8.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.

Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.
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http://dx.doi.org/10.1038/s41401-022-00927-1DOI Listing
June 2022

Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study.

Clin Cancer Res 2022 Jun 8:OF1-OF15. Epub 2022 Jun 8.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Patients And Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes.

Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003).

Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3648DOI Listing
June 2022

The Alteration of T-Cell Heterogeneity and PD-L1 Colocalization During dMMR Colorectal Cancer Progression Defined by Multiplex Immunohistochemistry.

Front Oncol 2022 20;12:867658. Epub 2022 May 20.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Background: Immune checkpoint inhibitors (ICIs) are quickly becoming key instruments in the treatment of mismatch repair-deficient (dMMR) colorectal cancers (CRCs). Despite their clinical value, ICIs have several limitations associated with their use. Only approximately 15% of all CRCs have a dMMR status, and the overall response rate of ICIs is approximately 40%. The mechanism of ICI resistance is not clear, and its study is limited by the lack of information available on the characterization of the immune microenvironment during the progression from early- to advanced-stage dMMR CRC.

Methods: We used multiplex immunohistochemistry (mIHC) with two panels, each containing five markers, to simultaneously analyze the proportions of immune microenvironment constituents in 59 patients with advanced-stage dMMR CRC and 24 patients with early-stage dMMR CRC. We detected immune cell-associated signatures in the epithelial and stromal regions and evaluated the predictive value of these immune molecules. Student's t-tests, Mann-Whitney U tests, Cox proportional hazards regression modeling, univariate Cox modeling, and Kaplan-Meier estimation were used to analyze immune cell proportions and survival data.

Results: We observed significantly higher proportions of CD8+ cytotoxic T cells (CD8+) ( = 0.001), CD8+ memory T cells (CD8+CD45RO+) ( = 0.032), and CD4+ regulatory T cells (CD4+FOXP3+) ( = 0.011) in the advanced-stage dMMR CRCs than in the early-stage dMMR CRCs. Furthermore, CD3+ T cells with PD-L1 colocalization (CD3+PD-L1+) ( = 0.043) and CD8+ T cells with PD-L1 colocalization (CD8+PD-L1+) ( = 0.005) were consistently more numerous in patients in the advanced stage than those in the early stage. Our analyses revealed that a high proportion of CD3+PD-1+ T cells was an independent prognostic factor of overall survival (OS) [hazard ratios (HR) = 9.6, < 0.001] and disease-free survival (DFS) (HR = 3.7, = 0.010) in patients in the advanced stage.

Conclusion: High numbers of CD8+ cytotoxic T cells and CD8+ memory T cells, which usually represent a cytotoxic function of the adaptive immune system and possibly enhanced inhibition factors, such as CD4+ regulatory T cells and PD-L1 colocalized T cells, were associated with the transformation of the immune microenvironment from the early stage to the advanced stage in dMMR CRCs. Furthermore, CD3+PD-1+ T cells are a prognostic factor for patients with dMMR.
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http://dx.doi.org/10.3389/fonc.2022.867658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163547PMC
May 2022

Herb-drug interaction between Shaoyao-Gancao-Fuzi decoction and tofacitinib via CYP450 enzymes.

J Ethnopharmacol 2022 Sep 3;295:115437. Epub 2022 Jun 3.

Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address:

Ethnopharmacology Relevance: Shaoyao-Gancao-Fuzi decoction (SGFD), a well-known traditional Chinese medicine formula, was originally described in "Treatise on Febrile Diseases" and has been extensively used to dispel wind, eliminate dampness and treat paralysis. It is widely used for the treatment of rheumatoid arthritis in clinic. However, the effect of SGFD on the activity of cytochrome P450 enzymes (CYP450s) and the herb-drug interactions are rarely studied.

Objective: The aim of this study was to investigate the effect of SGFD on the activity of CYP450s and evaluate the potential herb-drug interactions between SGFD and tofacitinib, commonly used disease-modifying antirheumatic drug in rheumatoid arthritis.

Materials And Methods: The cocktail approach was employed to assess the effect of SGFD on the activity of CYP1A2, 3A4, 2A6, 2E1, and 2C9. The pharmacokinetic profile of oral administration of tofacitinib in rats after two weeks of treatment with SGFD was investigated. RT-qPCR and molecular docking were performed to unveil the underlying mechanism of the herb-drug interaction.

Results: SGFD had no effect on the activities of CYP2E1 and 2C9, had a weak effect on CYP2A6, and had activatory effect on CYP1A2. However, it had a dramatically inhibitory effect on the activity of CYP3A4. Simultaneously, the values of C and AUC of tofacitinib were obviously increased after treatment with SGFD for 14 days. The mechanism study manifested that SGFD significantly reduced the gene transcription of CYP3A. Molecular docking work confirmed that the inhibitory activity of glycyrrhetinic acid, glycyrrhizic acid and liquiritin, the main ingredients of SGFD, occurred by occupying the active sites of CYP3A4 and by making favorable interactions with its key residues.

Conclusions: The system exposure of tofacitinib was increased by SGFD. SGFD could affect the activity and gene expression of the key metabolic enzyme CYP3A. These findings give a clear understanding to predict herb-drug interaction of SGFD for safe clinical use in future.
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http://dx.doi.org/10.1016/j.jep.2022.115437DOI Listing
September 2022
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