A Validation Study of cT-Categories in the Swedish National Urinary Bladder Cancer Register-Norrland University Hospital.

BACKGROUND: In Sweden, all patients with urinary bladder cancer (UBC) are recorded in the Swedish National Register for Urinary Bladder Cancer (SNRUBC). The purpose of this study was to validate the registered clinical tumour categories (cT-categories) in the SNRUBC for Norrland University Hospital, Sweden, from 2009 to 2020, inclusive. METHODS: The medical records of all 295 patients who underwent radical cystectomy for the treatment of UBC were reviewed retrospectively. Possible factors impacting the cT-categories were identified. To optimise cT-classification, computed tomography urography of all patients with suspected tumour-associated hydronephrosis (TAH) or suspected tumour in bladder diverticulum (TIBD) were retrospectively reviewed by a radiologist. Discrepancy was tested with a logistic regression model. RESULTS: cT-categories differed in 87 cases (29.5%). Adjusted logistic regression analysis found TIBD and TAH as significant predictors for incorrect registration; OR = 7.71 (p < 0.001), and OR = 17.7, (p < 0.001), respectively. In total, 48 patients (68.6%) with TAH and 12 patients (52.2%) with TIBD showed discrepancy regarding the cT-category. Incorrect registration was mostly observed during the years 2009-2012. CONCLUSION: The study revealed substantial incorrect registration of cT-categories in SNRUBC. A major part of the misclassifications was related to TAH and TIBD. Registration of these variables in the SNRUBC might be considered to improve correct cT-classification.

Insights into the evolution of enzymatic specificity and catalysis: From Asgard archaea to human adenylate kinases.

Enzymatic catalysis is critically dependent on selectivity, active site architecture, and dynamics. To contribute insights into the interplay of these properties, we established an approach with NMR, crystallography, and MD simulations focused on the ubiquitous phosphotransferase adenylate kinase (AK) isolated from Odinarchaeota (OdinAK). Odinarchaeota belongs to the Asgard archaeal phylum that is believed to be the closest known ancestor to eukaryotes. We show that OdinAK is a hyperthermophilic trimer that, contrary to other AK family members, can use all NTPs for its phosphorylation reaction. Crystallographic structures of OdinAK-NTP complexes revealed a universal NTP-binding motif, while 19F NMR experiments uncovered a conserved and rate-limiting dynamic signature. As a consequence of trimerization, the active site of OdinAK was found to be lacking a critical catalytic residue and is therefore considered to be "atypical." On the basis of discovered relationships with human monomeric homologs, our findings are discussed in terms of evolution of enzymatic substrate specificity and cold adaptation.

Computerized tomography before the final treatment cycle of neoadjuvant chemotherapy or induction chemotherapy in muscle-invasive urinary bladder cancer, cannot predict pathoanatomical outcomes and does not reflect prognosis-results of a single centre retrospective prognostic study.

BACKGROUND: Evaluating the routine of using control computer tomography (cCT) for determining the response status of muscle-invasive bladder cancer (MIBC) prior to final cycle of neoadjuvant chemotherapy (NAC) or induction chemotherapy (IC), in terms of predicting histopathological pTNM-staging and pathoanatomical responses/non-responses. Secondly, predicting two and three-year overall survival (OS). METHODS: Seventy-seven patients with localized MIBC (cT2-4aN0M0) and 3 patients with minimal nodal dissemination (cN1-2), undergoing NAC or IC and radical cystectomy (RC), the years 2006-2014 at Norrland university hospital in Umeå, Sweden. Baseline pre-cystectomy CTs and cCTs prior to final chemotherapy-cycle, were reviewed and underwent attempted RECIST-criteria categorization, into five response/non-response related subgroups (n=71). The diagnostic accuracy of cCT in comparison with pTNM was assessed using sensitivity, specificity, positive- and negative likelihood ratios. OS for 2 and 3 years was calculated, both in relation to histopathological pTNM-stages in all patients (n=80) and for the patients with cCT-evaluated categories (n=71). Multivariable analysis for OS, was performed in correlation to pTNM-stages firstly, and to radiological staging secondly. RESULTS: The sensitivity of cCT to predict non-responders according to pTMN was 64% and specificity 36%. The positive likelihood ratio=1 and the negative likelihood ratio =1. CT-evaluations couldn't accurately predict pTNM-stages in terms of response/non-response. No statistically significant results were found in correlating cCTs with two and three-year OS. CONCLUSIONS: cCT prior to planned final preoperative chemotherapy-cycle in MIBC patients undergoing NAC or IC, has a poor correlation with pTNM and cannot predict pathoanatomical responses. Prediction of OS based on cCTs is unfeasible.

Nucleation of an Activating Conformational Change by a Cation-π Interaction.

As a key molecule in biology, adenosine triphosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and cofactor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation-π interaction. In addition to recognition, the interaction was found to have dual functionality. First, it nucleates the activating conformational transition of the ATP binding domain and also affects the specificity in the distant AMP binding domain. In light of the functional consequences resulting from the cation-π interaction, it is possible that the mode of ATP recognition may be a useful tool in enzyme design.

Pigs, Unlike Mice, Have Two Distinct Colonic Stem Cell Populations Similar to Humans That Respond to High-Calorie Diet prior to Insulin Resistance.

Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics. We used a human-relevant pig model and developed an immunofluorescence technique to detect and quantify colonic stem cells. Pigs (n = 8/group) were provided either standard diet (SD; 5% fat) or HCD (23% fat) for 13 weeks. HCD- and SD-consuming pigs had similar total calorie intake, serum iron, insulin, and glucose levels. However, HCD elevated both colonic proliferative zone (KI-67) and stem cell zone (ASCL-2 and BMI-1). Proliferative zone correlated with elevated innate colonic inflammatory markers TLR-4, NF-κB, IL6, and lipocalin-2 (r ≥ 0.62, P = 0.02). Elevated gut bacterial phyla proteobacteria and firmicutes in HCD-consuming pigs correlated with proliferative and stem cell zone. Colonic proteome data revealed the upregulation of proteins involved in cell migration and proliferation and correlated with proliferative and stem cell zone expansion. Our study suggests that pig colon, unlike mice, has two distinct stem cells (ASCL-2 and BMI-1) similar to humans, and HCD increases expansion of colonic proliferative and stem cell zone. Thus, pig model can aid in the development of preventive strategies against gut bacterial dysbiosis and inflammation-promoted diseases, such as colon cancer. Cancer Prev Res; 10(8); 442-50. ©2017 AACR.

A food-based approach that targets interleukin-6, a key regulator of chronic intestinal inflammation and colon carcinogenesis.

Studies have shown a causal link between high-calorie diet (HCD) and colon cancer. However, molecular mechanisms are not fully elucidated. To understand etiology of HCD-induced colon carcinogenesis, we screened 10 pathways linked to elevated colonic cell proliferation and chronic inflammation in an HCD-consuming human-relevant pig model. We observed elevated colonic mucosal interleukin-6 (IL-6) expression in HCD-consuming pigs compared to standard diet controls (SD, P=.04), and IL-6 strongly correlated with Ki-67 proliferative index and zone, early biomarkers of colon cancer risk (r=0.604 and 0.743 and P=.017 and .002, respectively). Liquid chromatography-tandem mass spectrometry-based proteomic analysis and Ingenuity Pathway Analysis showed that HCD consumption altered IL-6 signaling pathway proteins (PI3KR4, IL-1α, Mapk10, Akt3, PIK3CG, PIK3R5, Map2k2). Furthermore, these proteins also correlated with Ki-67 proliferative index/zone. Anti-IL-6 therapeutics are available for treating colon cancer; however, they are expensive and induce negative side effects. Thus, whole foods could be a better way to combat low-grade chronic colonic inflammation and colon cancer. Whole plant foods have been shown to decrease chronic diseases due to the potential of anti-inflammatory dietary compounds acting synergistically. We observed that supplementation of HCD with anthocyanin-containing purple-fleshed potatoes (10% w/w), even after baking, suppressed HCD-induced IL-6 expression (P=.03) and the IL-6-related proteins IL-1α and Map2k1 (P≤.1). Our results highlight the importance of IL-6 signaling in diet-linked induction/prevention of colonic inflammation/cancer and demonstrate the potential of a food-based approach to target IL-6 signaling.

Iron depletion in blood donors - Have extended erythrocyte and reticulocyte parameters diagnostic utility?

