Serial circulating tumor DNA profiling predicts tumor recurrence after liver transplantation for liver cancer.

BACKGROUND: Minimal residual disease (MRD) is proposed to be responsible for tumor recurrence. The role of circulating tumor DNA (ctDNA) to detect MRD, monitor recurrence, and predict prognosis in liver cancer patients undergoing liver transplantation (LT) remains unrevealed. METHODS: Serial blood samples were collected to profile ctDNA mutational changes. Baseline ctDNA mutational profiles were compared with those of matched tumor tissues. Correlations between ctDNA status and recurrence rate (RR) and recurrence-free survival (RFS) were analyzed, respectively. Dynamic change of ctDNA was monitored to predict tumor recurrence. RESULTS: Baseline mutational profiles of ctDNA were highly concordant with those of tumor tissues (median, 89.85%; range 46.2-100%) in the 74 patients. Before LT, positive ctDNA status was associated with higher RR (31.7% vs 11.5%; p = 0.001) and shorter RFS than negative ctDNA status (17.8 vs 19.4 months; p = 0.019). After LT, the percentage of ctDNA positivity decreased (17.6% vs 47.0%; p < 0.001) and patients with positive ctDNA status had higher RR (46.2% vs 21.3%; p < 0.001) and shorter RFS (17.2 vs 19.2 months; p = 0.010). Serial ctDNA profiling demonstrated patients with decreased or constant negative ctDNA status had lower RR (33.3% vs 50.0%; p = 0.015) and favorable RFS (18.2 vs 15.0 months, p = 0.003) than those with increased or constant positive ctDNA status. Serial ctDNA profiling predicted recurrence months ahead of imaging evidence and serum tumor biomarkers. CONCLUSIONS: ctDNA could effectively detect MRD and predict tumor recurrence in liver cancer patients undergone LT.

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study.

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.

Solitary hyoid plasmacytoma with unicentric Castleman disease: A case report and review of literature.

BACKGROUND: Solitary plasmacytoma and unicentric Castleman disease (UCD) are rare lymphoproliferative disorders characterized by monoclonal plasma cells and a single set of locally enlarged lymph nodes, respectively. CASE SUMMARY: A 48-year-old Han Chinese man presented to our department with a neck mass and progressive foreign body sensation in his throat. 18F-FDG positron emission tomography revealed focally increased radioactivity centered around the hyoid, and computed tomography (CT) revealed osteolytic lesions. Histopathology revealed Castleman-like features and CD138/CD38-positive mature plasma cells. Systemic work-up ruled out the possibility of POEMS syndrome, lymphoma, and multiple myeloma, leading to a final diagnosis of solitary hyoid plasmacytoma with UCD. The patient underwent partial hyoid resection and selective neck dissection, followed by intensity-modulated radiotherapy. 99mTc-MDP single-photon emission computed tomography/CT reevaluation showed neither local recurrence nor distant bone metastasis at the 40-mo follow-up. CONCLUSION: The diagnostic process and differential diagnosis of this rare case provided valuable educational information to clinicians.

Plasma MicroRNA Panel Predicts Early Tumor Recurrence in Patients with Hepatocellular Carcinoma after Liver Transplantation.

Background: This study aimed to evaluate the role of plasma microRNA panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) for prediction and surveillance of early tumor recurrence in hepatocellular carcinoma (HCC) patients who had undergone liver transplantation (LT). Methods: The expression of plasma microRNA panel was assayed in 193 HCC patients (training cohort, n =151; validation cohort, n = 42). Sensitivity and specificity for detecting post-transplant HCC recurrence, and the relationship of microRNA panel expression with clinical characteristics were analyzed accordingly. The prognostic value of microRNA panel was compared with that of AFP (alpha-fetoprotein) and DCP (Des-gamma-carboxyprothrombin). Cox regression analyses were used to evaluate independent prognostic factors. Results: In the training cohort, the rate of positive plasma microRNA panel status at 7-14 days after LT (late phase; 44.2%) decreased than that before (76.2%, P < 0.001) and 1-6 days after LT (early phase; 78.5%, P < 0.001). At late phase, positive microRNA panel status correlated with higher early tumor recurrence rate (one year after LT) than negative status (45.9% vs 10.7%; P < 0.001). Patients with persistent positive microRNA panel status both before and after LT had the highest early tumor recurrence rate in this cohort (54.9%, P < 0.001). The results were consistent in the validation cohort. Cox regression analysis found that positive plasma microRNA panel status at late phase was the only independent risk factor for early recurrence (HR: 4.903, 95% CI = 2.195 - 10.951; P < 0.001). Dynamic monitoring demonstrated plasma microRNA panel status changed from negative to positive earlier than AFP and DCP upon recurrence, and the median time between positivity of plasma microRNA and imaging evidence of recurrence was 2.4 (0.5-10.0) months. Conclusions: Plasma microRNA panel could be a noninvasive biomarker for prediction and surveillance of early tumor recurrence in HCC patients who have undergone LT.

