The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer

RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression of the protein in hepatocellular and lung cancers is correlated with adverse prognosis. LARP1 associates with an mRNA interactome that is enriched for oncogenic transcripts. Here we explore the role of LARP1 in epithelial ovarian cancer, a disease characterized by the rapid acquisition of resistance to chemotherapy through the induction of pro-survival signalling. We show, using ovarian cell lines and xenografts, that LARP1 is required for cancer cell survival and chemotherapy resistance. LARP1 promotes tumour formation in vivo and maintains cancer stem cell-like populations. Using transcriptomic analysis following LARP1 knockdown, cross-referenced against the LARP1 interactome, we identify BCL2 and BIK as LARP1 mRNA targets. We demonstrate that, through an interaction with the 3 untranslated regions (3 UTRs) of BCL2 and BIK, LARP1 stabilizes BCL2 but destabilizes BIK with the net effect of resisting apoptosis. Together, our data indicate that by differentially regulating the stability of a selection of mRNAs, LARP1 promotes ovarian cancer progression and chemotherapy resistance

Multispectral Imaging of Organ Viability during Uterine Transplantation Surgery

Uterine transplantation surgery has been proposed as a treatment for permanent absolute uterine factor infertility (AUFI) in the case of loss of the uterus. Due to the complexity of the vasculature correct reanastomosis of the blood supply during transplantation surgery is a crucial step to ensure reperfusion and viability of the organ. While techniques such as fluorescent dye imaging have been proposed to visualise perfusion there is no gold standard for intraoperative visualisation of tissue oxygenation. In this paper results from a liquid crystal tuneable filter (LCTF)-based multispectral imaging (MSI) laparoscope are described. The system was used to monitor uterine oxygen saturation (SaO) before and after transplantation. Results from surgeries on two animal models (rabbits and sheep) are presented. A feature-based registration algorithm was used to correct for misalignment induced by breathing or peristalsis in the tissues of interest prior to analysis. An absorption spectrum was calculated at each spatial pixel location using reflectance data from a reference standard, and the relative contributions from oxy- and deoxyhaemoglobin were calculated using a least squares regression algorithm with non-negativity constraints. Results acquired during animal surgeries show that cornual oxygenation changes are consistent with those observed in point measurements taken using a pulse oximeter, showing reduced SaO following reanastomosis. Values obtained using the MSI laparoscope were lower than those taken with the pulse oximeter, which may be due to the latter’s use of the pulsatile arterial blood signal. Future work incorporating immunological test results will help to correlate SaO levels with surgical outcomes

Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients

Registration and analysis of multispectral images acquired during uterine transplantation surgery

Organ transplant success is dependent on blood supply health. A multispectral imaging laparoscope has been used to monitor tissue oxygenation changes during a rabbit uterine transplant. A feature tracking algorithm was used to compensate for movement. © OSA 2012

Association between social capital, health-related quality of life, and mental health: A structural-equation modeling approach

Aim To explore the association(s) between demographic factors, socioeconomic status (SES), social capital, healthrelated quality of life (HRQoL), and mental health among residents of Tehran, Iran. Methods The pooled data (n = 31 519) were extracted from a population-based survey Urban Health Equity Assessment and Response Tool-2 (Urban HEART-2) conducted in Tehran in 2011. Mental health, social capital, and HRQoL were assessed using the 28-item General Health Questionnaire (GHQ-28), social capital questionnaire, and Short-Form Health Survey (SF-12), respectively. The study used a multistage sampling method. Social capital, HRQoL, and SES were considered as latent variables. The association between these latent variables, demographic factors, and mental health was determined by structural-equation modeling (SEM). Results The mean age and mental health score were 44.48 ± 15.87 years and 23.33 ± 11.10 (range, 0-84), respectively. The prevalence of mental disorders was 41.76 (95 confidence interval 41.21-42.30). The SEM model showed that age was directly associated with social capital (P = 0.016) and mental health (P = 0.001). Sex was indirectly related to mental health through social capital (P = 0.018). SES, HRQoL, and social capital were associated both directly and indirectly with mental health status. Conclusion This study suggests that changes in social capital and SES can lead to positive changes in mental health status and that individual and contextual determinants influence HRQoL and mental health

Use of biomedical photonics in gynecological surgery: a uterine transplantation model

