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Wnt signaling is a critical regulatory pathway in development and disease. Very little is known about the mechanisms of Wnt signaling in prostate cancer, a leading cause of death in men. A quantitative analysis of the expression of Wnt5A protein in human tissue arrays, containing 600 prostate tissue cores, showed >50% increase in malignant compared to benign cores (p<0.0001). In a matched pair of prostate cancer and normal cell line, expression of Wnt5A protein was also increased. Calcium waves were induced in prostate cells in response to Wnt5A with a 3 fold increase in Flou-4 intensity. The activity of Ca(2+)/calmodulin dependent protein kinase (CaMKII), a transducer of the non-canonical Wnt/Ca(2+) signaling, increased by 8 fold in cancer cells; no change was observed in beta-catenin expression, known to activate the canonical Wnt/beta-catenin pathway. Mining of publicly available human prostate cancer oligoarray datasets revealed that the expression of numerous genes (e.g., CCND1, CD44) under the control of beta-catenin transcription is down-regulated. Confocal and quantitative electron microscopy showed that specific inhibition of CaMKII in cancer cells causes remodeling of the actin cytoskeleton, irregular wound edges and loose intercellular architecture and a 6 and 8 fold increase in the frequency and length of filopodia, respectively. Conversely, untreated normal prostate cells showed an irregular wound edge and loose intercellular architecture; incubation of normal prostate cells with recombinant Wnt5A protein induced actin remodeling with a regular wound edge and increased wound healing capacity. Live cell imaging showed that a functional consequence of CaMKII inhibition was 80% decrease in wound healing capacity and reduced cell motility in cancer cells. We propose that non-canonical Wnt/Ca(2+) signaling via CaMKII acts as a novel regulator of structural plasticity and cell motility in prostate cancer.

Prostate carcinoma is the most common cancer in men with few, quantifiable, biomarkers. Prostate cancer biomarker discovery has been hampered due to subjective analysis of protein expression in tissue sections. An unbiased, quantitative immunohistochemical approach provided here, for the diagnosis and stratification of prostate cancer could overcome this problem. Antibodies against four proteins BTF3, HINT1, NDRG1 and ODC1 were used in a prostate tissue array (> 500 individual tissue cores from 82 patients, 41 case pairs matched with one patient in each pair had biochemical recurrence). Protein expression, quantified in an unbiased manner using an automated analysis protocol in ImageJ software, was increased in malignant vs non-malignant prostate (by 2-2.5 fold, p<0.0001). Operating characteristics indicate sensitivity in the range of 0.68 to 0.74; combination of markers in a logistic regression model demonstrates further improvement in diagnostic power. Triple-labeled immunofluorescence (BTF3, HINT1 and NDRG1) in tissue array showed a significant (p<0.02) change in co-localization coefficients for BTF3 and NDRG1 co-expression in biochemical relapse vs non-relapse cancer epithelium. BTF3, HINT1, NDRG1 and ODC1 could be developed as epithelial specific biomarkers for tissue based diagnosis and stratification of prostate cancer.

Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, = 0.005), malabsorption more common (57.97 vs. 35.71%, = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea ( = 0.028; = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients ( = 0.009, = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation.