MiR-1180 from bone marrow-derived mesenchymal stem cells induces glycolysis and chemoresistance in ovarian cancer cells by upregulating the Wnt signaling pathway.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in cancer development and progression. However, the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown. METHODS: Conditioned media of BM-MSCs (BM-MSC-CM) were analyzed using a technique based on microRNA arrays. The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells. The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models. Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer. RESULTS: MiR-1180 was the most abundant microRNA detected in BM-MSC-CM, which simultaneously induces glycolysis and chemoresistance (against cisplatin) in ovarian cancer cells. The secreted frizzled-related protein 1 (SFRP1) gene was identified as a major target of miR-1180. The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components, namely Wnt5a, ß-catenin, c-Myc, and CyclinD1, which are responsible for glycolysis-induced chemoresistance. The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue. The overexpressed miR-1180 was associated with a poor prognosis for the long-term (96-month) survival of ovarian cancer patients. CONCLUSIONS: BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180. The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1. The enhanced Wnt signaling upregulates the glycolytic level (i.e. Warburg effect), which reinforces the chemoresistance property of ovarian cancer cells.

Long non-coding RNA 00607 as a tumor suppressor by modulating NF-κB p65/p53 signaling axis in hepatocellular carcinoma.

Accumulating evidence suggests that long non-coding RNA (lncRNA) plays important roles in some malignant tumors. However, the mechanism underlying how lncRNA regulates hepatocellular carcinoma (HCC) process remains largely unknown. In this study, we explored the potential role of lncRNA 00607 as a novel tumor suppressor in HCC. In this study, we examined the regulation of lncRNA 00607 by the important inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also determined the expression of LINC000607 in 159 HCC tumors and paired adjacent tissues. Effects of LINC000607 in HCC proliferation and apoptosis were examined in vitro in HCC cell lines and in vivo tumor xenografts. Furthermore, we also examine underlying mechanism by which lncRNA 00607 regulates NF-κB p65 and how LIN00607 exerts its tumor suppressor role in HCC. We found that lncRNA 00607 expression level is lower in HCC tumors compared with matched normal liver tissue, and its low expression predicts worse prognosis in HCC. Functionally, lncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity. Mechanistically, lncRNA 00607 inhibits the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC. Taken together, the findings of this study show that the TNF-α/IL-6-lncRNA 00607-NF-κB p65/p53 signaling axis represents a novel therapeutic avenue in cancer chemotherapy.

Dihydromyricetin-mediated inhibition of the Notch1 pathway induces apoptosis in QGY7701 and HepG2 hepatoma cells.

AIM: To investigate whether Dihydromyricetin (DHM) inhibits cell proliferation and promotes apoptosis by downregulating Notch1 expression. METHODS: The correlation between Notch1 and Hes1 (a Notch1 target molecule) expression in hepatoma samples was confirmed by qRT-PCR. In addition, MTT assays, flow cytometry and TUNEL analysis showed that DHM possessed strong anti-tumor properties, evidenced not only by reduced cell proliferation but also by enhanced apoptosis in QGY7701 and HepG2 hepatocellular carcinoma (HCC) cells. The expressions of Notch1, Hes1, Bcl-2 and Bax were determined by Western blot. RESULTS: Among the tested samples (n = 64), the expression levels of Notch1 (75% of patients) and Hes1 (79.7% of patients) mRNA in tumor tissues were higher than in the normal liver tissues. There was a negative correlation between the expression of Notch1 and the degree of differentiation and positively correlated with the Alpha Fetal Protein concentration. The viability of HCC cells treated with DHM was significantly inhibited in a dose and time-dependent manner. Apoptosis was induced in HepG2 and QGY7701 cell lines following 24 h of DHM treatment. After treatment with DHM, the protein expression of Notch1 was downregulated, the apoptosis-related protein Bax was upregulated and Bcl2 was downregulated. Notch1 siRNA further enhanced the anti-tumor properties of DHM. CONCLUSION: Notch1 is involved in the development of HCC and DHM inhibits cell proliferation and promotes apoptosis by down-regulating the expression of Notch1.

