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PURPOSEThis systematic review and meta-analysis of conventional enhanced magnetic resonance imaging (MRI) were conducted to evaluate the diagnostic performance of imaging features of microvascular invasion (MVI) prediction in hepatocellular carcinoma (HCC).METHODSRelevant studies on diagnosing MVI in HCC by MRI were searched in the MEDLINE, PUBMED, EMBASE, Cochrane library, and Web of Science databases. The pooled mean sensitivity and specificity were calculated using a random effects model. The corresponding positive likelihood ratio (PLR), negative likelihood ratio (NLR), and pooled diagnostic odds ratio (DOR) were calculated. The summary receiver operating characteristic (SROC) curve was used to summarize the overall diagnostic accuracy. Diagnostic performance was evaluated by determining the area under the curve (AUC). Regression analysis by subgroup and sensitivity analysis were used to explore potential sources of heterogeneity.RESULTSA total of 19 studies comprising 1920 HCC patients with 2033 tumors were ultimately enrolled. For the signs of the presence of peritumoral enhancement in the arterial phase, peritumoral hypointensity in the hepatobiliary phase, irregular non-smooth margin, and rim-like enhancement in the arterial phase, the pooled sensitivity values, the pooled specificity values, the pooled PLR values, the pooled NLR values, the pooled DOR values, and the values of the AUC of SROC curves were determined.CONCLUSIONThe conventional MRI features for predicting MVI showed poor diagnostic performance in HCC. Only signs of the presence of peritumoral enhancement in the arterial phase showed a moderate diagnostic accuracy.

Regulated Cell Death (RCD) is a mode of cell death that occurs through drug or genetic intervention. The regulation of RCDs is one of the significant reasons for the long survival time of tumor cells and poor prognosis of patients. Long non-coding RNAs (lncRNAs) which are involved in the regulation of tumor biological processes, including RCDs occurring on tumor cells, are closely related to tumor progression. In this review, we describe the mechanisms of eight different RCDs which contain apoptosis, necroptosis, pyroptosis, NETosis, entosis, ferroptosis, autosis and cuproptosis. Meanwhile, their respective roles in the tumor are aggregated. In addition, we outline the literature that is related to the regulatory relationships between lncRNAs and RCDs in tumor cells, which is expected to provide new ideas for tumor diagnosis and treatment.

Cancer stem cells (CSCs) are considered to be a kind of tumor cell population characterized by self-renewal, easy to metastasize and drug resistance, which play an indispensable role in the occurrence, development, metastasis and drug resistance of tumors, and their existence is an important reason for high metastasis and recurrence of tumors. Long non-coding RNAs (LncRNAs), which are more than 200 nucleotides in length, have a close relationship with the malignant progression of cancer.In recent years, abundant studies have reavling that LncRNAs are beneficial to the regulation of various cancer stem cells. Linc-ROR, as a newly discovered intergenic non-protein-coding RNA in recent years, is considered to be a key regulator affecting the development of human tumors. Dysregulation of Linc-ROR is related to stemness phenotype and functional regulation of cancer stem cells. For that, Linc-ROR has the potential to be used as a diagnostic biomarker for cancer patients and can serve as a clinically meaningful potential therapeutic target. In this review, we generalize the existing research results on the important role of Linc-ROR in regulation of CSCs.

The tumor microenvironment (TME) profoundly influences tumor progression and affects immunotherapy responses and resistance. Understanding its heterogeneity is the key for developing immunotherapy. However, the available methods can only partially portray the TME heterogeneity with a small number of cell types. Here, we developed a deep learning-based frame with a design visible, DCNet, that embeds the relationships between cells and their marker genes in the neural network, and can infer the cell landscape with more than 400 cell types based on bulk RNA-seq data. DCNet accurately recapitulated the cell landscape of multiple single cell RNA-seq datasets, which showed better robustness and stability. Based on the cell landscape of TCGA patients, which was built with DCNet, the patients were divided into two groups with significant differences in survival time and distinct cell-type populations. DCNet provides a foundation for decoding TME heterogeneity. The source code of DCNet can be found on GitHub: https://github.com/xindd/DCNet.

