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Muscle Invasive bladder cancer is known to have an abundance of mutations, particularly in DNA damage response and chromatin modification genes. The role of these mutations in the development and progression of the disease is not well understood. However, a mutually exclusive mutation pattern between gene pairs could suggest gene mutations of significance. For example, a mutually exclusive mutation pattern could suggest an epistatic relationship where the outcome of a mutation in one gene would have the same outcome as a mutation in a different gene. The significance of a mutually exclusive relationship was determined by establishing a normal distribution of the conditional probabilities for having a mutation in one gene and not the other as well as the reverse relationship for each gene pairing. Then these distributions were used to determine the sigma–magnitude of standard deviation by which the observed value differed from the expected, a value that can also be interpreted as the ‘p-value’. This approach led to the identification of mutually exclusive mutation patterns in KDM6A and KMT2D as well as KDM6A and RB1 that suggested the observed mutation pattern did not happen by chance. Upon further investigation of these genes and their interactions, a potential similar outcome was identified that supports the concept of epistasis. Knowledge of these mutational interactions provides a better understanding of the mechanisms underlying muscle invasive bladder cancer development, and may direct therapeutic development exploiting genotoxic chemotherapy and synthetic lethality in these pathways.

Muscle Invasive bladder cancer is known to have an abundance of mutations, particularly in DNA damage response and chromatin modification genes. The role of these mutations in the development and progression of the disease is not well understood. However, a mutually exclusive mutation pattern between gene pairs could suggest gene mutations of significance. For example, a mutually exclusive mutation pattern could suggest an epistatic relationship where the outcome of a mutation in one gene would have the same outcome as a mutation in a different gene. The significance of a mutually exclusive relationship was determined by establishing a normal distribution of the conditional probabilities for having a mutation in one gene and not the other as well as the reverse relationship for each gene pairing. Then these distributions were used to determine the sigma-magnitude of standard deviation by which the observed value differed from the expected, a value that can also be interpreted as the 'p-value'. This approach led to the identification of mutually exclusive mutation patterns in KDM6A and KMT2D as well as KDM6A and RB1 that suggested the observed mutation pattern did not happen by chance. Upon further investigation of these genes and their interactions, a potential similar outcome was identified that supports the concept of epistasis. Knowledge of these mutational interactions provides a better understanding of the mechanisms underlying muscle invasive bladder cancer development, and may direct therapeutic development exploiting genotoxic chemotherapy and synthetic lethality in these pathways.

Activating the immune system is crucial for successful cancer immunotherapies, various proteins, such as the Fes non-receptor tyrosine kinase exist to limit activation and maintain homeostasis. However, in cancer settings, this serves as a barrier to the desired effects of immune activation following immunomodulatory treatment. Here, we demonstrate the role of Fes, a protein abundantly expressed in macrophages, as a novel innate intracellular immune checkpoint. Fes inactivity is associated with delayed tumour onset in a dose-dependent manner, and its deletion delays tumour growth, improves survival, enhances response to doxorubicin treatment, and sensitizes resistant tumours to PD-1 immune checkpoint inhibition. These effects are associated with an increase in Toll-like receptor signaling in antigen presenting cells, leading to an increase in proinflammatory cytokine production and cytotoxic T cell effector functions. Furthermore, we demonstrate a novel role for Fes in regulating the presentation of IL-12 on macrophage cell surfaces to enhance T-cell activation. Our results highlight Fes as a novel innate immune checkpoint with potential to serve as predictive biomarker to effective immune checkpoint blockade, and a potential novel therapeutic target for improved response to immunotherapy.Competing Interest StatementThe authors have declared no competing interest.

Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrate a novel role of the Fes tyrosine kinase, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delays tumour onset in a gene dose-dependent manner and improves murine triple negative breast cancer and melanoma tumour control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization. These effects were associated with a shift to an anti-tumourigenic tumour immune microenvironment. In vitro, we observed increased Toll-like receptor signaling, and proinflammatory cytokine production and presentation from antigen presenting cells, leading to increased T cell activation, cancer cell killing and tumour control. This study highlights Fes as a novel innate immune checkpoint with potential as a predictive biomarker for effective immune checkpoint blockade treatment, and a potential therapeutic target to improve anti-cancer immunotherapy.

Non-muscle invasive bladder cancer (NMIBC) constitutes a significant clinical challenge, with over 50% of patients experiencing poor clinical outcomes in the form of early recurrence or progression following treatment with Bacillus Calmette-Guerin (BCG) immunotherapy. The pre-treatment tumor immune microenvironment (TIME) is an established determinant of response to BCG. This study explores the spatial profiles of CD79a+ B cells, CD163+ M2-like macrophages, proliferating and tissue-resident phenotypes of T cells, along with PD-1/PD-L1 checkpoint expression in pre-BCG treatment tumors of 173 patients (139 males, 34 females). Multiplex immunofluorescence staining of a tumor tissue microarray, revealed elevated infiltration of CD79a+ B cells, CD163+ M2-like macrophages, CD103+ cells, and CD8+ T cells at the tumor invasive margins. Increased epithelial PD-L1 immune-checkpoint expression in tumors was observed in female and male patients who exhibited significantly shorter recurrence-free survival (RFS). Importantly, high CD79a+ B cell density in BCG-treated females in both stromal and epithelial compartments exhibited significantly shorter RFS and progression-free survival compared to males. Stromal CD79a+ B cell density was positively correlated with M2-like macrophages, CD8+ T cells, CD103+ cells and PD-1 expressing cells. CD79a+ B cells, CD103+ cells, and M2-like macrophage density were associated with higher grade and enriched in basal subtype tumor. This study highlights the significance of an understudied role of B cells and their cellular neighborhoods in the pre-treatment TIME and BCG-therapy response. Overall, findings from this study underscore the importance of considering sex-related immunobiological differences in the stromal compartments of bladder tumors towards the development of optimal therapeutic targeting strategies.

Background The purpose of anterior cruciate ligament reconstruction (ACLR) is to restore stability to the knee. Persistent rotational laxity following ACLR has been correlated with poor outcome and graft failure. We hypothesize that anterolateral complex reconstruction by way of a Modified Lemaire Lateral Extra-articular Tenodesis (LET) in combination with single bundle ACLR would reduce the risk of persistent rotatory laxity in young individuals who are deemed as being at high risk of failure. We will conduct a pragmatic, multicenter, randomized clinical trial comparing standard single bundle hamstring ACLR with combined ACLR and LET. Methods Six-hundred patients (300 per group) aged 25 years or less with an ACL deficient knee that meet two of the following three criteria will be included: 1) Grade 2 pivot shift or greater; 2) Returning to high risk cutting or pivoting sports; 3) Generalized ligamentous laxity. Participants will be seen at 3-months, 6-months, 12-months and 24-months post-operatively. The primary outcome measure is graft failure requiring revision ACLR or symptomatic instability associated with a positive asymmetric pivot shift indicating persistent rotational laxity. Patients will complete secondary outcome measures at each follow-up visit including patient-reported outcome measures, functional and biomechanical testing, and magnetic resonance imaging. Discussion This protocol is the first adequately powered randomized clinical trial investigating the effects of augmenting ACLR with an LET in patients at high-risk of graft failure. The successful completion of this trial has the potential to change surgical practice and provide evidence for the role of the LET in ACLR. Trial registration The trial is registered at ClinicalTrials.gov: NCT02018354 , 23-12-2013.

TWO of our star soccer players Huw Garven and Kai Bradshaw were selected for the Newcastle Zone Representative Soccer Squad.

Purpose To assess how meniscal repair and excision impact short term patient-reported outcome measures (PROMs), knee stability, and early graft rupture rates following primary hamstring anterior cruciate ligament reconstruction (ACLR) with or without lateral extra-articular tenodesis (LET) in a group of young active patients where meniscal repair is commonly advocated. Methods Six hundred and eighteen patients under 25 years of age at high-risk of graft failure following ACLR were recruited to the Stability 1 study. Multivariable regression models were developed to identify statistically and clinically significant surgical and demographic predictors of Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee Subjective Knee Form (IKDC), ACL Quality of Life Questionnaire (ACL-QOL) and Marx Activity Rating Scale (MARS) scores. Chi-Square tests of independence were used to explore the association between meniscal status (torn, not torn), meniscal treatment (excision or repair), graft rupture, and rotatory knee laxity. Results Medial meniscus repair was associated with worse outcomes on the KOOS ( β  = −1.32, 95% CI: −1.57 to −1.10, p  = 0.003), IKDC ( β  = −1.66, 95% CI: −1.53 to −1.02, p  = 0.031) and ACL-QOL ( β  = −1.25, 95% CI: −1.61 to 1.02, p  = n.s.). However, these associations indicated small, clinically insignificant changes based on reported measures of clinical relevance. Other important predictors of post-operative PROMs included age, sex, and baseline scores. Medial meniscus excision and lateral meniscus treatment (repair or excision) did not have an important influence on PROMs. There was no significant association between meniscal treatment and graft rupture or rotatory knee laxity. Conclusion While repairing the medial meniscus may result in a small reduction in PROM scores at two-year follow-up, these differences are not likely to be important to patients or clinicians. Any surgical morbidity associated with meniscal repair appears negligible in terms of PROMs. Meniscal repair does not affect rotatory laxity or graft failure rates in the short term. Therefore, meniscal repair should likely be maintained as the standard of care for concomitant meniscal tears with ACLR. Level of evidence III.

This book details the research developments in insurance and its related fields. It starts with the history and foundations of insurance theory and moves on to review asymmetric information, risk management, insurance pricing and other advance topics.