HOXB7 promotes tumor progression via bFGF-induced activation of MAPK/ERK pathway and indicated poor prognosis in hepatocellular carcinoma.

The homeobox-containing gene HOXB7 plays an important role in the pathogenesis and progression of many cancers, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study comprehensively analyzed the expression and clinical significance of HOXB7 in HCC and explored its potential mechanism in tumor progression. We found HOXB7 was highly expressed in HCC cell lines with highly metastatic potential and cancerous tissues from patients with tumor recurrence. The abilities of proliferation, migration, and invasion were notably decreased by depletion of HOXB7, and were enhanced by its enforced expression in vitro. HOXB7 expression was positively correlated with tumor progression and lung metastasis in vivo. The gene microarray data implied that HOXB7 affects biological functions of HCC cells through MAPK/ERK pathway activation. Further study confirmed that the effect of HOXB7 in activating MAPK/ERK pathway via induction of basic fibroblast growth factor (bFGF) secretion, and the inhibition of bFGF secretion could abolish MAPK/ERK pathway activation after ectopic expression of HOXB7. Chromatin immunoprecipitation experiments and luciferase reporter assays confirmed that HOXB7 promoted bFGF secretion via binding its promoter directly. Furthermore, the clinical significance of HOXB7 expression was confirmed using tissue microarrays containing 394 HCC tissue specimens. Patients with high HOXB7 expression showed shorter survival times and higher recurrence rates, and HOXB7 was an independent indicator for survival and recurrence. Overall, HOXB7 promotes HCC cell proliferation, migration, and invasion through the bFGF-induced MAPK/ERK pathway activation. It might be a novel prognostic factor in HCC and a promising therapeutic target for tumor metastasis and recurrence.

Naive Treg-like CCR7(+) mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma.

Chemokine receptor-like 1 (CCRL1) has the potential in creating a low level of CCL19 and CCL21 to hinder CCR7(+) cell tracking to tumor tissue. Previously, we found a tumor suppressive role of CCRL1 by impairing CCR7-related chemotaxis of tumor cells in human hepatocellular carcinoma (HCC). Here, we reported a contribution of CCR7(+) mononuclear cells in the tumor microenvironment to the progression of disease. Immunohistochemistry was used to investigate the distribution and clinical significance of CCR7(+) cells in a cohort of 240 HCC patients. Furthermore, the phenotype, composition, and functional status of CCR7(+) cells were determined by flow cytometry, immunofluorescence, and in vitro co-culture assays. We found that CCR7(+) mononuclear cells were dispersed around tumor tissue and negatively related to tumoral expression of CCRL1 (P < 0.001, r = 0.391). High density of CCR7(+) mononuclear cells positively correlated with the absence of tumor capsule, vascular invasion, and poor differentiation (P < 0.05). Survival analyses revealed that increased number of CCR7(+) mononuclear cells was significantly associated with worse survival and increased recurrence. We found that CCR7(+) mononuclear cells featured a naive Treg-like phenotype (CD45RA(+)CD25(+)FOXP3(+)) and possessed tumor-promoting potential by producing TGF-ß1. Moreover, CCR7(+) cells were also composed of several immunocytes, a third of which were CD8(+) T cells. CCR7(+) Treg-like cells facilitate tumor growth and indicate unfavorable prognosis in HCC patients, but fortunately, their tracking to tumor tissue is under the control of CCRL1.

Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection.

BACKGROUND: Tie2-expressing monocytes (TEMs) are found in various tumors, involved in forming tumor blood vessels and expressing several important proangiogenic factors. The goals of this study were to evaluate the value of TEMs in diagnosing and predicting the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: Flow cytometry was performed to identify and count TEMs in peripheral blood monocytes from HCC patients (n = 84) receiving hepatectomy, HBV cirrhotic patients (n = 21), benign tumors patients (n = 15) and healthy volunteers (n = 23). Angiopoietin-2 (Ang-2) levels in the plasma were determined by enzyme linked immunosorbent assay. The distribution of TEMs in tumor tissue was observed by immunofluorescence staining. Then we determined the vascular area as a percentage of tumor area (vascular area/tumor area) by immunohistochemical staining. Finally the prognostic significance of TEMs and other clinicopathologic factors was evaluated. RESULTS: Percentage of TEMs in peripheral blood monocytes significantly increased in HCC patients compared with HBV cirrhotic patients and healthy donors (both P< 0.001). However there was no significance in benign liver tumor (P = 0.482). In addition, the percentage of circulating TEMs was positively correlated with plasma Ang-2 concentration (P<0.001, r2 = 0.294) and vascular area/tumor area (P<0.001, r2 = 0.126). Furthermore the percentage of intratumoral TEMs was significantly higher than that of paratumoral TEMs (P<0.001). Increased circulating TEMs was associated with poor overall survival (P = 0.043) and a shorter time to recurrence (P = 0.041). Multivariate Cox analysis also revealed that the percentage of TEMs in peripheral blood was an independent factor for HCC patients' prognosis. CONCLUSIONS: TEMs may promote angiogenesis in HCC regarding the angiopoietin/Tie2 signal pathway. Percentage of TEMs in peripheral blood monocytes may be applied as a biomarker for identifying HBV-related HCC and predicting the prognosis of these patients after resection.

Promyelocytic leukemia protein induces arsenic trioxide resistance through regulation of aldehyde dehydrogenase 3 family member A1 in hepatocellular carcinoma.

Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down-regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combined with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression.

[The Role of Leptin in Cognitive Development During Aging].

Brain aging is accompanied by alternations of brain structure, functions and the cognitive impairment. With respect to cognitive decline, the elderly population is far from homogeneous, as well as heterogeneous, which presents successful aging, normal aging, mild cognitive impairment and Alzheimer's disease. Studies demonstrated that higher serum leptin levels are associated with normal cognition in older adults without significant neurological conditions, while it is lower in most mild cognitive impairment patients. Leptin can improve cognitive disorders and referred to as a potential cognitive enhancer. Therefore, low level of leptin plays an significant role in cognitive impairment development in elderly people.

Diagnosis of 25 genotypes of human papillomaviruses for their physical statuses in cervical precancerous/cancerous lesions: a comparison of E2/E6E7 ratio-based vs. multiple E1-L1/E6E7 ratio-based detection techniques.

BACKGROUND: Cervical lesions caused by integrated human papillomavirus (HPV) infection are highly dangerous because they can quickly develop into invasive cancers. However, clinicians are currently hampered by the lack of a quick, convenient and precise technique to detect integrated/mixed infections of various genotypes of HPVs in the cervix. This study aimed to develop a practical tool to determine the physical status of different HPVs and evaluate its clinical significance. METHODS: The target population comprised 1162 women with an HPV infection history of > six months and an abnormal cervical cytological finding. The multiple E1-L1/E6E7 ratio analysis, a novel technique, was developed based on determining the ratios of E1/E6E7, E2/E6E7, E4E5/E6E7, L2/E6E7 and L1/E6E7 within the viral genome. Any imbalanced ratios indicate integration. Its diagnostic and predictive performances were compared with those of E2/E6E7 ratio analysis. The detection accuracy of both techniques was evaluated using the gold-standard technique "detection of integrated papillomavirus sequences" (DIPS). To realize a multigenotypic detection goal, a primer and probe library was established. RESULTS: The integration rate of a particular genotype of HPV was correlated with its tumorigenic potential and women with higher lesion grades often carried lower viral loads. The E1-L1/E6E7 ratio analysis achieved 92.7% sensitivity and 99.0% specificity in detecting HPV integration, while the E2/E6E7 ratio analysis showed a much lower sensitivity (75.6%) and a similar specificity (99.3%). Interference due to episomal copies was observed in both techniques, leading to false-negative results. However, some positive results of E1-L1/E6E7 ratio analysis were missed by DIPS due to its stochastic detection nature. The E1-L1/E6E7 ratio analysis is more efficient than E2/E6E7 ratio analysis and DIPS in predicting precancerous/cancerous lesions, in which both positive predictive values (36.7%-82.3%) and negative predictive values (75.9%-100%) were highest (based on the results of three rounds of biopsies). CONCLUSIONS: The multiple E1-L1/E6E7 ratio analysis is more sensitive and predictive than E2/E6E7 ratio analysis as a triage test for detecting HPV integration. It can effectively narrow the range of candidates for colposcopic examination and cervical biopsy, thereby lowering the expense of cervical cancer prevention.

High MUC2 expression in ovarian cancer is inversely associated with the M1/M2 ratio of tumor-associated macrophages and patient survival time.