BackgroundTinnitus can interfere with a patient’s speech discrimination, but whether tinnitus itself or the accompanying sensorineural hearing loss (SNHL) causes this interference is still unclear. We analyzed event-related electroencephalograms (EEGs) to observe auditory-related brain function and explore the possible effects of SNHL on auditory processing in tinnitus patients.MethodsSpeech discrimination scores (SDSs) were recorded in 21 healthy control subjects, 24 tinnitus patients, 24 SNHL patients, and 27 patients with both SNHL and tinnitus. EEGs were collected under an oddball paradigm. Then, the mismatch negativity (MMN) amplitude and latency, the clustering coefficient and average path length of the whole network in the tinnitus and SNHL groups were compared with those in the control group. Additionally, we analyzed the intergroup differences in functional connectivity among the primary auditory cortex (AC), parahippocampal gyrus (PHG), and inferior frontal gyrus (IFG).ResultsSNHL patients with or without tinnitus had lower SDSs than the control subjects. Compared with control subjects, tinnitus patients with or without SNHL had decreased MMN amplitudes, and SNHL patients had longer MMN latencies. Tinnitus patients without SNHL had a smaller clustering coefficient and a longer whole-brain average path length than the control subjects. SNHL patients with or without tinnitus had a smaller clustering coefficient and a longer average path length than patients with tinnitus alone. The connectivity strength from the AC to the PHG and IFG was lower on the affected side in tinnitus patients than that in control subjects; the connectivity strength from the PHG to the IFG was also lower on the affected side in tinnitus patients than that in control subjects. However, the connectivity strength from the IFG to the AC was stronger in tinnitus patients than that in the control subjects. In SNHL patients with or without tinnitus, these changes were magnified.ConclusionChanges in auditory processing in tinnitus patients do not influence SDSs. Instead, SNHL might cause the activity of the AC, PHG and IFG to change, resulting in impaired speech recognition in tinnitus patients with SNHL.

Diabetic nephropathy (DN) is a common chronic complication of diabetes. In this study, we aimed to explore the potential role of lncRNA LINC-00162 in the pathogenic process of DN. LncRNA microarray analysis, real-time PCR, IHC computational analysis and luciferase assay were performed to explore the regulatory relationship among LINC00162, miR-383 and HDAC9. There was an obvious difference between T2D + DN and T2D − DN patients in their levels of eGRF and albuminuria. A significant difference was observed between T2D + DN and T2D − DN groups in terms of their LINC00162 expression. In particular, LINC00162 and HDAC9 were highly expressed, while miR-383 was lowly expressed in tissues derived from the T2D + DN group compared with those in tissues derived from the T2D − DN group. MiR-383 was able to bind to LINC00162, while HDAC9 was a direct downstream target of miR-383 with a complementary miR-383 binding site located in the 3′ UTR of HDAC9. LINC00162 reduced miR-383 expression and further up-regulated HDAC9 expression, while miR-383 mimics reduced HDAC9 expression under a dose-dependent manner. In summary, we suggested for the first time that down-regulation of LINC00162 was associated with the development of DN in T2D via the up-regulation of miR-383 expression and reduction of HDAC9 expression.

Abstract Acute lymphoblastic leukemia (ALL) with granular blasts was historically referred to as “granular ALL”, but this is not recognized as a distinct entity in the current WHO classification. This rare morphological feature is predominantly associated with a B-cell immunophenotype, while T-ALL with prominent cytoplasmic granules is extremely rare, with limited available genetic, molecular, and prognostic data. Here, we report a unique case of ALL in a 9-year-old girl. Initial blood tests revealed leukocytosis, and both peripheral blood and bone marrow morphology showed a high number of blasts with granular cytoplasm and bilobed nuclei. Immunophenotyping confirmed T-cell origin. The patient tested positive for KMT2A::AFDN, with WT1 overexpression, and NRAS and EZH2 mutations were detected by next-generation sequencing (NGS). Remarkably, the patient achieved complete remission after treatment and has shown no signs of relapse for nearly four years. Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases.