Common variable immunodeficiency (CVID) is traditionally characterised by recurrent infections and immune dysregulation, but growing evidence suggests an increased risk of endothelial dysfunction and premature atherosclerosis in this population. To evaluate cardiovascular risk in patients with CVID through integration of clinical risk factors, biomarkers of endothelial dysfunction, and radiographic surrogates of subclinical atherosclerosis. A total of 101 CVID patients and 56 matched household controls were recruited. Data collected included cardiovascular risk factors, blood biomarkers (D-dimer, von Willebrand factor [vWF], fibrinogen, ESR, CRP), and immunological profiles. Existing imaging was reviewed, including thoracic CT for assessment of coronary artery calcification (CAC) and FibroScan for controlled attenuation parameter (CAP) scores; aortic pulse wave velocity (aPWV) was measured in a subset of participants. Subgroup analysis compared infection-only versus inflammatory/complex phenotypes of CVID. CVID patients demonstrated high rates of hyperlipidaemia (38.6%), hypertension (23.8%), and diabetes/prediabetes (14.9%). CAC was present in 37%, with 82.4% having no known prior cardiovascular disease. Hepatic steatosis and elevated aPWV were observed in 30% and 6.5%, respectively. Patients with CAC were older and had higher rates of hypertension, diabetes, hyperlipidaemia, chronic kidney disease, elevated median vWF (227.5 vs 167 IU/dL, p=0.001), D-dimer (370.5 vs 271 ng/mL, p=0.011), and aPWV (8.2 vs 6.0 m/s, p=0.006). Patients with an inflammatory phenotype had higher vWF (224 vs 163 IU/dL, p<0.001) and D-dimer (314 vs 205 ng/mL, p=0.043) levels than those with infection-only CVID. CVID is associated with a substantial burden of cardiovascular risk factors and subclinical atherosclerosis, especially in the inflammatory phenotype.

Single-port, single-incision laparoscopy is part of the natural development of minimally invasive surgery. Refinement and modification of laparoscopic instrumentation has resulted in a substantial increase in the use of laparoendoscopic single-site surgery (LESS) in urology over the past 2 years. Since the initial report of single-port nephrectomy in 2007, the majority of laparoscopic procedures in urology have been described with a single-site approach. This includes surgery on the adrenal, ureter, bladder, prostate, and testis, for both benign and malignant conditions. In this review, we describe the current clinical applications and results of LESS in Urological Surgery. To date this evidence comes from small case series in centres of excellence, with good results. Further well-designed prospective trials are awaited to validate these findings.

Purpose The COVID-19 pandemic has impacted on how health services deliver care and the mental health of the population. Due to their clinical vulnerability, to reduce in-hospital attendances during the COVID-19 pandemic, modifications in immunoglobulin treatment regimens were made for patients with antibody deficiency. These patients were also likely to experience social isolation due to shielding measure that were advised. We aimed to investigate the impact of modifying immunoglobulin treatment regimen on infection and mental health burden during shielding restrictions. Method Patients on immunoglobulin replacement therapy (IGRT) responded to a standardised questionnaire examining self-reported infection frequency, anxiety (GAD-7), depression (PHQ-8), fatigue (FACIT), and quality of life during the pandemic. Infection frequency and immunoglobulin trough levels were compared to pre-pandemic levels. Results Patients who did not change treatment modality or those who received immunoglobulin replacement at home during the pandemic reported fewer infections. In patients who received less frequent hospital infusions, there was no significant increase in infections whilst immunoglobulin trough levels remained stable. There was no significant difference in anxiety, or depression scores between the treatment modality groups. Patients reported higher fatigue scores compared to the pre-COVID general population and in those discharged following hospitalisation for COVID. Conclusion Changing immunoglobulin treatment regimen did not negatively impact infection rates or psychological wellbeing. However, psychological welfare should be prioritised for this group particularly given uncertainties around COVID-19 vaccination responsiveness and continued social isolation for many.

