Diagnosis of osteochondral lesions of the talus on Dual-layer spectral detector CT arthrography: clinical feasibility of virtual noncontrast images.

AIM: To compare the image quality of virtual noncontrast (VNC) and true noncontrast (TNC) CT images and to evaluate the clinical feasibility of VNC CT images for assessing osteochondral lesions of the talus (OLTs). MATERIALS AND METHODS: Forty-five OLT patients who underwent ankle CT arthrography (CTA) using dual-layer spectral detector CT were enrolled. Reconstruction of VNC and three-dimensional volume rendering images was performed. Afterward, image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For the subjective evaluation, two board-certified musculoskeletal radiologists [R2-1] assessed spatial resolution, overall image quality, and lesion conspicuity. The accuracy rate for OLT grading was determined in 23 patients who underwent arthroscopic surgery. RESULTS: While VNC images showed significantly less noise than TNC images, TNC images showed better SNRs and CNRs (p<.01). In the subjective analysis, TNC images showed better overall image quality (p<.001). For the 3D volume rendering images, VNC images scored significantly higher for lesion conspicuity (p<.001). The accuracy rates of CTA and CTA with VNC images for OLT grading were 79.2% and 83.3%, respectively. Regarding confidence level, when CTA and VNC images were evaluated together, the confidence level was significantly higher than that when only CTA images were evaluated (p<.001). CONCLUSION: VNC imaging can provide better confidence level of OLT grading and evaluation of the integrity of the subchondral bone plate when combined with conventional CTA without additional radiation dose to the patient. In addition, VNC images-based 3D volume rendering reconstruction would be helpful for preoperative planning in OLT patients.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.

Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study is to compare the risk of venous thromboembolic events (VTE) between patients suspending and continuing estrogen therapy perioperatively, in male to female gender-affirming surgery (vaginoplasty). MATERIALS AND METHODS: The authors conducted a systematic review and meta-analysis of existing research on male to female gender-affirming study, which compared the risk of VTE among the usage of estrogen perioperatively. RESULTS: A total of 209 studies were identified as potentially eligible among PubMed, Embase, and Cochrane library databases. Among the studies, 191 studies were excluded due to their abstract inappropriateness. Out of the remaining 18 studies, only 3 articles were eligible and were finally included. Meta-analysis was performed and showed odds ratio of 0.77 (95% CI: 0.04, 14.01). CONCLUSIONS: Perioperative estrogen therapy does not increase VTE risk on male to female gender-affirming surgery. Therefore, estrogen therapy may be continued perioperatively in vaginoplasty. More prospective studies are needed.

Efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy for advanced EGFR-mutated non-small cell lung cancer: systematic review and meta-analysis.

OBJECTIVE: It is controversial whether there is efficacy or safety benefit of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced EGFR-mutated non-small cell lung cancer (NSCLC) compared to standard chemotherapy. We aim to assess the efficacy and safety of EGFR-TKIs compared to other chemotherapeutics in EGFR-mutated NSCLC. MATERIALS AND METHODS: Up to April 27th, 2020, PubMed, Embase, Medline, Scopus, Cochrane library, and ClinicalTrials.gov were searched for articles or trials meeting the inclusion criteria. After filtering, 230 eligible studies were initially identified. Data extraction followed PRISMA and included outcomes were progression-free survival (PFS), overall survival (OS), and severe adverse events (SAEs). Direct and indirect meta-analyses were generated in the context of log-linear mixed-effects models, with fixed effects for each relative comparison and random effects for each study. RESULTS: The results showed that EGFR-TKI therapy had improved PFS with a hazard ratio (HR) of 0.40 (95% CI: 0.36-0.44, p<0.001) compared to standard chemotherapy. Nevertheless, the EGFR-TKIs showed no benefit on OS (HR: 0.96, 95% CI: 0.83-1.10, p=0.556). In the analysis of adverse events, EGFR-TKIs had fewer SAEs than standard chemotherapy (HR: 0.29, 95% CI: 0.26-0.33, p<0.001). CONCLUSIONS: Our systemic review indicates that EGFR-TKI therapy has improved PFS, and reduced SAEs compared to standard chemotherapy in advanced EGFR-mutated NSCLC.

