Combining chemotherapy with immunotherapy to treat mesothelioma: an investigation into the role of CD4+ T cells in a murine model

Cytotoxic chemotherapy remains the mainstay of treatment for patients with cancer, however immunotherapy is starting to emerge as an additional modality of treatment. Evidence suggests that chemotherapy can synergise with immunotherapy to improve responses. Although CD8 T cells have been regarded as the main anti-tumour effector cell, the role of CD4 T cells in orchestrating CD8 and other anti-tumour responses is increasingly recognised. However, the CD4 T cell population contains effector and suppressive subsets with diverse and opposing functions. This thesis describes the establishment of a murine mesothelioma model with which to study the effects of different CD4 subsets on anti-tumour immune responses, and investigate their capacity to provide cognate help to tumour antigen specific CD8 T cells. Haemagluttin (HA) specific CD4 T cells from transgenic mice were polarised in vitro into Th1, Th2, Th17 and Treg subsets and adoptively transferred alongside HA specific CD8 T cells into mice bearing HA expressing tumours derived from a mesothelioma cell line. The effects of the different CD4 subtypes on tumour growth and their capacity to provide ‘help’ to CD8 T cells was investigated in a prophylactic treatment model and in the context of treatment with gemcitabine chemotherapy. Results showed that survival and behaviour of in vitro differentiated CD4 subtypes after adoptive transfer was highly variable and that only Th1s displayed anti-tumour activity when injected prophylactically, prior to tumour inoculation. Cytotoxic chemotherapy did not provide a favourable environment for adoptive transfer of in vitro differentiated CD4 cells. No antitumour activity was seen against established tumours, which may have been due to overriding tumour induced immunosuppressive mechanisms. Successful treatment of established tumours that had been treated with chemotherapy required both the provision of HA specific CD8 cells and the prior removal of an established, endogenous regulatory CD4 T cell population

Combining chemotherapy with immunotherapy to treat mesothelioma: an investigation into the role of CD4+ T cells in a murine model

Cytotoxic chemotherapy remains the mainstay of treatment for patients with cancer, however immunotherapy is starting to emerge as an additional modality of treatment. Evidence suggests that chemotherapy can synergise with immunotherapy to improve responses. Although CD8 T cells have been regarded as the main anti-tumour effector cell, the role of CD4 T cells in orchestrating CD8 and other anti-tumour responses is increasingly recognised. However, the CD4 T cell population contains effector and suppressive subsets with diverse and opposing functions. This thesis describes the establishment of a murine mesothelioma model with which to study the effects of different CD4 subsets on anti-tumour immune responses, and investigate their capacity to provide cognate help to tumour antigen specific CD8 T cells. Haemagluttin (HA) specific CD4 T cells from transgenic mice were polarised in vitro into Th1, Th2, Th17 and Treg subsets and adoptively transferred alongside HA specific CD8 T cells into mice bearing HA expressing tumours derived from a mesothelioma cell line. The effects of the different CD4 subtypes on tumour growth and their capacity to provide ‘help’ to CD8 T cells was investigated in a prophylactic treatment model and in the context of treatment with gemcitabine chemotherapy. Results showed that survival and behaviour of in vitro differentiated CD4 subtypes after adoptive transfer was highly variable and that only Th1s displayed anti-tumour activity when injected prophylactically, prior to tumour inoculation. Cytotoxic chemotherapy did not provide a favourable environment for adoptive transfer of in vitro differentiated CD4 cells. No antitumour activity was seen against established tumours, which may have been due to overriding tumour induced immunosuppressive mechanisms. Successful treatment of established tumours that had been treated with chemotherapy required both the provision of HA specific CD8 cells and the prior removal of an established, endogenous regulatory CD4 T cell population

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

An overview of chemical additives present in plastics: Migration, release, fate and environmental impact during their use, disposal and recycling

Over the last 60 years plastics production has increased manifold, owing to their inexpensive, multipurpose, durable and lightweight nature. These characteristics have raised the demand for plastic materials that will continue to grow over the coming years. However, with increased plastic materials production, comes increased plastic material wastage creating a number of challenges, as well as opportunities to the waste management industry. The present overview highlights the waste management and pollution challenges, emphasising on the various chemical substances (known as “additives”) contained in all plastic products for enhancing polymer properties and prolonging their life. Despite how useful these additives are in the functionality of polymer products, their potential to contaminate soil, air, water and food is widely documented in literature and described herein. These additives can potentially migrate and undesirably lead to human exposure via e.g. food contact materials, such as packaging. They can, also, be released from plastics during the various recycling and recovery processes and from the products produced from recyclates. Thus, sound recycling has to be performed in such a way as to ensure that emission of substances of high concern and contamination of recycled products is avoided, ensuring environmental and human health protection, at all times

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome