Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE: To investigate lymph node metastasis (LNM) in the prostatic anterior fat pad (PAFP) of PCa patients after robot-assisted radical prostatectomy (RARP), and analyze the clinicopathological features and prognosis of LNM in the PAFP. METHODS: We retrospectively analyzed the clinicopathological data on 1 003 cases of PCa treated by RARP in the Department of Urology of PLA General Hospital from January 2017 to December 2022. All the patients underwent routine removal of the PAFP during RARP and pathological examination, with the results of all the specimens examined and reported by pathologists. Based on the presence and locations of LNM, we grouped the patients for statistical analysis, compared the clinicopathological features between different groups using the Student's t, Mann-Whitney U and Chi-square tests, and conducted survival analyses using the Kaplan-Meier and Log-rank methods and survival curves generated by Rstudio. RESULTS: Lymph nodes were detected in 77 (7.7%) of the 1 003 PAFP samples, and LNM in 11 (14.3%) of the 77 cases, with a positive rate of 1.1% (11/1 003). Of the 11 positive cases, 9 were found in the upgraded pathological N stage, and the other 2 complicated by pelvic LNM. The patients with postoperative pathological stage≥T3 constituted a significantly higher proportion in the PAFP LNM than in the non-PAFP LNM group (81.8% ［9/11］ vs 36.2% ［359/992］, P = 0.005), and so did the cases with Gleason score ≥8 (87.5% ［7/8］ vs 35.5% ［279/786］, P = 0.009). No statistically significant differences were observed in the clinicopathological features and biochemical recurrence-free survival between the patients with PAFP LNM only and those with pelvic LNM only. CONCLUSION The PAFP is a potential route to LNM, and patients with LNM in the PAFP are characterized by poor pathological features. There is no statistically significant difference in biochemical recurrence-free survival between the patients with PAFP LNM only and those with pelvic LNM only. Routine removal of the PAFP and independent pathological examination of the specimen during RARP is of great clinical significance.
Humans ; Male ; Prostatectomy/methods* ; Robotic Surgical Procedures ; Lymphatic Metastasis ; Retrospective Studies ; Prognosis ; Prostatic Neoplasms/pathology* ; Adipose Tissue/pathology* ; Prostate/pathology* ; Lymph Nodes/pathology* ; Middle Aged ; Aged

OBJECTIVE: By analyzing the differential miRNA in seminal plasma between individuals with normal and abnormal sperm DNA fragmentation index（DFI）, we aim to identify miRNA that may impact sperm DNA integrity and target genes, and attempt to analyze their potential mechanisms of action. METHODS: A total of 161 study subjects were collected and divided into normal control group, DFI-medium group and DFI-abnormal group based on the DFI detection values. Differential miRNA were identified through miRNA chip analysis. Through bioinformatics analysis and target gene prediction, miRNA related to DFI and specific target genes were identified. The relative expression levels of differential miRNA and target genes in each group were compared to explore the impact of their differential expression on DFI. RESULTS: Through miRNA chip analysis, a total of 11 differential miRNA were detected. Bioinformatics analysis suggested that miR-26a-5p may be associated with reduced sperm DNA integrity. And gene prediction indicated that PTEN was a specific target gene of miR-26a-5p. Compared to the normal control group, the relative expression levels of miR-26a-5p in both the DFI-medium group and the DFI-abnormal group showed a decrease, while the relative expression levels of PTEN showed an increase. The relative expression levels of miR-26a-5p in all groups were negatively correlated with DFI values, while the relative expression levels of PTEN showed a positive correlation with DFI values in the DFI-medium group and the DFI-abnormal group. The AUC of miR-26a-5p in the DFI-medium group was 0.740 (P<0.05), with a sensitivity of 73.6% and a specificity of 71.5%; the AUC of PTEN was 0.797 (P<0.05), with a sensitivity of 76.5% and a specificity of 78.4%. In the DFI-abnormal group, the AUC of miR-26a-5p was 0.848 (P<0.05), with a sensitivity of 81.3% and a specificity of 78.1%. While the AUC of PTEN was 0.763 (P<0.05), with a sensitivity of 77.2% and a specificity of 80.2%. CONCLUSION miR-26a-5p affects the integrity of sperm DNA by regulating the expression of PTEN negatively. The relative expression levels of seminal plasma miR-26a-5p and PTEN have good diagnostic value for sperm DNA integrity damage, which can help in the etiological diagnosis and prognosis analysis of abnormal DFI. This provides a diagnostic and treatment approach for the study and diagnosis of DFI abnormalities without clear etiology.
Male ; Humans ; MicroRNAs/genetics* ; PTEN Phosphohydrolase/genetics* ; Spermatozoa ; Semen/metabolism* ; DNA Fragmentation

OBJECTIVE: To precise classify sacral meningeal cysts, effective guide minimally invasive neurosurgery and postoperative personalized rehabilitation by multiple dimensions radiographic reconstruction MRI. METHODS: From March to December 2021, based on the original 3D-fast imaging employing steadystate acquisition (FIESTA) scanning sequence, 92 patients with sacral meningeal cysts were pre-operatively evaluated by multiple dimensional reconstruction MRI. The shape of nerve root and the leakage of cyst were reconstructed according to the direction of nerve root or leakage track showed on original MRI scans. Sacral canal cysts were accurately classified as including nerve root and without nerve root, so as to accurately design the incision of skin and formulate corresponding open range of the posterior wall of the sacral canal. Under the microscope intraoperation, the shape of the nerve roots inside cysts or leakage track of the cysts without nerve roots were verified and explored. After the reinforcement and shaping operation, several reexaminations of multiple dimensional reconstruction MRI were performed to understand the deformation of the nerve root and hydrops in the operation cavity, so as to formulate a persona-lized rehabilitation plan for the patients. RESULTS: Among the 92 patients with sacral mengingeal cyst, 58 (63.0%) cysts with nerve root cyst, 29 (31.5%) cysts without nerve root cyst, and 5 (5.4%) cysts with mixed sacral canal cyst. In 58 patients with nerve root cysts, the accuracy of preoperative clinical classification on MRI image reached 96.6% (56/58) through confirmation by operating microscope. Only 2 cases of large single cyst with nerve root on the head of cyst were mistaken for without nerve root type. In 29 patients with sacral cyst without nerve root, the accuracy of preoperative image reached 100% through confirmation by operating microscope. The accuracy of judging the internal nerve root and leakage of 12 cases with recurrent sacral cyst was also 100%. Two cases of delayed postoperative hydrops were found one month after operation. After rehabilitation treatment by moxibustion and bathing, the hydrops disappeared 4-6 months after operation. CONCLUSION Multiple dimensional reconstruction MRI can precisely make clinical classification of sacral meningeal cysts before operation, guide minimally invasive neurosurgery effectively, and improve the rehabilitation effect.
Humans ; Magnetic Resonance Imaging/methods* ; Male ; Female ; Sacrum/surgery* ; Adult ; Middle Aged ; Imaging, Three-Dimensional/methods* ; Cysts/rehabilitation* ; Aged ; Adolescent ; Young Adult ; Spinal Nerve Roots/diagnostic imaging* ; Minimally Invasive Surgical Procedures ; Neurosurgical Procedures/methods*

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets