This investigation was concerned with characterizing effects of this tumor line on lipid metabolism in DBA/lJ mice and serum protein levels and cellular changes in DBA/lJ and Swiss white mice. Total lipids, lipid phosphorus, neutral lipids, and changes in fatty acids were determined in liver, spleen, skin, and tumor of DBA/lJ mice bearing the lymphosarcoma at various days after injection of tumor cells.

No description available.

AimThe broad aim of this thesis was to explore the risk of malignancy in people with rheumatoid arthritis (RA), treated with anti-tumour necrosis factor (TNF) drugs.MethodsThis thesis used data from patients with RA registered with the British Society of Rheumatology Biologics Register-RA. The risk of cancer in biologic-naive patients treated with traditional disease modifying drugs (nbDMARD) was compared to that in the general population by calculating standardised incidence ratios (SIR). The influence of anti-TNF on cancer risk was then explored by comparing the risk in the anti-TNF cohort to that in the nbDMARD cohort using Cox proportional hazard models.ResultsThe risk of cancer was increased in the nbDMARD cohort by 28% compared to the general population (SIR 1.28, 95% confidence interval (CI) 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and Non-Hodgkin Lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were increased compared to the general population and both prostate cancer and cancers of the female genital organs reduced; SIRs 0.35 (95% CI 0.11, 0.82) and 0.35 (95% CI 0.10, 0.90) respectively. There was no difference in the risk of cancer in patients treated with anti-TNF compared to nbDMARD, after adjusting for differences in baseline characteristics; Hazard ratio for lymphoma: 1.00 (95% CI 0.49, 2.05); cancers of the solid organs: 0.83 (95% CI 0.64, 1.07); and keratinocyte skin cancer: basal cell carcinoma 1.06 (95% CI 0.64, 1.75), squamous cell carcinoma 1.62 (95% CI 0.44, 5.90). ConclusionsSubjects with RA, treated with nbDMARD were at increased risk of cancer compared to the general population. In particular, lung cancer, lymphoma and KSC were increased. Treatment with the TNF inhibitors ETA, INF or ADA was not associated with a difference in relative risk of lymphoma, solid cancer or skin cancers when compared to nbDMARD.

Urinary bladder paraganglioma (UBP) is a rare neuroendocrine neoplasm. It accounts for less than 1% of urinary bladder tumors and less than 6% among all types of paragangliomas. More commonly, UBP occurs in the female population aged 20-40 years old. UBP is classified into functional and non-functional types, and the majority is functional, leading to symptoms and signs of excess catecholamine, including hypertension, palpitation, syncope, and headache. Non-functional UBP comprises about 15% of UBPs and lacks the excess secretion of catecholamine, which often leads to misdiagnosis as urothelial cancer due to its rarity and nonspecific symptoms - increased urinary frequency/urgency and painless gross hematuria. Here, we present a rare case of a non-functional UBP. A 65-year-old male with BPH presented to ER with a 6-month history of urinary retention. He also was experiencing intermittent hematuria and dysuria during this time but otherwise remained asymptomatic without headache, dyspnea, wheezing, or diarrhea. Physical exam showed normal BP and no suprapubic tenderness on palpation. UA showed gross hematuria. Subsequent cystoscopy showed thickening of the bladder dome and an 8 mm lesion. Transurethral resection of bladder tumor (TURBT) was performed, and pathology showed 1 cm tumor confined to submucosa with questionable margins. Chromogranin, synaptophysin, CD56, GATA3, CD10 were stained positive; cytokeratin AE1/AE3, cytokeratin 34betaE12, SOX10, S100, and calretinin were negative. From morphology and immunochemistry, the diagnosis of UBP was made. Free metanephrine, plasma normetanephrine, 24-hour urine metanephrine and normetanephrine levels were not elevated. Post-TURBT MRI abdomen showed no other suspicious lesions. A wide re-resection of the bladder dome was performed due to the questionable margins from the initial surgery, and pathology showed benign bladder tissue with unremarkable immunostains, indicating no overt features of residual paraganglioma. Due to its paucity and uncertain biological behavior, the prognosis of UBP is not well established. While most UBP are benign, 10-15% of cases are malignant. High expression of VEGF and or abnormal vessel architecture in the tumor cells raise suspicion of malignancy. However, typically, definitive evidence of malignancy in paraganglioma is its invasion of adjacent organs or distant metastasis. The local recurrence rate ranges from 5-15%, thus necessitating long-term surveillance for 10-years. Systemic chemotherapy, including cyclophosphamide, vincristine, dacarbazine (CVD), or temozolomide, is necessary for distant metastatic or symptomatic disease. Iobenguane I-131 or Lutathera can be utilized with positive MIBG or 68Ga DOTATATE scan, respectively. Otherwise, surgical extirpation remains the choice of curative intent, and a multidisciplinary approach consisting of urologists, medical/radiation oncologists, and endocrinologists would be warranted for this rare entity of disease.