Mucin 2 (MUC2) is a mucin molecule aberrantly expressed by ovarian cancer cells. Previous in vitro studies have indicated that MUC2 promotes cancer growth and metastasis through a tumor-associated macrophage (TAM)-dependent mechanism. However, this mechanism has never been linked to clinical oncology, and its prognostic significance needed to be clarified. Here, we collected 102 consecutive ovarian cancer specimens and used the multiple immuno-histo-chemical/-fluorescent technique to determine the correlations between the MUC2 expression status, the ratio of M1/M2 TAMs and the densities of cyclooxygenase-2 (COX-2)(+) TAMs and COX-2(+) cancer cells. The Kaplan-Meier survival analysis and multivariate Cox regression analysis were used to evaluate the prognostic influences of these parameters. As a result, we found that the MUC2 overexpression (immunostaining ++/+++) was significantly correlated with a reduced ratio of M1/M2 TAMs (p<0.001), an increased density of COX-2(+) TAMs (p<0.001) and an increased density of COX-2(+) cancer cells (p=0.017). Moreover, most of the M2 TAMs (93%-100%) and COX-2(+) TAMs (63%-89%) overlapped; and the COX-2(+) cancer cells were frequently observed near the COX-2(+) TAMs. In the Cox regression analysis, MUC2 overexpression was found to be an independent prognostic factor for ovarian cancer patients, of which the hazard ratio (HR) was 2.354 (95% confidence interval (CI): 1.031-10.707, p=0.005). Also, the reduced ratio of M1/M2 TAMs and the increased densities of COX-2(+) TAMs and COX-2(+) cancer cells were demonstrated to be the predictors of poor prognosis, among which the reduced M1/M2 ratio possessed the highest HR (1.767, 95% CI: 1.061-6.957, p=0.019). All these findings revealed that MUC2 can concurrently exert M2-polarizing and COX-2-inducing effects on TAMs, by which it causes an imbalanced TAM M1-/M2-polarization pattern and induces local PGE2 synthesis (in both TAMs and cancer cells). The positive feedback between local PGE2 synthesis and TAM M2-polarization accelerates ovarian cancer progression.

[Risk of cervical cancer and precancerous diseases in the oral HPV carriers].

OBJECTIVE: To evaluate the risk of the occurrence of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer in the oral HPV carriers through a population-based investigation in Shanghai. METHODS: A total of 1200 cases of outpatients who attended the annual cervical examination and 50 preoperational cases of inpatients with CINIII or invasive cervical cancer were enrolled from three clinical centers in Shanghai. The oral HPV infection was determined by real-time PCR. In 1200-case cross-sectional study, the incidence rate of CIN was compared between the oral HPV positive and negative cohort. In 1250-case case-control study, the positive rate of oral HPV DNA test was compared among normal control group, CINI-III, and invasive cancer case groups, and all odds ratio (OR) values were calculated, respectively. The HPV transmission-related demographic and behavioral characters of the oral HPV carriers were also analyzed. RESULTS: The oral HPV carriers accounted for 5.9% (71/1200) of the investigated outpatients. The oral HPV DNA positive rates were gradually increased with the cervical disease grades, which were 5.8% (68/1182, normal), 2/13 (CIN I), 1/5 (CINII), 31.4% (11/35, CINIII) and 5/15 (invasive cancer). In cross-sectional cohort studies, the relative risks (RR) of CINI,II were 2.9 and 4.0 for oral HPV carriers, respectively. In case-control study, the OR values for CINI-III and invasive cervical cancer were 3.1(95%CI: 1.6-10.1), 4.2(95%CI: 1.7-28.4), 7.1(95%CI: 4.8-19.8) and 10.1(95%CI: 3.2-32.1), respectively. The oral sex and multi-sexual partner were two major risk factors for the oral and cervical HPV co-infection, HPV-related cervical cancer and precancerous diseases according to behavioral analysis. CONCLUSIONS: There are complicated transmission pathways between oral and cervical HPV. Oral HPV carriers should be intensively followed up and their oral HPV infection and HPV-related cervical diseases should be treated together.

Decreased serum hepcidin concentration correlates with brain iron deposition in patients with HBV-related cirrhosis.

PURPOSE: Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. METHODS: Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. RESULTS: Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. CONCLUSIONS: Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.

Plasma microRNA, a potential biomarker for acute rejection after liver transplantation.

