Different effects of CO2 laser and estrogen treatment on vaginal mucosa microbiota and function in genitourinary syndrome of menopause patients.

AIM: To characterize the effects of CO2 laser treatment and estrogen treatment on vaginal microbiota in patients with genitourinary syndrome of menopause (GSM). METHODS: Sixty-four patients with genitourinary syndrome were divided into the estrogen group, the CO2 laser group, and the control group. The control group did not receive any treatment. Vaginal mucosa was collected after 3 and 12 months of treatment. The former was used for 16S rRNA sequencing, and the latter was used for pathological evaluation. Vaginal health and voiding function were assessed using the vaginal health index (VHI) scale and the UDI-6 scale at 3 and 12 months after treatment. RESULTS: The results showed that both treatments reduced alpha diversity in the vaginal flora. Additionally, the abundance of 65 genera differed significantly between the treatment and control groups, with an increase in potentially beneficial bacteria such as Lactobacillus, IheB3_7, Mycoplasma urealyticum, and Streptococcus. In addition, the VHI and UDI-6 scores improved in both treatment groups compared to the control group after 3 months. Whereas VHI and UDI-6 scores were close to baseline in the estrogen group, and remained significantly improved in the CO2 laser group after 12 months. Pathological results showed that both methods improved the vaginal health status of patients with GSM after 12 months of treatment. However, the CO2 group exhibited a more significant increase in type III collagen. CONCLUSIONS: Both CO2 laser and estrogen therapies can regulate the vaginal flora imbalance of GSM and improve the corresponding symptoms. However, the long-term efficacy of CO2 laser therapy is superior compared to estrogen therapy.

Short- and Long-Term Outcomes of Indocyanine Green Fluorescence Navigation- Versus Conventional-Laparoscopic Hepatectomy for Hepatocellular Carcinoma: A Propensity Score-Matched, Retrospective, Cohort Study.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging technology is increasingly widely used in laparoscopic hepatectomy. However, whether it can provide long-term survival benefits to patients with liver malignancies remains unclear. This study investigated the clinical effect of laparoscopic hepatectomy for hepatocellular carcinoma (HCC) using ICG imaging technology. METHODS: We retrospectively analyzed HCC patients who underwent laparoscopic hepatectomy at Zhongnan Hospital of Wuhan University from January 2016 to December 2020. Propensity score matching (PSM) was used to match patients undergoing ICG fluorescence navigation laparoscopic hepatectomy (ICG-FNLH) with those undergoing conventional laparoscopic hepatectomy (CLH) in a 1:1 ratio to minimize the influence of confounding factors. We compared perioperative status and long-term prognosis between the two groups and performed multivariate analysis to identify risk factors associated with overall survival and recurrence-free survival. RESULTS: The original cohort consisted of 141 patients, with 50 patients in each group (100 patients in total) after PSM. The anatomical liver resection rate, R0 resection rate, and resection margin distance in the ICG-FNLH group were higher than those in the CLH group. The intraoperative blood loss was lower than that in the CLH group. The recurrence-free survival and overall survival of the ICG-FNLH group were better than those of the CLH group. ICG-FNLH improved the recurrence-free survival of HCC patients (hazard ratio [HR] = 2.165, 95% confidence interval [CI]: 1.136-4.127, P = 0.024). CONCLUSIONS: Compared with CLH, ICG-FNLH can improve the recurrence-free survival rate of patients with hepatocellular carcinoma and may help to improve the long-term prognosis of patients.

Indocyanine green fluorescent cholangiography improves the clinical effects of difficult laparoscopic cholecystectomy.

