Regulation of angiogenic processes in omental endothelial cells during metastasis of epithelial ovarian cancer

Epithelial ovarian cancer frequently metastasizes to the omentum, a process that requires pro-angiogenic activation of local microvascular endothelial cells (ECs) by tumour-secreted factors. We have previously shown that ovarian cancer cells secrete factors, other than vascular endothelial growth factor (VEGF), with possible roles in metastatic angiogenesis including the lysosomal proteases cathepsin L (CathL) and cathepsin D (CathD), and insulin-like growth factor binding protein 7 (IGFBP7). However, the mechanisms by which these factors may contribute to omental endothelial angiogenic changes are unknown. Therefore the aims of this thesis were a) to examine disease relevant human omental microvascular endothelial cell (HOMEC) proliferation, migration and angiogenesis tube-formation induced by CathL, CathD and IGFBP7; b) to investigate whether CathL and CathD act via a proteolytic or non-proteolytic mechanism; c) to identify activated downstream intracellular signalling cascades in HOMECs and their activation in proliferation and migration; and finally d) to identify activated cell surface receptors by these factors. CathL, CathD and IGFBP7 significantly induced proliferation and migration in HOMECs, with CathL and CathD acting in a non-proteolytic manner. Proteome-profiler and ELISA data identified increased phosphorylation of the ERK1/2 and AKT (protein kinase B) pathways in HOMECs in response to these factors. CathL induced HOMEC proliferation and migration via the ERK1/2 pathway, whereas, although CathD-induced proliferation was mediated by activation of ERK1/2, its migratory effect was dependent on both ERK1/2 and AKT pathways. Interestingly, CathL induced secretion of galectin-1 (Gal1) from HOMECs which in turn significantly induced HOMEC proliferation via ERK1/2. However, none of the ERK1/2 or AKT pathways was observed to be active in Gal1-induced HOMEC migration. Interestingly, Gal1-induced proliferation and migration were significantly inhibited by L-glucose, suggesting a role for a receptor with extracellular sugar moieties. IGFBP7-induced migration was shown to be mediated via activation of the ERK1/2 pathway only. CathL, Gal1 and IGFBP7 significantly induced angiogenesis tube-formation in HOMECs which was not observed in CathD-treated cells. Receptor tyrosine kinase array revealed activation of Tie-1 and VEGF receptor type 2 (VEGFR2) in CathL and IGFBP7-treated HOMECs respectively. In conclusion, all CathL, CathD, Gal1 and IGFBP7 have the potential to act as proangiogenic factors in the metastasis of ovarian cancer to the omentum. These in vitro data suggest all four factors activate intracellular pathways which are involved in well-known angiogenesis models.FORCE Cancer Charit

Beyond the COVID-19 pandemic: can online teaching reduce the carbon footprint of the internationalisation of UK higher education?

The COVID-19 pandemic has been a learning curve for Higher Education Institutions (HEIs) in devising and delivering teaching online. This transition has enabled HEIs to continue teaching students, especially international students, who were restricted to travel to their countries of study. In the UK, approximately 20% of the student cohort are international students. The pandemic resulted in a drop in international student recruitment, which generated concerns about a potentially alarming economic crisis in the UK HE sector. However, COVID-19 measures have also been portrayed as a significant contributor to reducing global CO2 emissions. Thus, the question arises: can online teaching reduce the carbon footprint of the internationalisation of education? This paper reviews online teaching as a potential solution to reduce carbon footprint and increase access to HE, whilst maintaining high student performance in HE within the remits of internationalisation

Reflecting on COVID-19 vaccine hesitancy among South Asian communities in the UK: a learning curve to decolonising the secondary school curriculum

COVID-19 has brought to light the systemic racism faced by ethnic minorities in the UK. During the pandemic, we saw an increase in anti-Asian hate crimes and a lack of support from the government given to both patients and healthcare workers from minority backgrounds on the front lines. This lack of support potentially contributed to the increased susceptibility of ethnic minorities to COVID-19 and also their hesitancy toward the vaccine, particularly the south Asian communities. In this paper we discuss potential reasons for COVID-19 vaccine hesitancy among south Asian groups. Additionally, we propose that introducing a decolonised curriculum in secondary school may enhance cultural awareness with historical context among the white British populations, allowing for more inclusion for south Asian communities. By exploring ways to decolonise specific subjects in the secondary curriculum, this paper aims to set out a guideline for teachers and education professionals on expanding secondary school pupils’ knowledge of racial issues and equality, to start the process of educating a new generation appropriately. We propose that decolonising the secondary school curriculum is a potential long-term solution to eradicating racism and discrimination

Advances in anti-cancer immunotherapy: car-T cell, checkpoint inhibitors, dendritic cell vaccines, and oncolytic viruses, and emerging cellular and molecular targets

Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response

Gamma-ray irradiation modulates PGRMC1 expression and the number of CD56⁺ and FoxP3⁺ cells in the tumor microenvironment of endometrial endometrioid adenocarcinoma