Faculty of Science; School of molecular and Cell Biology; MSC Dissertation / Background: Cancer of the oesophagus ranks as the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis. When these processes lose integration, such as cancer, then uncontrolled cell growth occurs. There are at least five ACBP subgroups and the two being focused on in this study is B-ACBP (brain specific) and 1-ACBP (found in nearly all tissues). ACBPs act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for ß-oxidation. ACBPs are also believed to be putative ligands of PBR (Peripheral Benzodiazepine Receptor), and bound to this receptor facilitates mitochondrial membrane permeabilization giving the notion that it favours apoptosis. Aim: To establish the expression patterns of 1-ACBP, B-ACBP, and PBR in oesophageal cancer, and to characterize their roles in this disease. Methodology: Paraffin-embedded sections of normal and malignant oesophageal tissues were utilized for localization studies. RNA probes was synthesized and labelled using Digoxigenin for colorimetric and fluorescent detection during the in situ hybridization (ISH) technique for localization. Real time quantitative RT-PCR was performed to determine the expression levels of the three genes in oesophageal cancer RNA using the Roche Lightcylcer .Results: All three genes showed substantial upregulation within the malignant tissue sections compared to normal oesophageal sections, all three transcripts localized specifically to plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelium cells. PBR localization occurred in tumour islands in invasive tissue sections. Quantitative RT-PCR also illustrated PBR expression level was the highest compared to the ACBP genes expression in tumours. Conclusion: These results show that 1-ACBP, B-ACBP and PBR play a role in the pathogenesis of oesophageal cancer as well as immunology. Further experiments are still required to determine the function of these genes and the role they play in apoptosis and oesophageal cancer.

Yes / Objective: The increasing prevalence of malignant disease has been associated with shifts in environmental, socioeconomic, and lifestyle risk factors as well as increased adult lifespan. We examine the relationship between malignant neoplasms affecting bone, age and industrialization. Materials: Pre-existing skeletal data from 11 medieval (1066-1547, n=8,973) and 14 industrial (1700-1890, n=4,748) cemeteries (N=13,721) from England. Methods: Context number, sex, age-at-death, evidence of skeletal malignancy, and diagnosis were collated. The data were compared using chi square, Kolmogorov-Smirnov tests and logistic regression (α=0.01). Results: There was a statistically significant increase in skeletal malignancy from 0.06% in the medieval sample to 0.36) in the industrial sample (p< 0.001). Age had a strong relationship with malignancy (p = 0.003), sex did not (p = 0.464). Logistic regression revealed that time-period (p < 0.001) was a stronger predictor of skeletal malignancy than age-at-death (p = 0.002). Conclusion: Our results confirm that even with the temporal increase in adult human lifespan the increase of malignant neoplasms of bone between the medieval and industrial time periods is still statistically significant. Significance: The augmented exposure to carcinogens and pollution during the Industrial Revolution had a strong effect on an individual’s susceptibility to developing malignant disease of bone. Limitations: This meta-analysis relies upon previously gathered data and diagnosis from a large number of researchers and did not include radiographic or CT screening. Only malignant neoplasms that affected bone could be included. Suggestions for further research: Increasing excavation and analysis of post-medieval cemeteries will provide more data. Multimethod approaches (radiography, CT, Micro-CT and histology) are encouraged.

No / Improved survival in patients with hematological malignancy (HM) admitted to the intensive care unit (ICU) has largely been reported in uncontrolled cohorts from single academic institutions. We compared hospital mortality between 147 patients with HM and 147 general medical admissions to five non-specialist ICUs. The proportion of patients surviving to hospital discharge was significantly worse in patients with HM (27% vs. 56%; p < 0.001). Six-month and 1-year survival in patients with HM was 21% and 18%, respectively. HM, greater age, mechanical ventilation (MV) and acute physiology and chronic health evaluation (APACHE) II score were independent predictors of poor outcome. For patients with HM, culture proven infection, age, MV and inotropes were negative predictors. Disease-specific factors including hematological diagnosis, neutropenia, remission status, prior stem cell transplant, time from diagnosis to admission and degree of prior treatment were not predictive. Overall survival of patients with HM was worse than that recently reported from specialist units.