Reversible cerebral vasoconstriction syndrome: a comprehensive systematic review.

OBJECTIVE: We aimed to analyze clinical characteristics, treatment patterns, and prognosis of patients with reversible cerebral vasoconstriction syndrome (RCVS). MATERIALS AND METHODS: Two investigators independently searched PubMed and EMBASE, and 191 cases were included in this study. Information regarding demographics, triggering factors, brain imaging findings, treatment modalities, recurrence, and clinical outcome was collected. RESULTS: The mean age of the patients was 39.9 years, and 155 (81.2%) were female. The most common triggering factor for RCVS was an exposure to vasoactive substances (41.4%), followed by pregnancy/postpartum (20.9%), and sexual intercourse (10.5%). Multifocal stenosis (84.0%) and beading shape (82.4%) were the leading abnormal findings on angiography, while cerebral ischemic lesions (47.6%) and cerebral hemorrhage (mainly subarachnoid hemorrhage) (35.1%) were the main findings on brain computed tomography (CT)/magnetic resonance imaging (MRI). Calcium channel blockers (nimodipine/verapamil) were the most commonly used medications (44.5%) in the treatment of RCVS. Multivariate analysis identified that RCVS was precipitated by trauma/surgery/procedure (hazard ratio (HR): 3.29, 95% confidence interval (CI) (1.21-8.88), p=0.019), and presence of aphasia/neglect/apraxia during the acute phase of the disease (HR: 3.83, 95% CI (1.33-11.05), p=0.013) were found to be the two independent risk factors for residual neurological deficit after RCVS. CONCLUSIONS: In our systematic review, vasoactive substances were the most frequent triggers for RCVS, which was most commonly accompanied by angiographic findings of multifocal stenotic lesions. Patients with RCVS precipitated by trauma or surgical procedures and those with focal cortical deficits had a higher risk of residual neurological deficits, and these patients should closely be monitored.

Risk factors of COVID-19 mortality: a systematic review of current literature and lessons from recent retracted articles.

OBJECTIVE: Recently, two influential articles that reported the association of (hydroxy)chloroquine or angiotensin converting enzyme (ACE) inhibitors and coronavirus disease 2019 (COVID-19) mortality were retracted due to significant methodological issues. Therefore, we aimed to analyze the same clinical issues through an improved research method and to find out the differences from the retracted papers. We systematically reviewed pre-existing literature, and compared the results with those of the retracted papers to gain a novel insight. MATERIALS AND METHODS: We extracted common risk factors identified in two retracted papers, and conducted relevant publication search until June 26, 2020 in PubMed. Then, we analyzed the risk factors for COVID-19 mortality and compared them to those of the retracted papers. RESULTS: Our systematic review demonstrated that most demographic and clinical risk factors for COVID-19 mortality were similar to those of the retracted papers. However, while the retracted paper indicated that both (hydroxy)chloroquine monotherapy and combination therapy with macrolide were associated with higher risk of mortality, our study showed that only combination therapy of hydroxychloroquine and macrolide was associated with higher risk of mortality (odds ratio 2.33; 95% confidence interval 1.63-3.34). In addition, our study demonstrated that use of ACE inhibitors or angiotensin receptor blockers (ARBs) was associated with reduced risk of mortality (0.77; 0.65-0.91). CONCLUSIONS: When analyzing the same clinical issues with the two retracted papers through a systematic review of randomized controlled trials and relevant cohort studies, we found out that (hydroxy)chloroquine monotherapy was not associated with higher risk of mortality, and that the use of ACE inhibitors or ARBs was associated with reduced risk of mortality in COVID-19 patients.

