USP11 regulates proliferation and apoptosis of human spermatogonial stem cells via HOXC5-mediated canonical WNT/ß-catenin signaling pathway.

Spermatogonial stem cells (SSCs) are capable of transmitting genetic information to the next generations and they are the initial cells for spermatogenesis. Nevertheless, it remains largely unknown about key genes and signaling pathways that regulate fate determinations of human SSCs and male infertility. In this study, we explored the expression, function, and mechanism of USP11 in controlling the proliferation and apoptosis of human SSCs as well as the association between its abnormality and azoospermia. We found that USP11 was predominantly expressed in human SSCs as shown by database analysis and immunohistochemistry. USP11 silencing led to decreases in proliferation and DNA synthesis and an enhancement in apoptosis of human SSCs. RNA-sequencing identified HOXC5 as a target of USP11 in human SSCs. Double immunofluorescence, Co-immunoprecipitation (Co-IP), and molecular docking demonstrated an interaction between USP11 and HOXC5 in human SSCs. HOXC5 knockdown suppressed the growth of human SSCs and increased apoptosis via the classical WNT/ß-catenin pathway. In contrast, HOXC5 overexpression reversed the effect of proliferation and apoptosis induced by USP11 silencing. Significantly, lower levels of USP11 expression were observed in the testicular tissues of patients with spermatogenic disorders. Collectively, these results implicate that USP11 regulates the fate decisions of human SSCs through the HOXC5/WNT/ß-catenin pathway. This study thus provides novel insights into understanding molecular mechanisms underlying human spermatogenesis and the etiology of azoospermia and it offers new targets for gene therapy of male infertility.

High progesterone levels on the day after HCG injection has no effect on clinical pregnancy outcomes in in vitro fertilization-embryo transfer.

Background: This study investigates the potential impact of high progesterone (P) level on the day following human chorionic gonadotropin (HCG) injection on the clinical pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET). Methods: Retrospective analysis was conducted on 6418 cycles of IVF-ET performed at Liuzhou Maternal and Child Health Hospital between August 2020 to December 2021. Excluding cycles with progesterone levels ≥1.5ng/ml on HCG injection, a total of 781 cycles were identified according to the standard, and they were divided into five groups according to the progesterone level on the day after HCG: Group A: progesterone level < 2.5 ng/ml (n = 128); Group B: 2.5 ng/ml ≤ progesterone level < 3.5 ng/ml (n = 174); Group C: 3.5 ng/ml ≤ progesterone level < 4.5 ng/ml (n = 153); Group D: 4.5 ng/ml ≤ progesterone level < 5.5 ng/ml (n = 132); Group E progesterone level ≥5.5 ng/ml(n=194). Comparative analyses of clinical data, including general clinical data, and clinical pregnancy outcomes such as clinical pregnancy rate, miscarriage rate, and live birth rate were performed among these groups. Results: There were significant differences in estradiol levels on HCG injection, but there were no differences in available embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Binary logistic regression analysis showed that there was no significant correlation between P level on the day after HCG injection and the live birth rate. Conclusion: Under the condition of low P level on HCG injection, high progesterone levels on the day after HCG injection does not affect the clinical pregnancy outcomes of IVF-ET.

Laparoscopic Anatomical Cranial Sub-segmentectomy of Segment VII (S7) with Super-Selective Intra-arterial Nano-ICG Positive Staining-Guided Trans-Parenchymal Approach.

BACKGROUND: With introduction of "cone unit," which is the smallest resectable anatomical area supplied by a tertiary branch of Glissonean pedicle, more precise subsegmental anatomical resection has been proposed.1 Super-selective intra-arterial ICG staining, delivering ICG and lipiodol mixing to arterial branch using interventional radiology, has been proved feasibility especially for complicated anatomy.2-6 It was difficult to uniformly mix water-soluble ICG with lipophilic lipiodol, rendering to inconsistency development of liver segment between angiography and laparoscopy. Nano-ICG is a uniform mixing of ICG and lipiodol.7 We demonstrated an exclusive "two-step" method to perform LAR for cranial S7 via super-selective intra-arterial nano-ICG staining guidance. METHODS: A 70-year-old male was admitted. CT scan showed tumor was located in cranial S7 with 2.1*1.9 cm. Preoperative AFP was 4.66 ng/ml and PIVKA-II was 2332 mAU/ml. The liver function was Child-Pugh class A and ICG-15R was 7.8%. Given that tumor was confined to cranial S7, precise anatomical sub-segmentectomy was warranted. This study was approved by the West China Hospital, Sichuan University Ethics Committee (approval number: 2023-2327). RESULTS: The operation was performed "two step." "First step" was super-selective intra-arterial nano-ICG embolization in intervention room, while "second step" was performed in operation room. ICG demarcation line was clearly identified even after 7 hr. After full mobilization of right hemiliver, we performed transparenchymal approach to find and clamp pedicle of cranial S7 under fluorescence guidance. Operation time was 150 min with 20 ml of blood loss with uneventful course. CONCLUSIONS: Although LAR of S7 remains challenging, super-selective intra-arterial nano-ICG positive staining guidance might be a feasible and safe option.