BACKGROUND: Near-infrared fluorescent cholangiography (NIRFC) with indocyanine green (ICG) as the developer yields clear visualization of the extrahepatic bile ducts and is effective in identifying key structures. Here, we analyzed and compared the surgical outcomes of fluorescent and conventional laparoscopy in cholecystectomy of various difficulties and then assessed the value of NIRFC. MATERIALS AND METHODS: This retrospective study collected clinical data from partial patients who underwent laparoscopic cholecystectomy (LC) at the Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University between 2020 and 2021. The study subjects were classified into ICG-assisted and white-light laparoscopy. Two cohorts with homogeneous baseline status were selected based on 1:1 ratio propensity score matching (PSM). Multivariate logistic regression analysis was performed to predict independent risk factors for LC difficulty. Thereafter, the matched cases were classified into difficult and easy subgroups by combining difficulty score and gallbladder disease type, and then the surgical outcomes of the two groups were compared. RESULTS: This study included a total of 624 patients. The patients were classified into the ICG group (n = 218) and the non-ICG group (n = 218) after a 1:1 ratio PSM. Our data showed significant differences between the groups in operative time (P = 0.020), blood loss (P = 0.016), length of stay (P = 0.036), and adverse reaction (P = 0.023). Stratified analysis demonstrated that ICG did not significantly improve the surgical outcomes in simple cases (n = 208). On the other hand, in difficult cases (n = 228), NIRFC shortened operative time (P = 0.003) and length of stay (P = 0.015), reduced blood loss (P = 0.028) and drain placement rate (P = 0.015), and had fewer adverse reactions (P = 0.023). The data showed that five cases were converted to laparotomy while two cases had minor bile leaks in the non-ICG group. There was no bile duct injury (BDI) in all the cases. Furthermore, high BMI, history of urgent admission and abdominal surgery, palpable gallbladder, thickened wall, and pericholecystic collection were risk factors for surgical difficulty. CONCLUSION: ICG-assisted NIRFC provides real-time biliary visualization. In complicated conditions such as acute severe inflammation, dense adhesions, and biliary variants, the navigating ability of fluorescence can enhance the operation progress, reduce the possibility of conversion or serious complications, and improve the efficiency and safety of difficult LC.

Indocyanine green fluorescence imaging-guided laparoscopic right posterior hepatectomy.

BACKGROUND: Laparoscopic right posterior hepatectomy is considered difficult on the basis of the surgery difficulty scoring system. In this study, we evaluated the safety and effectiveness of the technical application of indocyanine green (ICG) fluorescence imaging-guided laparoscopic right posterior hepatectomy. METHODS: Twenty-six patients who underwent ICG fluorescence imaging-guided laparoscopic right posterior hepatectomy at Hepatobiliary and Pancreatic Surgery Department of Zhongnan Hospital, Wuhan University, from June 2018 to December 2019, were included. The influence of patient position, trocar placement, hepatic inflow occlusion, central venous pressure (CVP), and the ICG fluorescence imaging-guided method were analyzed. RESULTS: In 17 patients, the left lateral position was maintained when the main tumor was in the S7, and in the remaining nine patients, the supine position was maintained with the right side of the body raised when the main tumor was in the S6. Ten patients who underwent preoperative injection of ICG were successfully developed for nonanatomical hepatectomy. Sixteen patients received intraoperative ICG injection for anatomical hepatectomy (2 cases had positive imaging findings, 14 cases had negative imaging findings, and 2 cases had failed imaging findings). All patients underwent the Pringle maneuver during the procedure. Four patients were preset with subhepatic vena cava blocking and one patient with suprahepatic inferior vena cava blocking. CVP was controlled at 3.00 ± 0.63 (mean ± SD) cmH2O. The operative time was 216.14 ± 52.05 min, and the bleeding volume was 128.57 ± 75.55 ml. Four patients had Clavien-Dindo level I complications, and one had level III complications. Postoperative hospitalization duration was 6.19 ± 1.40 days. There were 14 patients with hepatocellular carcinoma, 9 with metastatic liver malignancies, 2 with hepatic hemangioma, 1 with focal nodular hyperplasia of the liver, and 10 with hepatitis B liver cirrhosis. CONCLUSIONS: ICG fluorescence imaging guidance could be helpful for the safe implementation of laparoscopic right posterior hepatectomy.

Casein kinase 2 inhibitor CX-4945 elicits an anti-Warburg effects through the downregulation of TAp73 and inhibits gastric tumorigenesis.

Casein kinase 2 (CK2) has become a potential therapeutic target in gastric cancer; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, acts as a critical regulator of the Warburg effect. Recent study reveals that aberrant CK2 signaling is able to inhibit TAp73 function. Here we determine that TAp73 is overexpressed in AGS-1 but not in SNU-5 gastric cancer cell line as compared with normal gastric cells. In addition, we show that TAp73 expression is required for the maintenance of glucose uptake and lactate release in AGS-1 but not in SNU-5 gastric cancer cells. Importantly, the use of CX-4945, a selective inhibitor of protein kinase CK2, inhibits cell growth and invasion, and promotes cell apoptosis in AGS-1 with decreased TAp73 expression as well as downregulated glucose uptake and lactate release. Although TAp73 knockdown resulted in significant decreases in TAp73 expressions in SNU-5 cell line, no differences in glucose uptake and lactate release were observed between SNU-5 and normal gastric cells. Moreover, TAp73 gene overexpression promotes glucose uptake and lactate release and abolishes the anti-cancer effects of CX-4945 in gastric cancer cell line AGS-1. The impacts of CX-4945 on glycolysis and tumorigenesis were strongly limited in SNU-5 gastric cancer cell line. These findings suggest that CX-4945 elicits an anti-Warburg effects in gastric cancer overexpressing Tap73 and inhibits gastric tumorigenesis.