Aim: Uterine transplantation (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility. The study aims were to compare pulse oximetry and multispectral imaging (MSI), for intraoperative tracking of uterine oxygen saturation in animal UTx models (rabbit and sheep). Results/methodology: Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Comparison of oxygen saturation values between the pre-UTx donor and post-UTx recipient, and pre-UTx and post-UTx recipient reveals a statistically significant decrease in saturation levels post-UTx. Conclusion: The use of MSI is the first case in gynecology and has demonstrated promise of possible future human use. MSI technique has advantages over pulse oximetry - it provides spatial information in a real-time, noncontact manner

Use of Laser Speckle Contrast Analysis during pelvic surgery in a uterine transplantation model

Aim: Uterine transplantation (UTx) is proposed for treatment of uterine factor infertility. Our aim was to assess whether Endoscopic Laser Speckle Contrast Analysis (eLASCA) could evaluate pelvic blood flow at anastomotic sites required for sheep and rabbit UTx. Results/methodology: eLASCA detected blood flow in rabbit UTx #7 and #9. In sheep UTx #2, #3 and #5, the results allowed us to conclude that blood flow was present in the uterine graft following transplantation; and post-UTx, the animal had heart and respiratory rates, and oxygen saturation compatible with a normal hemodynamic status. Conclusion: These preliminary results establish the potential of Laser Speckle Contrast Analysis as noncontact and real-time tool for observation of spatially-resolved blood flow from which other parameters can be derived

Use of biomedical photonics in gynecological surgery: a uterine transplantation model

Aim: Uterine transplantation (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility. The study aims were to compare pulse oximetry and multispectral imaging (MSI), for intraoperative tracking of uterine oxygen saturation in animal UTx models (rabbit and sheep). Results/methodology: Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Comparison of oxygen saturation values between the pre-UTx donor and post-UTx recipient, and pre-UTx and post-UTx recipient reveals a statistically significant decrease in saturation levels post-UTx. Conclusion: The use of MSI is the first case in gynecology and has demonstrated promise of possible future human use. MSI technique has advantages over pulse oximetry – it provides spatial information in a real-time, noncontact manner

The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings

Diagnostic accuracy of FET-PET/CT, FDG-PET/CT and diffusion-weighted MRI in detection of nodal metastases in surgically treated endometrial and cervical carcinoma

PURPOSE:Pre-operative nodal staging is important for planning treatment in cervical cancer (CC) and endometrial cancer (EC) but remains challenging. We compare nodal staging accuracy of {18}^F-ethyl-choline-(FEC)-PET/CT, {18}^F-Fluoro-deoxy-glucose-(FDG)-PET/CT and diffusion-weighted-MRI (DW-MRI) with conventional morphological MRI. Experimental Design: A prospective, multicentre observational study of diagnostic accuracy for nodal metastases was undertaken in 5 gyne-oncology centres. FEC-PET/CT, FDG-PET/CT and DW-MRI were compared to nodal size and morphology on MRI. Reference standard was strictly correlated nodal histology. Eligibility included operable CC stage=>1B1 or EC (grade 3 any stage with myometrial invasion or grade 1-2 stage=>II). RESULTS: Among 162 consenting participants, 136 underwent study DW-MRI and FDG-PET/CT, and 60 underwent FEC-PET/CT. 267 nodal regions in 118 women were strictly correlated at histology (nodal positivity rate 25%). Sensitivity per-patient (n=118) for nodal size, morphology, DW-MRI, FDG- and FEC-PET/CT were 40%*, 53%, 53%, 63%* and 67% for all cases (*p=0.016); 10%, 10%, 20%, 30% and 25% in CC (n=40); 65%, 75%, 70%, 80% and 88% in EC (n=78). FDG-PET/CT outperformed nodal size (p=0.006) and size ratio (p=0.04) for per-region sensitivity. False positive rates were all <10%. CONCLUSIONS: All imaging techniques had low sensitivity for detection of nodal metastases and cannot replace surgical nodal staging. The performance of FEC-PET/CT was not statistically different to other techniques that are more widely available. FDG-PET/CT had higher sensitivity than size in detecting nodal metastases. False positive rates were low across all methods. The low false positive rate demonstrated by FDG-PET/CT may be helpful in arbitration of challenging surgical planning decisions