CDCA5-EEF1A1 interaction promotes progression of clear cell renal cell carcinoma by regulating mTOR signaling.

BACKGROUND: Cell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain. METHODS: Immunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC-MS/MS were performed to investigate the underlying mechanisms. RESULTS: We found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression. CONCLUSIONS: Taken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients.

The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy.

Background: Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. Objective: To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. Methods: A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. Results: With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. Conclusion: PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

Efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC): A systematic review and meta-analysis.

BACKGROUND: The optimal management of unresectable hepatocellular carcinoma (uHCC) remains an unresolved challenge. There is ongoing debate regarding the efficacy and safety of drug-eluting bead TACE (DEB-TACE) with tyrosine kinase inhibitors (TKIs). METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library for eligible studies. The main endpoints under investigation were survival outcomes, including overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Secondary outcomes encompassed tumor response rates and adverse events (AEs). Two researchers conducted the data extraction independently and assessed the quality of the studies. After pooling and analyzing the data, we assessed the heterogeneity and performed both subgroup analysis and sensitivity analysis. Additionally, we evaluated the potential for publication bias. RESULTS: Eight studies with 1513 patients were finally retrieved. Compared to monotherapy, although bigeminal therapy exhibited improved survival benefits (OS: HR: 0.56, 95 % CI 0.41-0.76, p < 0.001; TTP: HR: 0.72, 95 % CI 0.59-0.87, p = 0.001) and tumor response (ORR: RR: 1.59; 95 % CI 1.19-2.13, p = 0.002; DCR: RR: 1.14; 95 % CI 1.03-1.26, p = 0.010), the reliability of results was affected by significant heterogeneity. In the subgroup analysis, compared to DEB-TACE alone, the bigeminal therapy failed to show any statistical differences. Compared to TKIs, it demonstrated significant advantages in both survival (OS: HR: 0.49, 95 % CI 0.40-0.61, p < 0.001; TTP: HR: 0.60, 95 % CI 0.48-0.75, p < 0.001) and tumor response (ORR: RR: 2.40, 95 % CI 1.86-3.09, p < 0.001; DCR: RR: 1.36, 95 % CI 1.20-1.54, p < 0.001) while low heterogeneity was observed. Concerning safety, DEB-TACE provides no more severe AEs while TKIs-related AEs require close monitoring. CONCLUSION: Our findings suggest that DEB-TACE combined with TKIs may be a safe and effective treatment for uHCC, which is more suitable for patients in the advanced stage.

Role of microvascular invasion in early recurrence of hepatocellular carcinoma after liver resection: A literature review.

Hepatectomy is widely considered a potential treatment for hepatocellular carcinoma (HCC). Unfortunately, one-third of HCC patients have tumor recurrence within 2 years after surgery (early recurrence), accounting for more than 60% of all recurrence patients. Early recurrence is associated with a worse prognosis. Previous studies have shown that microvascular invasion (MVI) is one of the key factors for early recurrence and poor prognosis in patients with HCC after surgery. This paper reviews the latest literature and summarizes the predictors of MVI, the correlation between MVI and early recurrence, the identification of suspicious nodules or subclinical lesions, and the treatment strategies for MVI-positive HCC. The aim is to explore the management of patients with MVI-positive HCC.

Whole-Genome DNA Methylation Profiling of Intrahepatic Cholangiocarcinoma Reveals Prognostic Subtypes with Distinct Biological Drivers.

Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer. Although the genetic characterization of iCCA has led to targeted therapies for treating tumors with FGFR2 alterations and IDH1/2 mutations, only a limited number of patients can benefit from these strategies. Epigenomic profiles have emerged as potential diagnostic and prognostic biomarkers for improving the treatment of cancers. In this study, we conducted whole-genome bisulfite sequencing on 331 iCCAs integrated with genetic, transcriptomic, and proteomic analyses, demonstrating the existence of four DNA methylation subtypes of iCCAs (S1-S4) that exhibited unique postoperative clinical outcomes. The S1 group was an IDH1/2 mutation-specific subtype with moderate survival. The S2 subtype was characterized by the lowest methylation level and the highest mutational burden among the four subtypes and displayed upregulation of a gene-expression pattern associated with cell cycle/DNA replication. The S3 group was distinguished by high interpatient heterogeneity of tumor immunity, a gene-expression pattern associated with carbohydrate metabolism, and an enrichment of KRAS alterations. Patients with the S2 and S3 subtypes had the shortest survival among the four subtypes. Tumors in the S4 subtype, which had the best prognosis, showed global methylation levels comparable to normal controls, increased FGFR2 fusions/BAP1 mutations, and the highest copy-number variant burdens. Further integrative and functional analyses identified GBP4 demethylation, which is highly prevalent in the S2 and S3 groups, as an epigenetic oncogenic factor that regulates iCCA proliferation, migration, and invasion. Together, this study identifies prognostic methylome alterations and epigenetic drivers in iCCA. SIGNIFICANCE: Characterization of the DNA methylome of intrahepatic cholangiocarcinoma integrated with genomic, transcriptomic, and proteomic analyses uncovers molecular mechanisms affected by genome-wide DNA methylation alterations, providing a resource for identifying potential therapeutic targets.

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

Transhepatic arterial approaches for ICG injection to guide laparoscopic anatomical hepatectomy: A case series study.

BACKGROUND: Laparoscopic anatomical hepatectomy guided by near-infrared fluorescence imaging (NIR-FI) has been utilized extensively. However, it is difficult to resect "cone units" above the third branch of the Glissonean pedicle in the right posterior lobe using the laparoscopic positive or negative staining techniques. Therefore, we undertook a new laparoscopic segmentectomy based on the concept of "cone unit" assisted by interventional radiology combined with NIR-FI. METHODS: Laparoscopic segmentectomy guided by NIR-FI via super-selective hepatic arteriography and trans-arterial injection of ICG was carried out on 13 patients with early-stage HCC between September 2020 and January 2022.11 of cases were successful, and relevant pathological characteristics and perioperative outcomes were retrospectively analyzed. RESULTS: Two cases failed NIR-FI out of which one case involved over-staining to the non-target segment, and in the other case, which was to undergo laparoscopic segment V resection, only the ventral segment was stained while the imaging of the dorsal segment failed. In the intraoperative conditions, the tumor safe margin was 1.1 (0.7-1.55) cm, the interventional operation time was 50 (45.5-60.5) minutes, the operation time was 280 (242.5-307.5) minutes, the blood loss was 100 (50-200) ml, the postoperative hospital stay was 5 (4.5-5.5) days. No cases converted to laparotomy, and no serious postoperative complications developed. CONCLUSIONS: NIR-FI through super-selective hepatic arteriography and trans-arterial injection of ICG can provide a clear and lasting navigation aid for laparoscopic segmentectomy, which may have positive implication for early-stage HCC with poor preoperative liver reserves.

Erratum: CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2.

[This corrects the article DOI: 10.1016/j.omto.2019.12.007.].

Liver transplantation versus resection for patients with combined hepatocellular cholangiocarcinoma: A retrospective cohort study.