Clinical characteristics and mortality of patients with hematologic malignancies and COVID-19: a systematic review.

OBJECTIVE: Hematologic cancer patients with Coronavirus Disease 2019 (COVID-19) tend to have a more serious disease course than observed in the general population. Herein, we comprehensively reviewed existing literature and analyzed clinical characteristics and mortality of patients with hematologic malignancies and COVID-19. MATERIALS AND METHODS: Through searching PubMed until June 03, 2020, we identified 16 relevant case studies (33 cases) from a total of 45 studies that have reported on patients with COVID-19 and hematologic malignancies. We investigated the clinical and laboratory characteristics including type of hematologic malignancies, initial symptoms, laboratory findings, and clinical outcomes. Then, we compared those characteristics and outcomes of patients with hematologic malignancies and COVID-19 to the general population infected with COVID-19. RESULTS: The median age was 66-year-old. Chronic lymphocytic leukemia was the most common type of hematologic malignancy (39.4%). Fever was the most common symptom (75.9%). Most patients had normal leukocyte counts (55.6%), lymphocytosis (45.4%), and normal platelet counts (68.8%). In comparison to patients with COVID-19 without underlying hematologic malignancies, dyspnea was more prevalent (45.0 vs. 24.9%, p=0.025). Leukocytosis (38.9 vs. 9.8%, p=0.001), lymphocytosis (45.4 vs. 8.2%, p=0.001), and thrombocytopenia (31.3 vs. 11.4%, p=0.036) were significantly more prevalent and lymphopenia (18.2 vs. 57.4%, p=0.012) less prevalent in patients with hematologic malignancies. There were no clinical and laboratory characteristics predicting mortality in patients with hematologic malignancies. Mortality was much higher in patients with hematologic malignancies compared to those without this condition (40.0 vs. 3.6%, p<0.001). CONCLUSIONS: Co-occurrence of hematologic malignancies and COVID-19 is rare. However, due to the high mortality rate from COVID-19 in this vulnerable population, further investigation on tailored treatment and management is required.

Intraoperative Management to Prevent Cardiac Collapse in a Patient With a Recurrent, Large-volume Pericardial Effusion and Paroxysmal Atrial Fibrillation During Liver Transplantation: A Case Report.

BACKGROUND: Pericardial effusion is a common feature of end-stage liver disease. In this case report we describe the intraoperative management of recurrent pericardial effusion, without re-pericardiocentesis, to prevent circulatory collapse during a critical surgical time-point; that is, during manipulation of the major vessels and graft reperfusion. METHODS: A 47-year-old woman with hepatitis B was scheduled to undergo deceased donor liver transplantation (LT). A large pericardial effusion was preoperatively identified using transthoracic echocardiography (TTE). The patient also had paroxysmal atrial fibrillation. Two days before surgery, preemptive pericardiocentesis was performed and the 1150-mL effusion was drained. Intraoperatively, recurrence of the large pericardial effusion was identified using transesophageal echocardiography (TEE). During inferior vena cava manipulation, the surgeon consulted the anesthesiologist to evaluate the hemodynamic changes in the patient. After 3 attempts, the transplant team was able to determine the most appropriate anastomosis site, defined as that with the least impact on cardiac function. To prevent the development of severe postreperfusion syndrome, 10% MgSO4 (2 g) was gradually infused 20 minutes before portal vein declamping, and immediately before graft reperfusion a 100-µg bolus of epinephrine was administered. RESULTS: During graft reperfusion, there was no evidence of heart chamber collapse or flow disturbance, as seen on the TEE findings. Postoperatively, the patient recovered completely and was discharged from the hospital. Six months after surgery, there was no sign of pericardial effusion on follow-up TTE. CONCLUSION: Our intraoperative strategy may prevent cardiac collapse in patients with pericardial effusion detected during LT. Intraoperative TEE plays an important role in guiding hemodynamic management.