Wnt signaling is a critical regulatory pathway in development and disease. Very little is known about the mechanisms of Wnt signaling in prostate cancer, a leading cause of death in men. A quantitative analysis of the expression of Wnt5A protein in human tissue arrays, containing 600 prostate tissue cores, showed >50% increase in malignant compared to benign cores (p<0.0001). In a matched pair of prostate cancer and normal cell line, expression of Wnt5A protein was also increased. Calcium waves were induced in prostate cells in response to Wnt5A with a 3 fold increase in Flou-4 intensity. The activity of Ca.sup.2+ /calmodulin dependent protein kinase (CaMKII), a transducer of the non-canonical Wnt/Ca.sup.2+ signaling, increased by 8 fold in cancer cells; no change was observed in [beta]-catenin expression, known to activate the canonical Wnt/[beta]-catenin pathway. Mining of publicly available human prostate cancer oligoarray datasets revealed that the expression of numerous genes (e.g., CCND1, CD44) under the control of [beta]-catenin transcription is down-regulated. Confocal and quantitative electron microscopy showed that specific inhibition of CaMKII in cancer cells causes remodeling of the actin cytoskeleton, irregular wound edges and loose intercellular architecture and a 6 and 8 fold increase in the frequency and length of filopodia, respectively. Conversely, untreated normal prostate cells showed an irregular wound edge and loose intercellular architecture; incubation of normal prostate cells with recombinant Wnt5A protein induced actin remodeling with a regular wound edge and increased wound healing capacity. Live cell imaging showed that a functional consequence of CaMKII inhibition was 80% decrease in wound healing capacity and reduced cell motility in cancer cells. We propose that non-canonical Wnt/Ca.sup.2+ signaling via CaMKII acts as a novel regulator of structural plasticity and cell motility in prostate cancer.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is safe and effective for adolescents and adults with inborn errors of immunity (IEI) with severe manifestations of their disease. The haematopoietic cell transplantation comorbidity index (HCT-CI) score predicts transplant survival in non-malignant diseases, including IEIs. We hypothesised that immune dysregulation pre-transplant may also influence transplant outcomes. We calculated the pre-transplant immune dysregulation and disease activity score (IDDA v2.1) for 82 adolescent and adult IEI patients (aged ≥ 13 years). Three-year overall survival (OS) for the whole cohort was 90% ( n  = 82) with a median follow up of 44.7 months (range 8.4 to 225.8). Events were defined as acute graft-versus-host disease (GvHD) grades II or above, chronic GvHD of any grade, graft failure, or death from any cause. Three-year event free survival (EFS) for the whole cohort was 72%. In multivariable analysis the IDDA v2.1 score pre-transplant and HCT-CI score significantly impacted OS (hazard ratio 1.08, p  = 0.028) and EFS (hazard ratio 1.04, p  = 0.0005). Importantly, 35% of this cohort had a high IDDA v2.1 score (≥ 15) and low HCT-CI score (< 3) suggesting that the risks of alloHSCT may be underestimated in a proportion of patients with IEI if the HCT-CI score is used alone. These findings support the potential for improved outcomes following successful modulation of immune dysregulation pre-transplant. The IDDA v2.1 score has utility as an objective measurement of pre-transplant immune dysregulation providing additional information regarding the risks and potential complications of alloHSCT in an individual IEI patient.

Diarrhea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Different pathologies in patients’ bowel biopsies have been described and links with infections have been demonstrated. The aim of this study was to analyze the bowel histology of CVID patients in the Royal-Free-Hospital (RFH) London CVID cohort. Ninety-five bowel histology samples from 44 adult CVID patients were reviewed and grouped by histological patterns. Reasons for endoscopy and possible causative infections were recorded. Lymphocyte phenotyping results were compared between patients with different histological features. There was no distinctive feature that occurred in most diarrhea patients. Out of 44 patients (95 biopsies), 38 lacked plasma cells. In 14 of 21 patients with nodular lymphoid hyperplasia (NLH), this was the only visible pathology. In two patients, an infection with Giardia lamblia was associated with NLH. An IBD-like picture was seen in two patients. A coeliac-like picture was found in six patients, four of these had norovirus. NLH as well as inflammation often occurred as single features. There was no difference in blood lymphocyte phenotyping results comparing groups of histological features. We suggest that bowel histology in CVID patients with abdominal symptoms falls into three major histological patterns: (i) a coeliac-like histology, (ii) IBD-like changes, and (iii) NLH. Most patients, but remarkably not all, lacked plasma cells. CVID patients with diarrhea may have an altered bowel histology due to poorly understood and likely diverse immune-mediated mechanisms, occasionally driven by infections.