Background: Combined hepatocellular cholangiocarcinoma (CHC) is a rare primary liver cancer, and whether liver transplantation should be implemented among CHC patients is still controversial. We intend to conduct a retrospective cohort study based on the Surveillance, Epidemiology, and End Results (SEER) database to investigate the prognosis of liver transplantation vs. liver resection among CHC patients. Methods: Patients diagnosed with CHC (ICD-O-3:8180/3) and treated with transplantation or hepatectomy were extracted from the SEER database (2000-2018). We utilized Propensity Score Matching to control confounding bias. Kaplan-Meier curve was used for survival analysis, and Cox regression was used to find independent factors associated with prognosis. Results: We identified 123 (transplantation: 49; resection: 74) patients with CHC who were treated between 2004 and 2015. In the entire cohort, survival analysis demonstrated transplantation group was associated with better overall survival and cancer-specific survival (log-rank p = 0.004 and p = 0.003, respectively). In addition, liver transplantation still conferred better overall and cancer-specific survival than liver resection after Propensity Score Matching (log-rank p = 0.024 and p = 0.048, respectively). However, this advantage didn't appear in the subgroup, regardless of whether the tumor size was greater than 3 cm or not. (≤3 cm: OS log-rank p = 0.230, CSS log-rank p = 0.370; >3 cm: OS log-rank p = 0.110, CSS log-rank p = 0.084). Multivariate analysis validated the finding that liver transplantation was a protective factor for overall survival (HR = 0.55 [0.31-0.95], p = 0.032). Conclusions: Liver transplantation may be an option in individuals with CHC and should be taken into consideration due to its advantages in terms of overall survival and cancer-specific survival. However, a sizable sample is required for future studies to determine which subset of CHC patients may benefit more from liver transplantation.

Safety and efficacy of laparoscopic transperitoneal versus retroperitoneal resection for benign retroperitoneal tumors: a retrospective cohort study.

BACKGROUND AND OBJECTIVE: Benign retroperitoneal tumors (BRTs) are clinically rare solid tumors. This study aimed to compare the safety and efficacy of laparoscopic transperitoneal versus retroperitoneal resection for BRTs. METHODS: The clinical data of 43 patients who had pathologically confirmed BRTs and underwent laparoscopic resection in a single center from January 2019 to May 2022 were retrospectively analyzed. Patients were divided into two groups according to the surgical methods: the Transperitoneal approach group (n = 24) and the Retroperitoneal approach group (n = 19). The clinical characteristics and perioperative data between the two groups were compared. The baseline data and surgical variables were analyzed to determine the impact of different surgical approaches on the treatment outcomes of BRTs. RESULTS: No significant difference was observed between the two groups in gender, age, body mass index, the American Society of Anesthesiologists score, presence of underlying diseases, tumor size, tumor position, operation duration, intraoperative hemorrhage, postoperative hospital stay, intestinal function recovery time, and postoperative complication rate. The conversion rate from laparoscopic to open surgery was significantly lower in the Transperitoneal approach group than in the Retroperitoneal approach group (1/24 vs. 5/19, χ2 = 4.333, P = 0.037). Tumor size was an independent influencing factor for the effect of surgery (odds ratio = 1.869, 95% confidence interval = 1.135-3.078, P = 0.014) and had a larger efficacy on the retroperitoneal group (odds ratio = 3.740, 95% confidence interval = 1.044-13.394, P = 0.043). CONCLUSION: The laparoscopic transperitoneal approach has the inherent advantages of anatomical hierarchies and surgical space, providing a better optical perspective of the targeted mass and improved bleeding control. This approach may have better efficacy than the retroperitoneal approach, especially in cases of a large tumor or when the tumor is located near important blood vessels.

Clinical outcomes of immune checkpoint inhibitor plus nab-paclitaxel in metastatic upper tract urothelial carcinoma.

Background: Metastatic upper tract urothelial carcinoma (mUTUC) is a malignant cancer associated with poor prognosis. Few studies have investigated the clinical outcome of a recently developed combination regimen of programmed cell death 1 (PD-1) inhibitor plus nab-paclitaxel in mUTUC. Methods: We retrospectively retrieved data from the electronic medical records of cisplatin-ineligible or cisplatin-refractory mUTUC patients from five participating Chinese centers, who received treatment of PD-1 inhibitor plus nab-paclitaxel between April 2018 and January 2022. Clinical response was assessed according to Response Evaluation Criteria in Solid Tumors criteria version 1.1 (RECIST 1.1). Duration of response (DOR), overall survival (OS), and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. Results: The confirmed overall response rate (ORR) was 14/34 (41.2%), and the disease control rate (DCR) was 24/34 (70.6%). Complete response (CR) was achieved in one case, partial response (PR) in 13 cases (38.2%), stable disease (SD) in 10 cases (29.4%), and progressive disease (PD) occurred in 10 cases (29.4%). After a median follow-up period of 16.0 months [95% confidence interval (CI): 9.9-22.1], 14 deaths were reported, with a median OS of 15.0 months (95% CI: 9.9-20.1); 22 progressions were reported, with a median PFS of 6.0 months (95% CI: 2.4-9.6). Patients with visceral metastasis had a similar PFS [hazard ratio (HR): 1.28, 95% CI: 0.53-3.09, P=0.574) and OS (HR: 1.94, 95% CI: 0.64-5.83, P=0.279] to patients with lymph node metastasis only. Conclusions: This real-world study suggests that PD-1 inhibitor plus nab-paclitaxel is effective in cisplatin-ineligible and cisplatin-refractory mUTUC patients with acceptable toxicity, especially for patients with visceral metastasis.