Aim: To investigate the efficacy of postoperative adjuvant transarterial chemoembolization (TACE) in patients with intrahepatic cholangiocarcinoma (ICC) after resection. Methods: Studies were systematically searched until August 2021 in the following databases: MEDLINE, EMBASE, PUBMED, Web of Science, Cochrane Library, Science Direct, and Springer Link. Overall survival (OS) and recurrence-free survival (RFS) were considered as the main outcomes. Pooled hazard ratio (HR) with 95% confidence interval (95%CI) was reported as results for the survival data. Subgroup analysis was conducted on the outcomes stratified by early-stage ICC and intra-arterial chemotherapeutic regimen. Results: Eleven studies with 2,757 patients were finally included in the study. The pooled HR of OS was 0.68 (95%CI: 0.50-0.87, I²=83.7%). The pooled HR of RFS was 1.00 (95%CI: 0.69-1.31, I²=88%). Receipt of postoperative adjuvant TACE improved the OS in the early-stage ICC subgroup (HR=0.68, 95%CI: 0.50-0.86, I²=54%). Addition of carboplatin could slightly improve the OS (HR=0.6, 95%CI: 0.35-0.85, I²=48%). But receipt of postoperative adjuvant TACE (HR=1.06, 95%CI: 0.83-1.29, I²=41.2%) or use of carboplatin (HR=1.30, 95%CI: 0.93-1.67, I²=0%) caused no significant improvement in the RFS in the early-stage ICC subgroup. Conclusions: Postoperative adjuvant TACE could improve the OS in ICC patients after hepatectomy but could not prevent late recurrence. Survival benefit was also found in early-stage ICC patients undergoing postoperative adjuvant TACE after hepatectomy. Addition or non-addition of carboplatin in chemoembolization showed a similar OS outcome. [ABSTRACT FROM AUTHOR]

Abstract Biliary tract cancer (BTC) that contains cholangiocarcinoma, gallbladder cancer, and ampullary cancer is highly malignant and mostly diagnosed in elderly patients. Over the past decades, human life has globally risen; thus, aging emerges as the primary risk factor for BTC. However, an effective treatment for this vulnerable population remains a large clinical challenge. As a result, the incidence and mortality of TBC remains high. Here, we discuss the potential link between aging and BTC from the aspects of molecular and cellular mechanisms, surgical resection, and chemotherapy. In addition, we update a number of clinical trials that are currently ongoing in elderly patients. The overview of BTC in elderly patients is expected to help develop a new therapeutic strategy tailored to this elderly population, ultimately improving their life quality.

Abstract Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

Abstract Exploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.

Abstract Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2–5 and 15–23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

Abstract Background Breast cancer is a one of the malignant carcinomas partially caused by genetic risk factors. Germline BRCA1 gene mutations are reportedly associated with breast cancers. Identification of BRCA1 mutations greatly improves the preventive strategies and management of breast cancer. The aim of our study was to investigate the frequency of the deleterious BRCA1: p.Ile1845fs variant in breast carcinomas, as well as the correlation between p.Ile1845fs variant with clinicopathological parameters and clinical outcomes. Results A total of 23,481 clinically high-risk patients with breast cancer and 6489 healthy controls were recruited for p.Ile1845fs variant sequencing (either sanger or next generation sequencing). We identified 94 breast cancer patients (0.40%, 94/23481) as well as 11 healthy controls (0.17%, 11/6489) carried p.Ile1845fs variant. BRCA1: p.Ile1845fs variant showed a higher frequency in patients with TNBC molecular typing (20.21%, 19/94) and family history (37.23%, 35/94) compared with non-carriers (P = 3.62E-6 and 0.034, respectively). According to our data, we advanced the frequency of p.Ile1845fs variant and we confirmed that BRCA1: p.Ile1845fs variant was associated with increased risk of breast cancer (OR = 2.36, 95%CI = 1.26–4.89, P = 0.004). Conclusions BRCA1: p.Ile1845fs variant was a frequently pathogenic mutation in breast cancer in Han Chinese women and our data may be helpful for diagnosis and therapy of breast cancer.

Objectives: Offspring born to preeclamptic women are at high risk for metabolic diseases in later life, but the mechanisms are not known. The purposes of the current investigation were to clarify the changes in DNA methylation at MEST and DLK1 DMRs in fetus of preeclampsia and to explore the possible mechanisms behind the high risk of adult diseases in the offspring of preeclampsia. Methods: Fetal lymphocytes were isolated from umbilical cord blood of 78 women with preeclampsia and 95 women with normal pregnancy. Genomic DNA was extracted and then DNA methylation levels of MEST and DLK1 DMRs were determined by MassARRAY quantitative methylation analysis. Results: The methylation levels were detected in 20 CpG sites of MEST DMR and 16 sites of DLK1 DMR. Methylation changes were significantly different at CPG1, 3, 4, 7.8, 15, 18.19, and 20 of MEST between preeclampsia and normal pregnancy (P = 0.014, 0.001,