BACKGROUND: Blood donation is associated with iron depletion, but donor iron status is not usually investigated, as such tests are cumbersome and costly. It would therefore be desirable to have simple, fast and inexpensive tests that give information on a donor's risk of developing iron depletion. In a pilot study we investigated whether novel erythrocyte and reticulocyte parameters can serve this goal. METHODS: In regular blood donors extended red cell parameters were measured using the Abbott CELL-DYN Sapphire hematology analyzer and conventional biochemical tests of iron status. Donors were compared with a regionally matched group of non-donating controls. RESULTS: In the controls, the reference ranges of extended RBC parameters were well comparable to published data. Donors had significantly more microcytic RBC than controls (median 0.9 vs 0.6%), lower serum ferritin concentration (median 43 vs 91 mg/L) and higher soluble transferrin receptor/ferritin index (median 1.60 vs 1.27). Overall 18-28% of the donors were iron depleted. Moreover, 3.3% of donors had iron-restricted erythropoiesis. Microcytic RBC and reticulocyte mean cell hemoglobin content predicted iron depletion with 70% and 64% sensitivities and specificities of 72% and 78%, respectively. When combined these two parameters increased the sensitivity to 82%. CONCLUSIONS: Our results in Swedish blood donors confirm a high prevalence of iron depletion, despite iron supplementation used by about half of the donors. Microcytic RBC and MCHr appeared to be helpful in identifying iron-depleted donors, who might benefit from iron supplementation. We recommend larger prospective investigations in order to confirm and extend the findings of this pilot study.

Telephone advice nursing: parents' experiences of monitoring calls in children with gastroenteritis.

A common reason for calling a telephone advice nurse is gastroenteritis symptoms in children. A monitoring call is a follow-up call from the telephone nurse to the care seeker in order to follow up on given advice and make a new assessment. The aim of the study was to describe the parents' experiences of monitoring calls in telephone advice nursing in children with gastroenteritis. A qualitative interview method was chosen and data were analysed inductively with a qualitative latent content analysis. Ten parents, nine mothers and one father were interviewed. Four main categories and 13 subcategories were identified and described as useful, and the main categories were convenience - parents found it convenient to get access to self-care advice at home, confirmation - the interaction between the telephone nurse and the parent seemed to become deeper and closer as a result of the monitoring call, support - in a vulnerable situation receiving further information and an opportunity to let the telephone nurse monitor the sick child and guidance - to be guided through the most acute phase in the child's gastroenteritis symptoms. Monitoring calls seemed to be experienced as a security enhancing, positive opportunity and a robust complement to seeking care at a healthcare facility. The results of the study indicate how inhabitants can receive expert advice, support and guidance for care and provide a useful basis for Swedish Healthcare Direct (SHD) to develop the modalities for monitoring calls.

Sentinel node detection in renal cell carcinoma. A feasibility study for detection of tumour-draining lymph nodes.

OBJECTIVE: To evaluate the feasibility of performing sentinel node detection in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: An open series of 13 arbitrarily selected patients with T1b-T3b RCC scheduled for radical nephrectomy at a single Tertiary Academic Centre were examined with different modalities of sentinel node detection. Preoperative ultrasonography-guided injection of radioactive isotope, lymphoscintigram and single photon emission computed tomography/computed tomography, followed by intraoperative gamma-probe detection and Patent Blue detection, as well as postoperative scintigram of the main specimen were the planned interventions. These investigations were performed in conjunction with intended open radical nephrectomy. RESULTS: In 10 of the 13 patients sentinel node detection was achieved with 32 sentinel nodes displayed. Radio-guided surgery using an intraoperative gamma-probe resulted in the highest realtive detection rate with detection of sentinel nodes in nine patients. In total, nine metastatic sentinel nodes were detected in three patients. One patient, preoperatively staged as N+, was restaged after sentinel node detection and histopathology as pN0. CONCLUSIONS: Sentinel node detection in renal tumours is feasible although evaluation of different modes of detection needs further refinement and standardization. All nodes preoperatively detected by routine computed tomography as suspicious metastatic lesions were confirmed as sentinel nodes, including two nodes considered as metastatic by preoperative routine imaging but ultimately staged as non-metastatic sentinel nodes.