Patient acceptance of transvaginal sonographic endometrial thickness assessment compared with hysteroscopy and biopsy for exclusion of endometrial cancer in cases of postmenopausal bleeding.

INTRODUCTION: Available examinations for women with postmenopausal bleeding include transvaginal sonography to measure endometrial thickness (TVS-ET), and invasive endometrial assessment using hysteroscopy/endometrial biopsy. However, selection of the examination method seldom involves consideration of patient preferences. The aim of this study was to examine patient preferences for the method used to investigate postmenopausal bleeding. METHODS: Women were asked to complete an interviewer-administered structured survey before they underwent clinical investigations at a university gynaecology unit from June 2016 to June 2017. Using the standard gamble approach, women were asked to choose between invasive assessment by hysteroscopy/endometrial biopsy (gold standard) or TVS-ET with a risk of missing endometrial cancer. The risk of missing endometrial cancer during TVS-ET was varied until each woman was indifferent to either option. RESULTS: The median detection rate for endometrial cancer required using TVS-ET was 95% (interquartile range=80%-99.9%). In total, 200 women completed the survey, and 77 (38.5%) women required TVS-ET to have a 99.9% detection rate for endometrial cancer. Prior hysteroscopy experience was the only factor that influenced the women's decisions: a significantly higher detection rate was required by this patient group than by patients without previous hysteroscopy experience (P=0.047). CONCLUSION: A substantial proportion of women would accept TVS-ET alone for the investigation of postmenopausal bleeding. In the era of patientcentred care, clinicians should incorporate patient preferences and enable women to make informed choices concerning the management of postmenopausal bleeding.

Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study.

OBJECTIVE: To estimate the accuracy of transvaginal ultrasound (TVS) measurement of endometrial thickness (ET) in diagnosing endometrial cancer in postmenopausal women with vaginal bleeding (PMB). DESIGN: Retrospective cohort study. SETTING: One-stop PMB clinic in a Hong Kong teaching hospital. POPULATION: A cohort of 4383 women with PMB. METHODS: Transvaginal ultrasonic measurement of ET and endometrial biopsies were obtained in women presenting with PMB between 2002 and 2013. Endometrial histology was used as the reference standard to calculate accuracy estimates. MAIN OUTCOME MEASURES: Accuracy data for TVS ET presented as sensitivity, specificity, and area under the receiver operator characteristic (ROC) curve. RESULTS: Endometrial cancer was diagnosed in 3.8% of women. The median ET in those with endometrial cancer was significantly higher than those with benign conditions (15.7 versus 3.2 mm, P < 0.001). The area under the ROC curve was 0.92 (95% CI 0.89-0.94). The sensitivity for the detection of endometrial cancer at 3-, 4-, and 5-mm cut-offs were 97.0% (95% CI 94.5-99.6%), 94.1% (95% CI 90.5-97.6%), and 93.5% (95% CI 89.7-97.2%), respectively. The corresponding estimates of specificity at these thresholds were 45.3% (95% CI 43.8-46.8%), 66.8% (65.4-68.2%), and 74.0% (72.7-75.4%). CONCLUSIONS: Transvaginal ultrasound using a 3-mm cut-off has high sensitivity for detecting endometrial cancer and can identify women with PMB who are highly unlikely to have endometrial cancer, thereby avoiding more invasive endometrial biopsy.

Hypoxia triggers a Nur77-ß-catenin feed-forward loop to promote the invasive growth of colon cancer cells.

BACKGROUND: ß-Catenin is a potent oncogenic protein in colorectal cancer (CRC), but the targets and regulation of this important signalling molecule are not completely understood. Hypoxia is a prominent feature of solid tumours that contributes to cancer progression. METHODS: Here, we analysed the regulation between Nur77 and ß-catenin under hypoxic conditions. Cell proliferation, migration, and invasion assays were performed to assess functional consequences. RESULTS: We showed that hypoxia stimulated co-upregulation of ß-catenin and Nur77 in a number of human CRC cell lines. Interestingly, expression of ß-catenin and Nur77 by hypoxia formed a mutual feedback regulation circuits that conferred aggressive growth of CRC. Overexpression of ß-catenin increased Nur77 transcription through hypoxia-inducible factor-1α rather than T-cell factor. Nur77-mediated activation of ß-catenin by hypoxia was independent of both DNA binding and transactivation. Further, we showed that hypoxic activation of ß-catenin was independent of the classical adenomatous polyposis coli and p53 pathways, but stimulated by phosphatidylinositol 3-kinase/Akt in a Nur77-dependent manner. Under hypoxic conditions, enhanced ß-catenin and Nur77 expression synergistically stimulated CRC cell migration, invasion, and epithelial-mesenchymal transition. CONCLUSION: These findings provide a novel molecular mechanism for hypoxic CRCs that may contribute to tumour progression, and its targeting may represent an effective therapeutic avenue.

Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

A novel maskless approach towards aligned, density modulated and multi-junction ZnO nanowires for enhanced surface area and light trapping solar cells.

A maskless method of employing polymer growth inhibitor layers is used to modulate the conflicting parameters of density and alignment of multi-junction nanowires via large-scale low temperature chemical route. This low temperature chemical route is shown to synthesize multi-junction nanostructures without compromising the crystal quality at the interfaces. The final morphology of optimized multi-junctions nanowire arrays can be demonstrated on various substrates due to substrate independence and low temperature processing. Here, we also fabricated devices based on density modulated multi-junction nanowires tuned to infiltrate nanoparticles. The fabrication of hierarchically structured nanowire/nanoparticles composites presents an advantageous structure, one that allows nanoparticles to provide large surface areas for dye adsorption, whilst the nanowires can enhance the light harvesting, electron transport rate, and also the mechanical properties of the films. This work can be of great scientific and commercial interest since the technique employed is of low temperature (<90 degrees C) and economical for large-scale solution processing, much valued in today's flexible display and photovoltaic industries.

Does primary closure of direct inguinal hernia defect during laparoscopic mesh repair reduce the risk of early recurrence?

PURPOSE: Hernia recurrence is an important complication following inguinal hernia repair. Primary closure of ventral hernia defects laparoscopically has been shown to reduce the risk of recurrence and seroma formation. The results for ventral hernias may potentially be applied to direct inguinal hernias. Our aim was to evaluate the value of primary closure of direct defects during laparoscopic inguinal hernia mesh repair in reducing the incidence of early recurrence. METHODS: A retrospective, single-center cohort study was conducted on cases performed from August 2016 to February 2018. Patients with direct inguinal hernias undergoing elective laparoscopic mesh repair were included. When performed, the direct hernia defect was primarily closed with extracorporeal non-absorbable interrupted sutures followed by standard placement of a lightweight mesh covering myopectineal orifices. Early recurrence was defined as occurring within 1 year of surgery. RESULTS: A total of 75 direct inguinal hernias in 53 patients who underwent surgery and completed at least 1 year of follow-up were analyzed. The mean age of patients was 63 years (range 44-82 years); with majority of patients being male (98.1%). There were no significant differences observed between the two patient populations in terms of demographics, mean operative time and risk factors. In 9 (16.9%) patients, the direct hernias were recurrent hernias and all underwent open mesh repair during the index hernia surgery. The majority of hernia repairs (63 hernias in 45 patients, 85%) were performed via the totally extraperitoneal (TEP) approach. 19 patients (35.8%) with 28 direct inguinal hernias underwent primary closure of the direct defect prior to mesh placement; while, 34 patients (64.2%) with 47 direct hernias did not undergo primary closure. There were 3 direct hernia recurrences (6.4%) at 1 year post-operatively, and all occurred in the non-closure group. In comparison, there were no recurrences in the closure group; however, this difference was not statistically significant (p = 0.289) in our study due to the small sample size. CONCLUSION: Closure of direct inguinal hernia defects during laparoscopic mesh repair has been shown to reduce the incidence of early hernia recurrence in our retrospective study but future randomized controlled trials with large numbers would enable us to draw more robust conclusions and perhaps change the way we perform laparoscopic inguinal hernia repair.

Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Herbicide formulations containing known amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and exposed to natural sunlight on leaves, soil, or glass plates lost most or all of the TCDD during a single day, due principally to photochemical dechlorination. Despite the known persistence of pure TCDD, it is not stable as a contaminant in thin herbicide films exposed to outdoor light.

Photodecomposition of Chlorinated Dibenzo-p-Dioxins.

The toxic herbicide impurity 2,3,7,8-tetrachlorodibenzo-p-dioxin and its homologs decomposed rapidly in alcohol solution under artificial light and natural sunlight, the rate of decomposition depending upon the degree of chlorination. However, photodecomposition was negligible in aqueous suspensions and on wet or dry soil.

Controlled synthesis and application of ZnO nanoparticles, nanorods and nanospheres in dye-sensitized solar cells.

Several important synthetic parameters such as precursor concentration, rate of evaporation and reaction time are found to determine the growth of ZnO nanostructures. These reaction parameters can be tailored and tuned to produce a variety of nanostructures ranging from nanoparticles, nanorods and nanospheres. The nanorods are structurally uniform made up of crystallographically oriented attached nanoparticles while the nanospheres are made up of several closely packed and randomly aligned nanocrystallites. XRD spectra of both the nanoparticles and nanorods exhibit typical diffraction peaks of a well-crystalline wurtzite ZnO structure. Finally, solar cells made up of ZnO nanoparticles and nanorods electrodes with absorbed ruthenium dye (N3) were measured to have a power conversion efficiency of 0.87% and 1.32%, respectively.