Cytochrome bc[sub 1] is an integral membrane protein complex essential to cellular respiration and photosynthesis. The Q cycle reaction mechanism of bc[sub 1] postulates a separated quinone reduction (Q[sub i]) and quinol oxidation (Q[sub o]) site. In a complete catalytic cycle, a quinone molecule at the Q[sub i] site receives two electrons from the b[sub H] heine and two protons from the negative side of the membrane; this process is specifically inhibited by antimycin A and NQNO. The structures of bovine mitochondrial bc[sub 1] in the presence or absence of bound substrate ubiquinone and with either the bound antimycin A[sub 1] or NQNO were determined and refined. A ubiquinone with its first two isoprenoid repeats and an antimycin A[sub 1] were identified in the Q[sub i] pocket of the substrate and inhibitor bound structures, respectively; the NQNO, on the other hand, was identified in both Q[sub i] and Q[sub o] pockets in the inhibitor complex. The two inhibitors occupied different portions of the Q[sub i] pocket and competed with substrate for binding. In the Q[sub o] pocket, the NQNO behaves similarly to stigmatellin, inducing an iron-sulfur protein conformational arrest. Extensive binding interactions and conformational adjustments of residues lining the Q[sub i] pocket provide a structural basis for the high affinity binding of antimycin A and for phenotypes of inhibitor resistance. A two-water-mediated ubiquinone protonation mechanism is proposed involving three Q[sub i] site residues His[sup 201], Lys[sup 227], and Asp[sup 228]. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis and occurs with high frequency in China. The germline mutation profile in ESCC remains unclear, and therefore, the discovery of oncogenic alterations in ESCC is urgently needed. This study investigates the germline mutation profile and reveals associations among genotype-environment interactions in ESCC.Methods: Whole exome sequencing and follow-up analysis were performed in 77 matched tumor-normal ESCC specimens to examine the germline profiles. Additionally, associations among genotype-environment interactions were investigated.Results: We identified 84 pathogenic/likely pathogenic mutations and 51 rare variants of uncertain significance (VUS). Twenty VUS with InterVar evidence of a score of moderate pathogenicity (PM) 2/PM2+ supporting pathogenicity (PP) 1 were found to have pathogenic significance. CYP21A2 was the most frequently mutated gene, and the p.Gln319* variant was identified in 6.5% (5/77) of patients. The TP53 p.V197E mutation, located within the DNA binding domain, was found in 1.3% (1/77) of patients. In total, the 11.7% (9/77) of individuals with homologous recombination (HR) VUS were more likely to have well-differentiated tumors than those without (P = 0.003). The degree of lymph node metastasis was correlated with homologous recombination deficiency (HRD) and VUS group (P < 0.05). Moreover, the 10.4% (8/77) of individuals with mismatch repair (MMR) VUS had a higher tumor mutational burden (TMB), although the correlation was not significant.Conclusions: Our study identified the germline mutation profiles in ESCC, providing novel insights into the molecular pathogenesis of this disease. Our results may also serve as a useful resource for the exploration of the underlying mechanism of ESCC and may provide information for the prevention, diagnosis and risk management of ESCC.

[Objective] This study aimed to investigate the chemical constituents from the flowers of Dendrobium chrysanthum and determine its bioactive compounds. [Method] The compounds were extracted by 95% alcohol and isolated by column chromatography on silica gel and Sephadex LH-20. Their structures were identified by spectroscopic analysis (1H NMR, 13CNMR and EIMS). [Result] Nine compounds were obtained and identified as stigmasterol (1), β-sitosterol (2), linoleic acid (3), stigmast-4-en-3-one (4), dibutyl phthalate (5), moscatilin (6), ergosterol (7), ergosterol peroxide (8) and daucosterol (9). [Conclusion] All compounds were isolated from its flowers for the first time. [ABSTRACT FROM AUTHOR]

Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10(-5)) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96×10(-6)) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele of rs17653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases.

[Objective] This study aimed to investigate the chemical constituents of Dendrobium thyrsiflorum and determine its bioactive compounds. [Method] The compounds were extracted by 95% alcohol and isolated by column chromatography on silica gel and Sephadex LH-20. Their structures were identified by spectroscopic analysis (¹H NMR and 13C NMR). [Result] Seven compounds were obtained and identified as 4, 7-dihydroxy-2-methoxy-9, 10-dihydrophenan-threne (1), syringaldehyde (2), moscatin (3), gigantol (4), batatasin ill (5), tristin (6) and stigmasteroi (7). [Conclusion] Compounds 1 and 2 were isolated from this medicinal plant for the first time. [ABSTRACT FROM AUTHOR]