Perioperative Changes in the Psoas Muscle Index in Patients Undergoing ABO-Incompatible Living-Donor Liver Transplantation: A Single-Center Experience.

INTRODUCTION: In the era of rituximab, ABO-incompatible living-donor liver transplantation (ABOi LDLT) is clinically accepted as a feasible therapy for end-stage liver disease. To date, no data on postoperative sarcopenic changes in patients undergoing ABOi LDLT are available. PATIENTS AND METHODS: Thirty-six adult patients undergoing ABOi LDLT between October 2010 and July 2017 at our hospital were retrospectively analyzed. The cross-sectional areas of both psoas muscles between the third and fourth lumbar vertebrae were manually estimated from abdominal computed tomography images obtained within 1 month before surgery, and 1 and 3 weeks, 6 months, and 1 year after surgery. The mean psoas muscle areas were calculated and normalized by the height squared to create psoas muscle indices (PMIs). RESULTS: The PMIs on postoperative days (PODs) 7 and 21 were significantly lower than the preoperative PMI in each whole study and male cohort. In whole study cohort, the absolute and relative PMIs on POD 7 were 308.8 (271.5-375.8) mm2/m2 and 95.3% (89.9%-101.1%). On POD 21, the values were 297.8 (258.5-349.6) mm2/m2 and 90.7% (81.1%-99.2%). In men, they were 335.3 (276.7-389.4) mm2/m2 and 94.2% (89.0%-98.8%) on POD 7, and 305.0 (271.6-357.0) mm2/m2 and 89.2% (83.2%-98.2%) on POD 21. In women, they were 281.2 (231.1-313.7) mm2/m2 and 101.4% (95.2%-106.0%) on POD 7, and 260.7 (245.9-273.9) mm2/m2 and 98.9% (77.9%-124.3%) on POD 21. CONCLUSION: Patients undergoing ABOi LDLT were most vulnerable to core muscle loss soon after surgery.

Intraoperative Management of a Patient With Impaired Cardiac Function Undergoing Simultaneous ABO-Compatible Liver and ABO-Incompatible Kidney Transplant From 2 Living Donors: A Case Report.

BACKGROUND: Combined liver and kidney transplant is a very complex surgery. To date, there has been no report on the intraoperative management of patients with impaired cardiac function undergoing simultaneous ABO-compatible liver and ABO-incompatible kidney transplant from 2 living donors. CASE REPORT: A 60-year-old man underwent simultaneous ABO-compatible liver and ABO-incompatible kidney transplant from 2 living donors because of IgA nephropathy and alcoholic liver cirrhosis. The preoperative cardiac findings revealed continuous aggravation, shown by large left atrial enlargement, severe left ventricular hypertrophy, a very prolonged QT interval, and a calcified left anterior descending coronary artery. Severe hypotension with very weak pulsation and severe bradycardia developed, with an irregular junctional rhythm noted immediately after the liver graft was reperfused. Although epinephrine was administered as a rescue drug, hemodynamics did not improve, and central venous pressure and mean pulmonary arterial pressure increased to potentially fatal levels. Emergency phlebotomy via the central line was performed. Thereafter, hypotension and bradycardia recovered gradually as the central venous pressure and mean pulmonary arterial pressure decreased. The irregular junctional rhythm returned to a sinus rhythm, but the QTc interval was slightly more prolonged. Because of poor cardiac capacity, the volume and rate of fluid infusion were increased aggressively to maintain appropriate kidney graft perfusion after confirming vigorous urine production of the graft. CONCLUSIONS: A heart with impaired function due to both end-stage liver and kidney diseases may be less able to withstand surgical stress. Further study on cardiac dysfunction will be helpful for the management of patients undergoing complex transplant surgery.

Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis.

RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that recapitulates early breast tumorigenesis, the fraction of actively transcribed Pol III genes increases reaching a plateau during immortalization. Hyper-methylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. When Pol III genes are hypo-methylated, MYC amplifies their transcription, regardless of its recognition DNA motif. Thus, Pol III expression during tumorigenesis is delineated by methylation and magnified by MYC.

Ureteral Complications in Kidney Transplantation: Analysis and Management of 853 Consecutive Laparoscopic Living-Donor Nephrectomies in a Single Center.

BACKGROUND: We report the incidence and nature of ureteral and surgical complications in our series of 853 consecutive living-donor renal transplants after laparoscopic living-donor nephrectomy. The aim of this study was to analyze the therapeutic approaches to ureteral complications in kidney transplantations and their relationship with recipient outcome. METHODS: The medical records of patients who underwent kidney transplantation from 2000 to 2014 were reviewed retrospectively. After the donor nephrectomies were performed with the use of laparoscopic, hand-assisted laparoscopic, and vesico-ureteral anastomosis, the recipient's ureteral complications were classified according to the mechanism and site of urinary tract involvement: anastomosis stricture, anastomosis leakage, vesico-ureteral reflux, and urolithiasis. RESULTS: Among the 853 cases of kidney transplantation, ureteral complications occurred in 66 patients (7.73%). The most common complication was urinary tract infection caused by vesico-ureteral reflux (n = 24, 2.81%), which was managed with by means of sub-ureteral polydimethylsiloxane injection. The second most common complication was the anastomosis site stricture (n = 23, 2.69%), which was treated by means of ureteral re-implantation or percutaneous nephrostomy. Anastomosis site leakage occurred in 11 patients (1.28%) and was managed by percutaneous nephrostomy with double-J stenting and drainage or ureteral re-implantation. Urolithiasis occurred in 8 patients (0.93%). CONCLUSIONS: There was an 8% rate of recipient ureteral complications at our institution. Of the 66 patients, 46 (5.4%) required surgical repair. The remaining 20 patients with ureteral complications were treated with conservative care or minimally invasive procedures. The keys to successful management of these problems are early diagnosis and prompt reconstruction whenever possible. Most ureteral complications are easily managed with a successful outcome with early intervention.

Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+ mice.

Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/ß-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin/+ mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/ß-catenin pathway and can downregulate ß-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3ß (Akt-glycogen synthase kinase-3ß) pathway. We have shown that both Wnt and nuclear factor-κB (NF-κB) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/ß-catenin and NF-κB pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play.

Tumour volume changes assessed with high-quality KVCT in lung cancer patients undergoing concurrent chemoradiotherapy.

OBJECTIVE: We evaluated tumour volume changes in patients with lung cancer undergoing concurrent chemoradiotherapy using image-guided radiotherapy (RT). METHODS: The kilovoltage image was obtained using CT on rail at every five fractions. The gross tumour volumes (GTVs), including the primary tumour and lymph nodes (LNs), were contoured to analyse the time and degree of tumour regression. RESULTS: 46 patients [32, non-small-cell lung cancer (NSCLC), and 14, small-cell lung cancer (SCLC)] were included in this study. In total, 281 CT scans and 82 sites of GTVs were evaluated. Significant volume changes occurred in both the NSCLC and SCLC groups (p < 0.001 and 0.002), and the average GTV change compared with baseline was 49.85 ± 3.65 [standard error (SE)]% and 65.95 ± 4.60 (SE)% for the NSCLC and SCLC groups, respectively. A significant difference in the degree of volume reduction between the primary tumour and LNs was observed in only the NSCLC group (p < 0.0001) but not in the SCLC group (p = 0.735). The greatest volume regression compared with the volume before the five fractions occurred between the 15 and 20 fractions in the NSCLC group and between the 5 and 10 fractions in the SCLC group. CONCLUSION: Both primary tumour and LNs were well defined using CT on rail. Significant volume changes occurred during RT, and there was a difference in volume reduction between the NSCLC and SCLC groups, regarding the degree and timing of the tumour reduction in the primary tumour and LNs. ADVANCES IN KNOWLEDGE: NSCLC and SCLC groups showed differences in the degree and timing of volume reduction. The primary tumour and LNs in NSCLC regressed differently.