Microsuture repair of intra-operative ruptures of cerebral aneurysms of the internal carotid artery.

We report on two patients with intra-operative rupture of cerebral aneurysms that were managed by microsuturing. This is one of only a few reports of successful direct repair using suturing. We found that stitching remains an option to repair a tear of a saccular part of an aneurysm and a torn neck of a blister-like aneurysm, and thus this technique can be considered before sacrificing the artery.

Associations between pre-injury racing history and tibial and humeral fractures in Australian Thoroughbred racehorses.

Long bone fractures in racehorses may present as stress fractures which have a good prognosis, or complete fractures, which often result in a fatal outcome. In order to identify differences in modifiable management practices that may contribute to these outcomes, racing histories of horses with humeral or tibial fractures and of matched controls were examined. A retrospective case-control study of Australian Thoroughbred racehorses diagnosed with a fracture of the humerus or tibia by scintigraphy or at post-mortem between 2002 and 2016 was undertaken. Control horses were matched from the same race or trial on age and sex. Statistical analysis was performed using conditional logistic regression, χ2 and Mann-Whitney U tests. More humeral fractures than tibial fractures were fatal (12/47, 26% vs. 3/35, 8.6%, P = 0.049). No differences in pre-injury racing histories were observed between cases and controls for humeral and tibial fractures. Both humeral and tibial fracture case horses were younger than the registered Thoroughbred racing population (P < 0.001), but horses sustaining humeral fractures were older than those with tibial fractures (3.3 ± 0.9 vs. 2.8 ± 0.8 years, P = 0.005) yet raced fewer times prior to the injury (0.5 ± 1.1 vs. 1.3 ± 1.7 races, P = 0.009). Horses with fatal humeral fractures were less likely to have raced than those with non-fatal humeral fractures (16.7% vs. 55.6%, P = 0.02). In conclusion, tibial and humeral fractures occur in young racehorses, and humeral fractures are more likely to be fatal in those with the least exposure to trialling and racing.

Ovarian surface epithelium: biology, endocrinology, and pathology.

The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2.

Chemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin- and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer.

Post-traumatic pericallosal artery aneurysm presenting with subdural haematoma without subarachnoid haemorrhage.

A 27-year-old patient presented with severe headache and seizures about a month after the initial head trauma. Computed tomography (CT) brain scan revealed acute subdural bleed continuous into the interhemispheric region, with no subarachnoid haemorrhage. This was due to rupture of a traumatic pericallosal artery aneurysm. This represents a rare case of traumatic pericallosal artery aneurysm presenting with subdural haematoma without subarachnoid haemorrhage.

Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor.

BACKGROUND AND PURPOSE: Angiogenesis is a crucial step in tumour growth and metastasis. Ginsenoside-Rb1 (Rb1), the major active constituent of ginseng, potently inhibits angiogenesis in vivo and in vitro. However, the underlying mechanism remains unknown. We hypothesized that the potent anti-angiogenic protein, pigment epithelium-derived factor (PEDF), is involved in regulating the anti-angiogenic effects of Rb1. EXPERIMENTAL APPROACHES: Rb1-induced PEDF was determined by real-time PCR and western blot analysis. The anti-angiogenic effects of Rb1 were demonstrated using endothelial cell tube formation assay. Competitive ligand-binding and reporter gene assays were employed to indicate the interaction between Rb1 and the oestrogen receptor (ER). KEY RESULTS: Rb1 significantly increased the transcription, protein expression and secretion of PEDF. Targeted inhibition of PEDF completely prevented Rb1-induced inhibition of endothelial tube formation, suggesting that the anti-angiogenic effect of Rb1 was PEDF specific. Interestingly, the activation of PEDF occurred via a genomic pathway of ERbeta. Competitive ligand-binding assays indicated that Rb1 is a specific agonist of ERbeta, but not ERalpha. Rb1 effectively recruited transcriptional activators and activated an oestrogen-responsive reporter gene. Furthermore, Rb1-mediated PEDF activation and the subsequent inhibition of tube formation were blocked by the ER antagonist ICI 182,780 or transfection of ERbeta siRNA, indicating ERbeta dependence. CONCLUSIONS AND IMPLICATIONS: Here we show for the first time that the Rb1 suppressed the formation of endothelial tube-like structures through modulation of PEDF via ERbeta. These findings demonstrate a novel mechanism of the action of this ginsenoside that may have value in anti-cancer and anti-angiogenesis therapy.

Export of toxic chemicals - a review of the case of uncontrolled electronic-waste recycling.