BACKGROUND: Acute rejection (AR) of an organ transplant is a life-threatening complication. Currently, there are few diagnostic biomarkers suitable for clinical application. We aim to determine the potential of plasma microRNAs as biomarkers for AR. METHODS: Using rat orthotopic liver transplantation model and microarrays, we compared the difference in the spectrum and levels of microRNAs in both plasma and grafts between AR rats and control. AR-related plasma microRNAs were selected and validated using real-time quantification polymerase chain reaction. Plasma from AR rats with or without tacrolimus treatment was used for microRNA dynamic monitoring. To clarify the origin of AR-related plasma microRNAs, drug-induced liver damage rat model were performed and in situ hybridization was used to detect and localize the specific microRNA in allografts. RESULTS: We found that plasma miR-122, miR-192, and miR-146a was significantly up-regulated when AR occur (fold change>2; P<0.05) and the elevation could be repressed by immunosuppression. In liver injury rat model, up-regulated plasma miR-122 (fold change=22.126; P=0.002) and miR-192 (fold change=8.833; P<0.001) rather than miR-146a (fold change=1.181; P=0.594) were observed. Further study demonstrated that miR-146a was up-regulated by sixfold in microvesicles isolated from AR plasma, whereas miR-122 and miR-192 showed no distinct change. In situ hybridization revealed that the portal areas of the AR graft were brimming with lymphocytes, which showed highly intense staining for miR-146a. CONCLUSIONS: Our study provides the global fingerprint of plasma microRNAs in AR rats and suggests that plasma miR-122 and miR-192 reflect liver injury, whereas miR-146a may associate with cellular rejection.

T2* MRI of minimal hepatic encephalopathy and cognitive correlates in vivo.

PURPOSE: To evaluate regional brain iron deposition in minimal hepatic encephalopathy (MHE) patients using T2*-weighted gradient-echo imaging and to explore the relationship between T2* MR changes and cognitive performance. MATERIALS AND METHODS: Forty hepatitis-B virus (HBV)-related cirrhotic patients and 22 age-, sex-, and education-matched healthy controls were included in this study. Of the patients, twenty eight patients were diagnosed with MHE. All subjects were administered Number Connection Test-A (NCT-A), Letter Digit Substitution Test (LDST), Rey-Osterrieth Complex Figure Test (RCFT), and the Mini-Mental State Examination (MMSE). T2*-weighted gradient-echo images were acquired using 3 Tesla MRI. Phase values (putative iron levels) in the frontal-basal ganglia-thalamocortical circuits were measured. Spearman correlation and multiple linear regression analysis were performed. RESULTS: MHE patients exhibited significantly prolonged NCT-A time and decreased LDST, RCFT immediate and delayed recall scores. Significant decreases of phase values in the bilateral putamen were detected in MHE patients compared to without MHE patients and controls. Multiple linear regression analysis confirmed significant correlations between the phase values in the putamen and right frontal white matter and cognitive performances by MHE patients. CONCLUSION: Decreased phase values in the frontal cortical-basal ganglial circuits independently contribute to cognitive impairments in MHE patients.

[Experimental study of Duffy antigen receptor for chemokines in tissue and the inflammatory reaction of limb with venous hypertension].

OBJECTIVE: To explore the role and mechanism of Duffy antigen receptor for chemokines (DARC) of tissue in promoting the inflammatory reaction of the limb with venous hypertension. METHODS: moral arteriovenous fistula was surgically created to establish the rat model of venous hypertension. A total of 36 SD rats were randomly divided into pcDNA3.1-DARC (Group A), empty plasmid of pcDNA3.1 (Group B) and control (Group C) groups. The animals were sacrificed at Days 14 and 42 post-operation respectively. The expressions of DARC at the RNA and protein level were detected by real-time polymerase chain reaction (PCR) and Western blot. And the serum level of interleukin (IL)-8 was detected by enzyme linked immunosorbent assay (ELISA) and the degrees of apoptosis and leukocytic infiltration of local tissue were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and hematoxylin and eosin (HE) staining. RESULTS: With the elapsing time of venous hypertension, the DARC expression in tissue, the extent of apoptosis and leukocytic infiltration in tissue showed an increasing trend in Groups A and B. Group A was obviously higher than Group B during the corresponding period. And the differences were statistically significant (P < 0.05). The serum levels of IL-8 of Groups A and B showed a decreasing trend. And Group A was obviously lower than Group B. Both groups were higher than the control group. The differences were statistically significant (P < 0.05). CONCLUSIONS: The level of DARC in tissue and the degree of inflammatory reaction of venous hypertension have a positive correlation. And DARC may promote the development of venous hypertension inflammation through augmenting the adhesion and migration of leukocytes.