Predictive value of serum soluble B7-H4 in acute pancreatitis.

BACKGROUND: Studies reported that soluble B7-H4 (sB7-H4) was significantly related to the progression and prognosis of inflammatory diseases, and whether sB7-H4 is related to the severity and prognosis of acute pancreatitis (AP) timely has not been reported. MATERIALS AND METHODS: Clinical database data of 446 AP patients were retrospectively collected, and the correlation between the expression serum levels of sB7-H4 with inflammatory factors and prognostic scores was analysed in AP patients. RESULTS: Soluble B7-H4 was significantly correlated with IL-6, IL-8, TNF-α, PCT, CRP levels and WBC count (P < .01), with correlation coefficients of R = .61, .53, .46, .60, .57 and .47, respectively, and AUCs were 0.905, 0.837, 0.797, 0.858, 0.890, 0.841 and 0.855, respectively. In addition, sB7-H4 was significantly correlated with the Ranson score, APACHE II score and BISAP score (P < .001), with correlation coefficients of R = .58, .63 and .59, respectively. The AUCs of assessing local complications of AP were 0.908, 0.863, 0.785 and 0.844, respectively; assessing organ failure were 0.872, 0.790, 0.796 and 0.857, respectively; and assessing in-hospital mortality were 0.839, 0.821, 0.796 and 0.823, respectively. CONCLUSIONS: Soluble B7-H4 could be used as a marker for the diagnosis, severity assessment and poor prognosis assessment of AP patients, which may have potential clinical applications.

Down-regulation of MARCO associates with tumor progression in hepatocellular carcinoma.

Hepatocellular carcinoma(HCC) is a malignant tumor with high mortality due to lack of early diagnostic methods and effective treatments, and the molecular mechanisms are intricate and remain unclear. In the present study, the role of macrophage receptor with collagenous structure (MARCO) in tumor advancement of HCC was investigated. We examined expression level of MARCO in HCC samples, corresponding adjacent nontumor tissues and six hepatoma cell lines by polymerase chain reaction and immunohistochemistry (IHC). Clinical information of HCC patients was also analyzed. The role of MARCO involved in HCC progression via multiple functional experiments in vitro and in vivo was investigated. Bioinformatics analysis was conducted to further explore biological functions of MARCO. We found MARCO was suggestively down-regulated in HCC and associated with favorable prognosis, and MARCO upregulation oppressed tumor cell migration and invasion. Besides, overexpression of MARCO not only promoted apoptosis of hepatoma cells but also suppressed proliferation in vivo and in vitro. Furthermore, gene set enrichment analysis (GSEA) analysis suggested that MARCO may be related to the P53 signaling pathway, and this prediction was confirmed in this study as well. In sum, our study indicated that MARCO was involved in HCC progression and it can be defined as a novel probable biomarker as well as treatment target for HCC.

Effect of CLIC1 gene silencing on proliferation, migration, invasion and apoptosis of human gallbladder cancer cells.

This study aimed to explore the effects of CLIC1 gene silencing on proliferation, migration, invasion and apoptosis of human gallbladder cancer (GBC). GBC and normal gallbladder tissues were extracted for the detection of mRNA and protein expressions of CLIC1. GBC-SD and NOZ cells in the logarithmic growth phase were selected to conduct the experiment. Three different siRNA recombined expression vectors were established using CLIC1 as a target at different sites. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were, respectively, used to detect the CLIC1 mRNA and protein expressions. MTT assay was performed to detect the cell proliferation. Flow cytometry was applied to measure the cell apoptosis and cell cycle distribution. The variations of cell migration and invasion were evaluated using Transwell assay. GBC tissues showed higher CLIC1 mRNA and protein expressions than normal gallbladder tissues. The CLIC1 mRNA and protein expressions in the CLIC1 siRNA group were significantly lower than those in the NC and blank groups. Compared with the NC and blank groups, the CLIC1 siRNA group showed a significant decrease in cell proliferation but an obvious increase in apoptosis rate in GBC cells. Besides, in the CLIC1 siRNA group, cell percentage in G0/G1 and G2/M phase was gradually increased but decreased in S phases. The migration and invasion abilities in GBC cells were significantly lower than those in the NC and blank groups. Our study demonstrates that CLIC1 gene silencing could promote apoptosis and inhibit proliferation migration and invasion of GBC cells.