Purpose Although the conventional gamma ray brachytherapy has been successful in treating endometrioid endometrial adenocarcinoma (EC), the molecular and cellular mechanisms of this anti-tumorigenic response remain unclear. Therefore, we investigated whether gamma ray irradiation induces changes in the number of FoxP3+ T-regulatory lymphocytes (Tregs), CD56+ natural killer cells (NK), and the expression of progesterone receptor membrane component 1 (PGRMC1) in the tumor microenvironment (TME). Materials and Methods According to the inclusion criteria, 127 cases were selected and grouped into irradiation-treated (Rad+) and control (underwent surgery) groups and analyzed using immunohistochemistry. Predictive prognostic values were analyzed using Mann-Whitney U test, ROC analysis, relative risk, log-rank, Spearman rank tests and multivariate Cox’s regression. Results We observed significant differences (p < 0.001) between the radiation-treated patients and the control groups in FoxP3+ Tregs numbers, CD56+ NK cells and PGRMC1 expression. Gamma ray induced a 3.71- and 3.39-fold increase in the infiltration of FoxP3+ cells, CD56+ NK cells, respectively and 0.0034-fold change in PGRMC1 expression. Univariate and multivariate analyses revealed predictive role of the parameters. In the irradiated patients’ group, inverted correlations between clinical unfavorable outcome, FoxP3+ Tregs and CD56+ NK cells were observed. Conclusion Our results suggest an immune-modulating role, specifically by increasing immune cell infiltration, of gamma radiation in the TME which may potentially be utilized as biomarkers in prognostic values

IMPORTANCE OF FAILURE MODES AND EFFECT ANALYSIS APPLICATION FOR RISK ANALYSIS IN BARAPUKURIA COAL MINE, BANGLADESH

Because of the complex working situations, mining is known for being one of the most hazardous industries in the world. The working activities in such risky conditions in the underground coal mine often leads to many types of accidents. The working condition of Barapukuria Coal Mine (BCM) which is a producing underground coal mine in the North-western part of Bangladesh, has become insecure due to the lack of practising appropriate plan and methodology for reducing risk.Therefore, this study aims to assess the potential hazards by failure modes and effect analysis (FMEA) method in BCM. FMEA is a quality management tool often used to identify possible failure mode by calculating a risk priority number (RPN) from severity, occurrence, and detection scores. A noteworthy aspect in FMEA is the estimation of RPN to prioritize failure modes. In this phase, a quality point scale (1-10) is typically used to measure the three facets of a failure mode's risks, and it indicates that the higher the score, the greater the chance of accidents. We have studied some accidents data in BCM it indicates that roof fall is more hazardous compared to other accidents. With the help of FMEA method, we have assessed causes and effects of accidents and finally recommended actions to reduce hazards. Therefore, an integrated approach is a burning necessity that can predict the risk before the actual mishaps and the FMEA can be a handy solution in this case as it is a robust tool for identifying multi-horizon risks and mitigating threats that can be strengthened further

Increase in FoxP3, CD56 immune cells and decrease in glands PGRMC1 expression in the endometrium are associated with recurrent miscarriages

OBJECTIVE: Recurrent miscarriage (RM) is a multifactorial condition that involves frequent uterine anatomical abnormalities, parental karyotype abnormalities, and clotting disorders. We investigate the potential roles of endometrium FoxP3+ Tregs and CD56+ cells (uNK cells) and endometrial expression of PGRMC1 in the development of recurrent miscarriage. STUDY DESIGN: This prospective study included 102 out of 286 cases of SA patients. The cases were divided into groups with RM (+RM) and without RM (-RM). Immunohistochemistry staining was made using primary antibodies to FoxP3, CD56, and PGRMC1 in both groups. Morphometry analyses were carried out in 10 non-overlapping high power fields. Mann-Whitney U test, Fisher two-tail test, correlation analysis and relative risk (RR) were evaluated. A p < 0.05 was considered statistically significant. RESULTS: An increased presence of CD56-positive (p < 0.001) and FoxP3+ Treg (p = 0.0005) cells was found in the endometrium, with a reduction in PGRMC1 expression compared with -RM group (p = 0.004). A positive correlation was shown between the number of CD56-positive cells and FoxP3+ cells (r = 0.55), and an inverse correlation with PGRMC1 (r =  -0.35) in the + RM group. A similar observation was found in the -RM group, with a positive correlation of uNK cell number with the number of pregnancies (p < 0.001; r = 0.34). Endometrial infiltration of CD56-positive (p < 0.0001) and FoxP3+ (p < 0.0001) cells revealed an increased relative risk of RM. This increased risk was also revealed in SA with a loss of PGRMC1 expression (p < 0.0001). CONCLUSION: Our prospective study suggests, for the first time, that increased endometrial infiltration of uNK, FoxP3+ Treg cells and a decreased PGRMC1 expression may play potential roles in the development of RM

The Potential Roles of MELF-Pattern, Microvessel Density, and VEGF Expression in Survival of Patients with Endometrioid Endometrial Carcinoma: A Morphometrical and Immunohistochemical Analysis of 100 Cases

Background In this study, we hypothesized that microcystic, elongated, fragmented (MELF)-pattern, vascular endothelial growth factor (VEGF) expression by cancer cells and microvessel density of cancer stroma may be associated with progression of endometrioid adenocarcinoma. Methods The study used data from the Belarus Cancer Registry and archival histological material of 100 patients with retrospectively known good (survival) and poor (disease progression and death) outcomes. All cases were immunohistochemically stained for CD34 and VEGF. Two independent samples were compared for the characteristics of signs, and obtained results were analyzed by receiver operating characteristic analysis, Mann-Whitney U test, χ2 test (Yates correction), and Mantel-Cox test. Multivariate Cox hazard analysis and Spearman correlation test were used. A p-value of less than .05 was considered statistically significant. Results The observed survival rate of patients with endometrioid adenocarcinoma was significantly lower (p = .002) in MELF-pattern positive patients when compared with MELF-pattern negative patients. The overall survival rate of patients whose tumors had more than 114 vessels/mm2 of tissue was significantly low (p < .001). Interestingly, a similar observation was found in patients with increased vessel area, evidenced by VEGF expression in the glandular tumor component. Conclusions Our study suggests, for the first time, that these criteria may be used as risk factors of endometrioid adenocarcinoma progression during 5 years after radical surgical treatment. However, a large independent cohort of samples should be considered in the future to validate our findings