Hepatic differentiation of porcine embryonic stem cells for translational research of hepatocyte transplantation.

Porcine embryonic stem cells (ES) are considered attractive preclinical research tools for human liver diseases. Although several studies previously reported generation of porcine ES, none of these studies has described hepatic differentiation from porcine ES. The aim of this study was to generate hepatocytes from porcine ES and analyze their characteristics. We optimized conditions for definitive endoderm induction and developed a 4-step hepatic differentiation protocol. A brief serum-free condition with activin A efficiently induced definitive endoderm differentiation from porcine ES. The porcine ES-derived hepatocyte-like cells highly expressed hepatic markers including albumin and α-fetoprotein, and displayed liver characteristics such as glycogen storage, lipid production, and low-density lipoprotein uptake. For the first time, we describe a highly efficient protocol for hepatic differentiation from porcine ES. Our findings provide valuable information for translational liver research using porcine models, including hepatic regeneration and transplant studies, drug screening, and toxicology.

The MRI appearances of cancellous allograft bone chips after the excision of bone tumours.

Cancellous allograft bone chips are commonly used in the reconstruction of defects in bone after removal of benign tumours. We investigated the MRI features of grafted bone chips and their change over time, and compared them with those with recurrent tumour. We retrospectively reviewed 66 post-operative MRIs from 34 patients who had undergone curettage and grafting with cancellous bone chips to fill the defect after excision of a tumour. All grafts showed consistent features at least six months after grafting: homogeneous intermediate or low signal intensities with or without scattered hyperintense foci (speckled hyperintensities) on T1 images; high signal intensities with scattered hypointense foci (speckled hypointensities) on T2 images, and peripheral rim enhancement with or without central heterogeneous enhancements on enhanced images. Incorporation of the graft occurred from the periphery to the centre, and was completed within three years. Recurrent lesions consistently showed the same signal intensities as those of pre-operative MRIs of the primary lesions. There were four misdiagnoses, three of which were chondroid tumours. We identified typical MRI features and clarified the incorporation process of grafted cancellous allograft bone chips. The most important characteristics of recurrent tumours were that they showed the same signal intensities as the primary tumours. It might sometimes be difficult to differentiate grafted cancellous allograft bone chips from a recurrent chondroid tumour.

Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance.

Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous phenotypes. Although low-stage tumors carry a favorable prognosis, >50% of high-risk NB relapses after treatment with a fatal outcome. Thus developing therapies targeting refractory NB remains an unsolved clinical problem. Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to protect NB cells from chemotherapy-induced cell death, while neuropeptide Y (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and angiogenic factor crucial for maintaining NB tumor growth. Here we show that in NB cells, BDNF stimulates the synthesis of NPY and induces expression of another one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R positively correlated with the expression of BDNF and TrkB. Functionally, BDNF triggered Y5R internalization in NB cells, whereas Y5R antagonist inhibited BDNF-induced p44/42 mitogen-activated protein kinase activation and its pro-survival activity. These observations suggested TrkB-Y5R transactivation that resulted in cross-talk between their signaling pathways. Additionally, NPY and Y5R were upregulated in a BDNF-independent manner in NB cells under pro-apoptotic conditions, such as serum deprivation and chemotherapy, as well as in cell lines and tissues derived from posttreatment NB tumors. Blocking Y5R in chemoresistant NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis and inhibited their growth in vivo by augmenting cell death. In summary, the NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via its interactions with TrkB receptor and exerts an additional BDNF-independent anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, the NPY/Y5R pathway may become a novel therapeutic target for patients with refractory NB, thus far an incurable form of this disease.

Γ-glutamyl transferase as an early and sensitive marker in ethanol-induced liver injury of rats.