CUL4B promotes metastasis and proliferation in pancreatic cancer cells by inducing epithelial-mesenchymal transition via the Wnt/ß-catenin signaling pathway.

This study determines whether cullin 4B (CUL4B) promotes pancreatic cancer (PC) metastasis by inducing epithelial-mesenchymal transition (EMT) via the Wnt/ß-catenin signaling pathway. A total of 64 PC patients were enrolled in this study. Human PC cell lines were distributed into blank, negative control, shCUL4B, PLOC, PLOC-CUL4B, and PLOC-CUL4B + siRNA-ß-catenin groups. The expressions of CUL4B, Wnt/ß-catenin signaling pathway-related proteins, and EMT-related proteins were determined using RT-qPCR and Western blotting. The positive expressions of CUL4B and ß-catenin protein in tissues were detected by immunohistochemistry. MTT assay and flow cytometry was performed for cell proliferation and cell cycle, scratch test, and transwell assay for cell migration and invasion ability. CUL4B and ß-catenin were expressed at a higher level in PC tissues than in paracancerous tissues though paracancerous tissues had higher expressions of CUL4B and ß-catenin than normal tissues. The PLOC-CUL4B group showed increased CUL4B, Wnt, ß-catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; decreased E-cadherin expression; accelerated cell proliferation; increased S-phase cell percentages; increased cell migration ability; more liver metastases; and enlarged tumor than the PLOC and PLOC-CUL4B + siRNA-ß-catenin groups. The shCUL4B group showed decreased CUL4B, Wnt, ß-catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; increased E-cadherin expression; decelerated cell proliferation; decreased S-phase cell percentages; reduced cell migration ability; less liver metastases; and decreased tumor weight than the blank and negative control groups. We demonstrate that CUL4B promotes PC metastasis by inducing EMT via the Wnt/ß-catenin signaling pathway. Therefore, CUL4B might be the clinical target for treating PC.

Glucocorticoid-induced S-adenosylmethionine enhances the interferon signaling pathway by restoring STAT1 protein methylation in hepatitis B virus-infected cells.

Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon α (IFN-α). An alternative approach to increase the response rate of IFN-α might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-α, but the underlying mechanism remains unclear. We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine (AdoMet) when hepatitis B virus (HBV) replication was effectively suppressed by IFN-α. Here, we investigated the effect of GCs and IFN-α on AdoMet production and methionine adenosyltransferase 1A (MAT1A) expression in vitro. Furthermore, we determined whether post-transcriptional regulation is involved in HBV-repressed MAT1A expression and AdoMet production induced by dexamethasone (Dex). We found that AdoMet homeostasis was disrupted by Dex and that Dex directly regulated MAT1A expression by enhancing the binding of the glucocorticoid receptor (GR) to the glucocorticoid-response element (GRE) of the MAT1A promoter. HBV reduced AdoMet production by increasing methylation at GRE sites within the MAT1A promoter. The X protein of hepatitis B virus led to hypermethylation in the MAT1A promoter by recruiting DNA methyltransferase 1, and it inhibited GR binding to the GRE in the MAT1A promoter. Dex could increase an antiviral effect by inducing AdoMet production via a positive feedback loop when HBV is effectively suppressed by IFN-α, and the mechanism that involves Dex-induced AdoMet could increase STAT1 methylation rather than STAT1 phosphorylation. These findings provide a possible mechanism by which GC-induced AdoMet enhances the antiviral activity of IFN-α by restoring STAT1 methylation in HBV-infected cells.

Primary Urethra Non-Hodgkin Lymphoma in a 46-Year-Old Man on FDG PET/CT.

ABSTRACT: Primary lymphoma of the male urethra is exceptionally rare. A 46-year-old man complained of low back pain, hematuria, and dysuria. Cystourethroscopy revealed a pale, annular thickening of the urethral mucosa. A biopsy revealed that the patient had diffuse large B-cell lymphoma. Before treatment, an 18 F-FDG PET/CT was used for staging. The urethra and left inguinal lymph nodes showed increased FDG uptake. The patient was then diagnosed with primary urethral lymphoma that had invaded the left inguinal lymph node.

Axillary Lymph Node Metastasis as the First Symptom of Colon Cancer.