CircPTEN suppresses human clear cell renal carcinoma progression and resistance to mTOR inhibitors by targeting epigenetic modification.

Renal cell carcinoma (RCC) is known to be the most commonly diagnosed kidney cancer. Clear cell RCC (ccRCC) represents approximately 85 % of diagnosed RCC cases. Targeted therapeutics, such as multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, are widely used in ccRCC therapy. However, patients treated with mTOR and TKI inhibitors easily acquire drug resistance, making the therapy less effective. Here, we demonstrated that circPTEN inhibits the expression of its parental gene PTEN by reducing methylation of the PTEN promotor and inhibits GLUT1 expression by reducing m6A methylation of GLUT1, which suppresses ccRCC progression and resistance to mTOR inhibitors.

MDIG-mediated H3K9me3 demethylation upregulates Myc by activating OTX2 and facilitates liver regeneration.

The mineral dust-induced gene (MDIG) comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation (H3K9me3). Previous studies have indicated the significance of MDIG in promoting cell proliferation by modulating cell-cycle transition. However, its involvement in liver regeneration has not been extensively investigated. In this study, we generated mice with liver-specific knockout of MDIG and applied partial hepatectomy or carbon tetrachloride mouse models to investigate the biological contribution of MDIG in liver regeneration. The MDIG levels showed initial upregulation followed by downregulation as the recovery progressed. Genetic MDIG deficiency resulted in dramatically impaired liver regeneration and delayed cell cycle progression. However, the MDIG-deleted liver was eventually restored over a long latency. RNA-seq analysis revealed Myc as a crucial effector downstream of MDIG. However, ATAC-seq identified the reduced chromatin accessibility of OTX2 locus in MDIG-ablated regenerating liver, with unaltered chromatin accessibility of Myc locus. Mechanistically, MDIG altered chromatin accessibility to allow transcription by demethylating H3K9me3 at the OTX2 promoter region. As a consequence, the transcription factor OTX2 binding at the Myc promoter region was decreased in MDIG-deficient hepatocytes, which in turn repressed Myc expression. Reciprocally, Myc enhanced MDIG expression by regulating MDIG promoter activity, forming a positive feedback loop to sustain hepatocyte proliferation. Altogether, our results prove the essential role of MDIG in facilitating liver regeneration via regulating histone methylation to alter chromatin accessibility and provide valuable insights into the epi-transcriptomic regulation during liver regeneration.

The impact of the COVID-19 pandemic on erectile function in Chinese CP/CPPS patients.

This study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on erectile function in Chinese patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). A retrospective study was conducted on 657 CP/CPPS patients who visited The Third Xiangya Hospital of Central South University (Changsha, China) from November 2018 to November 2022. Patients were divided into two groups based on the timeline before and after the COVID-19 outbreak in China. The severity of CP/CPPS, penile erection status, anxiety, and depression was evaluated using the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Index of Erectile Function-5 (IIEF-5), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) scales, respectively. Compared with patients before the COVID-19 outbreak, more CP/CPPS patients developed severe erectile dysfunction (ED) due to depression and anxiety caused by the pandemic. After developing moderate-to-severe ED, mild and moderate-to-severe CP/CPPS patients exhibited more apparent symptoms of anxiety and depression ( P < 0.001 and P = 0.001, respectively), forming a vicious cycle. The COVID-19 pandemic has adversely affected the psychological status of CP/CPPS patients, exacerbating their clinical symptoms and complicating ED. The exacerbation of clinical symptoms further worsens the anxiety and depression status of patients, forming a vicious cycle. During the COVID-19 pandemic, paying more attention to the mental health of CP/CPPS patients, strengthening psychological interventions, and achieving better treatment outcomes are necessary.