This paper reviews the concentrations of persistent organic pollutants such as flame retardants (PBDEs), dioxins/furans (PCDD/Fs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and heavy metals/metalloid concentrations of different environmental media at Guiyu, a traditional rice-growing village located in southeastern Guangdong Province (PR China), which has turned into an intensive electronic-waste (e-waste) recycling site. Incomplete combustion of e-waste in open air and dumping of processed materials are the major sources of various toxic chemicals. By comparing with existing data available in other areas and also guidelines adopted in different countries, it is obvious that the environment is highly contaminated by these toxic chemicals derived from the recycling processes. For example, the monthly concentration of the sum of 22 PBDE congeners contained in PM(2.5) (16.8ngm(-3)) of air samples at Guiyu was 100 times higher than published data. In order to safeguard the environment and human health, detailed investigations are urgently needed, especially on tracking the exposure pathways of different toxic chemicals which may affect the workers and local residents especially mothers, infants and children.

ß-catenin downregulates Dicer to promote ovarian cancer metastasis.

Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes-highly metastatic (HM) and non-metastatic (NM)-both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases, although it was equally tumorigenic. Using comparative label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS), we identified ß-catenin, which we demonstrated for the first time as having a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of ß-catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the miRNA-processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to-mesenchymal transition and subsequent stem cell traits. Silencing ß-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. ß-catenin-knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover ß-catenin as a critical factor in promoting ovarian cancer aggressiveness and a new mechanism linking between ß-catenin and miRNA downregulation underlying this process.

Actin cytoskeleton stiffness grades metastatic potential of ovarian carcinoma Hey A8 cells via nanoindentation mapping.

Recent studies have indicated that the nanoindentation measured stiffness of carcinoma adherent cells is in general lower than normal cells, thus suggesting that cell stiffness may serve as a bio-marker for carcinoma. However, the proper establishment of such a conclusion would require biophysical understanding of the underlying mechanism of the cell stiffness. In this work, we compared the elastic moduli of the actin cytoskeletons of Hey A8 ovarian carcinoma cells with and without metastasis (HM and NM), as measured by 2D atomic force microscopy (AFM) with low-depth nanoindentation via a rate-jump method. The results indicate clearly that HM cells showed lower actin cytoskeleton stiffness atop of their nucleus position and higher actin cytoskeleton stiffness at their rims, compared to NM cells, suggesting that the local stiffness on the cytoskeleton can reflect actin filament distribution. Immunofluorescence staining and scanning electron microscopy (SEM) also indicated that the difference in stiffness in Hey A8 cells with different metastasis is associated with their F-actin rearrangement. Finite-element modelling (FEM) shows that a migrating cell would have its actin filaments bundled together to form stress fibers, which would exhibit lower indentation stiffness than the less aligned arrangement of filaments in a non-migrating cell. The results here indicate that the actin cytoskeleton stiffness can serve as a reliable marker for grading the metastasis of adherent carcinoma cells due to their cytoskeleton change and potentially predicting the migration direction of the cells.

Predictive factors for residual disease in hysterectomy specimens after conization in early-stage cervical cancer.

OBJECTIVE: To identify predictive factors for residual disease in hysterectomy specimens after a loop electrical excision procedure (LEEP) or cold knife conization in early-stage cervical cancer. STUDY DESIGN: A retrospective review was undertaken of the clinical records and pathology reports of 108 consecutive patients who were diagnosed with early invasive cervical cancer stage IA1 to IB1 by cold knife conization or LEEP, and underwent subsequent hysterectomy or radical hysterectomy at the Gynae-oncology Unit, Queen Elizabeth Hospital between 2000 and 2012. Residual disease was defined as the presence of cervical intra-epithelial neoplasia (CIN) 2-3 or invasive carcinoma in hysterectomy specimens. Clinicopathological factors associated with residual disease were analyzed. Risk factors for the prediction of residual disease were identified by univariate and multivariate analysis. RESULTS: Residual disease was found in 32 (29.7%) patients. Stage, tumour size, depth of invasion, lymphovascular space invasion, ectocervical margin, endocervical margin, and combined ectocervical and endocervical margin were significantly associated with residual disease in hysterectomy specimens on univariate analysis. On multivariate analysis, depth of invasion (odds ratio 2.1, p=0.033) and combined margin status (odds ratio 10.8, p≤0.001) were independent risk factors for residual disease. In a subgroup analysis using depth of invasion ≤5mm and a negative combined margin, none (0%) of the 52 patients who met the criteria had residual disease. CONCLUSIONS: Conization (combined ectocervical and endocervical) margin and tumour depth of invasion are independent predictors of residual disease in hysterectomy specimens. A negative conization margin and depth of invasion ≤5mm are associated with low risk of residual disease in patients with early-stage cervical cancer.