ABSTRACT: Axillary lymph node metastasis in colon cancer is extremely rare. We describe the FDG PET/CT findings in a 61-year-old woman who presented with a mass in the right axilla, which revealed irregular thickening of the ascending colon wall, as well as multiple enlarged lymph nodes in the ileocecal mesentery, para-aortic region, and right axilla with higher uptake of FDG. Ascending colon carcinoma with lymph node metastasis in the right axilla was confirmed by pathological examination.

The X protein of hepatitis B virus inhibits apoptosis in hepatoma cells through enhancing the methionine adenosyltransferase 2A gene expression and reducing S-adenosylmethionine production.

The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NF-κB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NF-κB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2ß expression. Thus, we proposed that HBx activates MAT2A expression through NF-κB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC.

Clinical analysis of patients with autoimmune disease complicated by mesenteric vein thrombosis: a retrospective study in a hospital.

BACKGROUND/AIMS: To analyze the clinical characteristics of patients with mesenteric venous thrombosis related to autoimmune disease (AID). METHODOLOGY: Retrospective study of 5 AID patients with mesenteric vein thrombosis in a single hospital. RESULTS: All 5 patients were female with an average age of 57.6 years. At the clinical visit all patients had clinical manifestations with signs of mesenteric blood vessel involvement and a significant increase of inflammatory markers. Surgical exploration identified peritonitis in all 5 cases - 2 cases of intestinal stenosis with mucosal ulcers and 3 cases of intestinal necrosis complicated by perforation. All 5 patients underwent partial bowel resection. Pathological examination confirmed chronic inflammation and vasculitis of intestinal connective tissue, combined with the formation of mesenteric vein thrombosis. CONCLUSIONS: Mesenteric vein thrombosis is a serious complication of AID. AID patients with digestive tract symptoms should be screened by abdominal imaging. In addition to early hormonal therapy and immunosuppressant treatment of the primary disease, surgical treatment should be performed as soon as possible if the disease progresses.

The effect of afatinib in a pretreated patient with invasive mucinous adenocarcinoma of the lung harboring HER2 YVMA insertion: a case report.

Background: Invasive mucinous adenocarcinoma (IMA) is an uncommon variant of lung adenocarcinoma. The survival data and therapeutic methods for IMAs are limited. The frequency of human epidermal growth factor receptor 2 (HER2) mutations in IMAs is low, and the clinical benefit of HER2 inhibitors in patients with IMA is still being explored. Afatinib is a pan-HER inhibitor and the studies of afatinib treatment in IMA patients are very limited. Case Description: Herein, we present the case of a 49-year-old female, never-smoker stage IVa IMA patient with persistent cough and sputum expectoration diagnosed with stage IVa IMA. Polymerase chain reaction (PCR) and next-generation sequencing (NGS) were utilized to detect mutations for targeted therapies on lung biopsy, but no mutation was found. After treatment failures of chemotherapy and a multiple-kinase inhibitor, liquid biopsy identified HER2 exon 20 insertion p.A775_G776insYVMA with NGS. The patient was then treated with afatinib as the third-line treatment. Following administration for one month, the patient's symptoms of coughing, sputum expectoration, and dyspnea improved. Stable disease (SD) was observed, and the patient achieved durable clinical benefit with prolonged progression-free survival (PFS) of 20 months. Her overall survival was 5.8 years. Conclusions: This is the first report of afatinib treatment achieving long-lasting and stable disease control in an IMA patient with a HER2 exon 20 YVMA insertion. Our results will help to improve the treatment of IMA.

Concordance of Genomic Profiles in Matched Tissue and Plasma Samples From Chinese Patients With Lung Cancer.

Background: Next-generation sequencing (NGS) has been widely used to identify targetable variants for patients with solid tumors, especially lung cancer. Circulating tumor DNA (ctDNA) has emerged as an alternative approach for tumor biopsy. However, the feasibility of ctDNA in detecting molecular variants remains debatable. Methods: Herein, we performed NGS on matched tissue and plasma samples from 146 Chinese patients with lung cancer. The concordance of variants between tissue and plasma samples was explored at patient and variant levels. Results: More than 80% of patients harbored at least one concordant variant in tissue and plasma samples. A total of 506 variants were shared between tissue and plasma samples, and 432 variants were identified in tissue only and 92 variants were identified in plasma only. The sensitivity and positive predictive value (PPV) of all variants detected in plasma were 53.9% and 84.6%, respectively. High concordance was observed in several driver genes. In details, epidermal growth factor receptor exon 19 deletion (EGFR 19del), EGFR p.S768I, anaplastic lymphoma kinase (ALK) fusion, rearranged during transfection (RET) fusion, and kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C achieved a sensitivity of 90%, 100%, 85.7%, 100%, and 85.7%, respectively. Four EGFR-altered lung adenocarcinoma patients who underwent ctDNA-based NGS at initial diagnosis benefited from first-line gefitinib/icotinib with a median progression-free survival of 379.5 days. Conclusions: Our work provided the clinical evidence of feasibility of ctDNA-based NGS in guiding decision-making in treatment. ctDNA-based NGA could be a reliable alternative approach for tissue biopsy in patients with lung cancer.