γ-Glutamyl transferase (GGT) has been regarded as a biological marker of heavy alcohol consumption or hepatobiliary disease such as fatty liver. However, the role of GGT is unknown in the molecular pathway during alcohol-induced liver injury. To determine the role of GGT in alcohol-induced liver injury, Sprague-Dawley rats were administered 22% and 38% ethanol for 3 days as acute and 5 weeks as subchronic model. In serologic analysis, the level of GGT was significantly increased and the level of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were not changed at 3 days and 5 weeks. In histologic analysis, ethanol exposure induced granular deposit formation and sinusoidal dilation in the acute model for 3 days. In the subchronic model for 5 weeks, ethanol exposure further increased the granular deposit formation, sinusoidal congestion, and mild fatty liver change. To determine whether ethanol-exposed liver is associated with changes of antioxidants levels, we performed reverse-transcriptase polymerase chain reaction (RT-PCR) analysis on ethanol-exposed livers of rats. In RT-PCR analysis, the mRNA levels of GPX1 and SOD1 were significantly increased as well as up-regulation of CYP2E1. In the glutathione assay, the level of glutathione was significantly reduced in response to ethanol in rats. Therefore, in this study, ethanol increased the level of serum GGT but depleted the level of glutathione. Moreover, the CYP2E1 was rapidly reflected to ethanol in rats. Taken together, our findings suggest that the elevated GGT is associated with cellular antioxidant defense system, and the CYP2E1 can be used for early diagnosis in alcohol-related diseases.

DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression.

BACKGROUND: DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear. METHODS: Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate DJ-1-dependent KLF17 expression changes. In addition, Epistasis analysis of DJ-1 and KLF17 was performed to evaluate their regulatory interactions. Ras inhibitors were pretreated to determine whether DJ-1 regulates cell invasion in a Ras-dependent manner. RESULTS: I n the present study, we found increased DJ-1 expression in highly invasive breast cancer cells as compared with non-metastatic cells. Furthermore, DJ-1 promoted breast cancer cell invasion by downregulating E-cadherin and increasing Snail expression. Interestingly, exogenous DJ-1 overexpression markedly decreased mRNA and protein expression of KLF17, the EMT negative regulator. These data were confirmed by ID-1 promoter activity, which is directly regulated by DJ-1-dependent KLF17 transcription factor. Epistasis analysis showed that KLF17 overexpression overcomes increased cell invasion by DJ-1, suggesting that KLF17 might be one of the downstream signalling molecules of DJ-1. Acceleration of cell invasion by DJ-1 was alleviated by Ras inhibitors, suggesting that DJ-1 cooperates with Ras to increase cell invasion. CONCLUSION: Altogether, these data suggest for the first time that DJ-1 acts as an EMT-positive regulator in breast cancer cells via regulation of the KLF17/ID-1 pathway.

A genome-wide association study of survival in small-cell lung cancer patients treated with irinotecan plus cisplatin chemotherapy.

We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) influencing overall survival (OS) of small-cell lung cancer (SCLC) patients. We prospectively collected blood samples from 139 SCLC patients who participated in phase II studies of irinotecan and cisplatin (IP) chemotherapy as first-line therapy. Among 334 127 SNPs, which passed quality control, seven showed significant association with OS. The rs16950650CT, rs7186128AG or GG, rs17574269AG, rs8020368CC, rs4655567CC, rs2166219TT or rs2018683TT showed shorter OS compared with control alleles. Among the seven SNPs, rs4655567, rs8020368 and rs2018683 were significantly associated with a resistant relapse (RR). In the multivariate analysis, rs8020368CC was significantly associated with higher risk of RR (odds ratio=16.7, P=0.007). In vitro and in silico analysis showed that SNPs in C14orf49 might be associated with epithelial-to-mesenchymal transition. This exploratory GWAS identified candidate SNPs that may be predictive of the clinical outcome of SCLC patients receiving IP.