BACKGROUND: The incidence and mortality of renal cell carcinoma (RCC) after kidney transplantation (KTx) remain unclear. This study's aims were (1) to investigate the pooled incidence/incidence trends, and (2) to assess the mortality/mortality trends in KTx patients with RCC. METHODS: A literature search was conducted using the MEDLINE, EMBASE and Cochrane databases from inception through October 2018. Studies that reported the incidence or mortality of RCC among kidney transplant recipients were included. The pooled incidence and 95% CI were calculated using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO; no. CRD42018108994. RESULTS: A total of 22 observational studies with a total of 320,190 KTx patients were enrolled. Overall, the pooled estimated incidence of RCC after KTx was 0.7% (95% CI: 0.5-0.8%, = 93%). While the pooled estimated incidence of de novo RCC in the native kidney was 0.7% (95% CI: 0.6-0.9%, = 88%), the pooled estimated incidence of RCC in the allograft kidney was 0.2% (95% CI: 0.1-0.4%, = 64%). The pooled estimated mortality rate in KTx recipients with RCC was 15.0% (95% CI: 7.4-28.1%, = 80%) at a mean follow-up time of 42 months after RCC diagnosis. While meta-regression analysis showed a significant negative correlation between year of study and incidence of de novo RCC post-KTx (slopes = -0.05, = 0.01), there were no significant correlations between the year of study and mortality of patients with RCC ( = 0.50). Egger's regression asymmetry test was performed and showed no publication bias in all analyses. CONCLUSIONS: The overall estimated incidence of RCC after KTX was 0.7%. Although there has been a potential decrease in the incidence of RCC post-KTx, mortality in KTx patients with RCC has not decreased over time.

Many haematological malignancies are associated with widespread alterations of the transcriptional and epigenetic programmes. Changes in DNA methylation provide the clearest example of epigenetic changes, but the mechanism(s) underlying such changes is unknown. To investigate this I studied DNA methylation across an ~80kb segment of the genome which is not known to be mutated in haematological malignancies. Methylation was perturbed in 35-100% of samples of DNA from individuals with a wide range of haematological malignancies but not in non-malignant haematological disorders. DNA methylation was comprehensively assessed by Southern blot analysis, classical bisulphite sequencing and using a newly developed capture bisulphite sequencing protocol. The results were also compared with analysis by MeDIP, an immunoprecipitation-based technique. These analyses provide methylation status at various levels including individual CpG resolution. This showed both gain and loss of methylation at CpG dinucleotides. Of interest, hypomethylation was most frequently seen in intergenic regions corresponding to transcription factor binding sites and areas of increased chromosome accessibility. These observations suggested that hypomethylation of the genome in haematological malignancies could arise from aberrantly expressed DNA binding proteins which, recruited to sequences in regions of open chromatin, would protect the underlying CpG dinucleotides from the methylation machinery. This, in turn, could lead to passive demethylation accumulating with increasing cell divisions. This hypothesis was tested with electrophoretic mobility shift assays using oligonucleotides representing the DNA underlying one such region. This showed that, compared to nuclear extracts from the lymphocytes of normal individuals, those from patients with CLL were enriched for a protein which binds to oligonucleotides containing the underlying sequence. Using a mass spectrometry approach, I identified a variety of proteins that may bind such regions and account for their passive demethylation in haematological malignancies.

Periocular malignancy represents an increasing burden and currently requires disfiguring surgery in an attempt to cure patients. Basal cell carcinoma (BCC) is the commonest cancer worldwide and morphoeic BCC (mBCC) is an aggressive subtype. Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition that often requires blinding surgery to prevent mortality, especially in the pagetoid subtype. MBCC has a high risk of local recurrence compared to the more indolent nodular subtype reflected by a different set of driver genes including FLNB and HECTD4. Surrounding mBCC stroma is abnormal, containing mutations in EPHA3 and GLI3. Four common dysregulated pathways detected using both whole exome and RNA sequencing for mBCC were; 'hedgehog (Hh) signalling pathway', 'BCC', 'Natural killer cell mediated cytotoxicity' and 'Fc Epsilon RI signalling pathway'. Hh mutational profile for nodular BCC was not reflected in the RNA and protein expression. In contrast, Hh overexpression is seen in the tumour and stroma of morphoeic tissue with the latter potentially being partly responsible for its aggressive nature and risk of recurrence that may warrant removal to prevent recurrence. SGC has a low overall mutational burden, no UV signature and defective mismatch repair signature. Driver genes included TP53, RB1 and the dynein family is a novel driver possibly involved in chromatid segregation as marked chromosomal instability was demonstrated on copy number analysis. Correlation of whole exome and RNA sequencing data demonstrated upregulated 'cell cycle', 'ubiquitin mediated proteolysis' and 'wnt signalling'. Subtype analysis of pagetoid and nodular SGC revealed the histone gene cluster family as important to both. Oncomir hsa-miR-21 was overexpressed in both and loss of hsa-miR-199a occurs in pagetoid. Increased protein expression of HIST1H2BD was seen in both subtypes as was Hh expression. These novel SGC findings support a chromosomally unstable cancer with the ability to invade extracellular matrix.