Unexpected discovery of intrahepatic cholangiocarcinoma during follow-up in two cases of liver cysts: case report.

Background: The liver cyst is commonly treated by hepatobiliary surgery. Generally, most patients show no apparent symptoms and often get diagnosed accidentally during the imaging examinations. In addition, most patients with liver cysts follow a benign course, with fewer severe complications and rare occurrences of malignant changes. Therefore, based on disease characteristics and healthcare costs, long-term regular follow-up of liver cysts are rarely performed clinically. Case Description: Here, we reported two previously treated or observed cases for liver cysts, where intrahepatic neoplastic lesions were found unexpectedly at the liver cyst during follow-up. These two patients' clinical manifestations and laboratory examinations lacked specificity with unclear pre-operative diagnosis, whereas the post-operative pathology confirmed cholangiocarcinoma. One of the patients was a 64-year-old female with right upper abdominal distension. She underwent cyst fenestration for a liver cyst 3 years ago. In the latest admission, imaging examination revealed a tumor in the left inner lobe of the liver. The tumor was located in the exact fenestration location, and the pathological diagnosis of cholangiocarcinoma was made after surgical resection. The patient received Lenvatinib post-operatively and had no recurrence during the follow-up. Another patient, a 68-year-old woman, was asymptomatic, but the liver margin was palpable under the ribs on her physical examination. She had a previous diagnosis of liver cysts and was on regular yearly follow-up. In the last follow-up, a tumor was found close to a cyst. It was diagnosed as intrahepatic cystadenocarcinoma before surgery; however, the pathological features after surgical resection were more consistent with the cholangiocarcinoma. The patient had lung metastases 2 months after the surgery, but her condition improved after receiving targeted therapy and immunotherapy. Moreover, she is alive to this day. Conclusions: We reported 2 cases of intrahepatic cholangiocarcinoma discovered accidentally during the follow-up of hepatic cysts. The location of the malignant tumor coincided with the location of the cyst, making the clinical differential diagnosis problematic. Therefore, it is necessary to be vigilant about the possibility of combined malignant tumors for the follow-up of complex cysts, as early detection and treatment may help improve the prognosis of these patients. After surgery, multimodal therapy, including chemotherapy, immunotherapy, and targeted therapy, is helpful.

Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.

Noninvasive evaluation of diabetic patients with high fasting blood glucose using DWI and BOLD MRI.

PURPOSE: To investigate the renal microstructure changes and hypoxia changes in type 2 diabetic patients and the relationship between them and glucose using both diffusion-weighted imaging (DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD MRI). METHODS: After measuring morning fasting blood glucose, DWI and BOLD MRI were performed in 57 patients with type 2 diabetes mellitus (DM group) and 14 healthy volunteers (NC group). According to the fasting blood glucose levels, diabetic patients were divided into a normoglycemic diabetes group (group A), a less hyperglycemic diabetes group (group B) and a more hyperglycemic diabetes group (group C). The renal parenchymal apparent diffusion coefficient (ADC), renal cortical R2* (CR2*), and medullary R2* (MR2*) were measured, and the R2* ratio between the medulla and cortex (MCR) was calculated. To test for differences in ADC, R2*, and MCR among the four groups, the data were analyzed by separate one-way ANOVAs. The correlations between ADC, R2*, and MCR and the clinical index of renal function were analyzed. RESULTS: Groups B and C had significantly lower ADC values in the renal parenchyma (P = 0.048, 0.002) and significantly higher MR2* and MCR values (P < 0.000, P = 0.001, 0.001, and 0.005, respectively) than the NC group. ADC was negatively correlated with glucose, and MR2*, MCR and glucose showed a weak positive correlation. CONCLUSION: DWI and BOLD may indirectly and qualitatively reflect the kidney microstructure status and hypoxia level of diabetic patients at different blood glucose levels to a certain extent, and possibly guide the clinical treatment of diabetic patients with different blood glucose levels.