Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

As gastrin may play a role in the pathophysiology of gastrointestinal (GI) malignancies, the elucidation of the mechanisms governing gastrin-induced proliferation has recently gained considerable interest. Several studies have reported that a large percentage of colorectal tumours overexpress or stabilise the β-catenin oncoprotein. We thus sought to determine whether gastrin might regulate β-catenin expression in colorectal tumour cells. Amidated gastrin-17 (G-17), one of the major circulating forms of gastrin, not only enhanced β-catenin protein expression, but also one of its target genes, cyclin D1. Furthermore, activation of β-catenin-dependent transcription by gastrin was confirmed by an increase in LEF-1 reporter activity, as well as enhanced cyclin D1 promoter activity. Finally, G-17 prolonged the τ1/2 of β-catenin protein, demonstrating that gastrin appears to exert its mitogenic effects on colorectal tumour cells, at least in part, by stabilising β-catenin

Interpretability of radiomics models is improved when using feature group selection strategies for predicting molecular and clinical targets in clear-cell renal cell carcinoma: insights from the TRACERx Renal study

BACKGROUND: The aim of this work is to evaluate the performance of radiomics predictions for a range of molecular, genomic and clinical targets in patients with clear cell renal cell carcinoma (ccRCC) and demonstrate the impact of novel feature selection strategies and sub-segmentations on model interpretability. METHODS: Contrast-enhanced CT scans from the first 101 patients recruited to the TRACERx Renal Cancer study (NCT03226886) were used to derive radiomics classification models to predict 20 molecular, histopathology and clinical target variables. Manual 3D segmentation was used in conjunction with automatic sub-segmentation to generate radiomics features from the core, rim, high and low enhancing sub-regions, and the whole tumour. Comparisons were made between two classification model pipelines: a Conventional pipeline reflecting common radiomics practice, and a Proposed pipeline including two novel feature selection steps designed to improve model interpretability. For both pipelines nested cross-validation was used to estimate prediction performance and tune model hyper-parameters, and permutation testing was used to evaluate the statistical significance of the estimated performance measures. Further model robustness assessments were conducted by evaluating model variability across the cross-validation folds. RESULTS: Classification performance was significant (p  0.1. Five of these targets (necrosis on histology, presence of renal vein invasion, overall histological stage, linear evolutionary subtype and loss of 9p21.3 somatic alteration marker) had AUROC > 0.8. Models derived using the Proposed pipeline contained fewer feature groups than the Conventional pipeline, leading to more straightforward model interpretations without loss of performance. Sub-segmentations lead to improved performance and/or improved interpretability when predicting the presence of sarcomatoid differentiation and tumour stage. CONCLUSIONS: Use of the Proposed pipeline, which includes the novel feature selection methods, leads to more interpretable models without compromising prediction performance. TRIAL REGISTRATION: NCT03226886 (TRACERx Renal

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality

Nuclear β-catenin expression is closely related to ulcerative growth of colorectal carcinoma

Although most colorectal cancer develops based on the adenoma–adenocarcinoma sequence, morphologically, colorectal cancer is not a homogeneous disease entity. Generally, there are two distinct morphological types: polypoid and ulcerative colorectal tumours. Previous studies have demonstrated that K-ras codon 12 mutations are preferentially associated with polypoid growth of colorectal cancer; however, little is known about the molecular mechanism that determines ulcerative growth of colorectal cancer. β-catenin complex plays a critical role both in tumorigenesis and morphogenesis. We examined the differential expression of β-catenin and its related factors among different types of colorectal cancer in order to determine any relationship with gross tumour morphology. Immunohistochemical staining of β-catenin, E-cadherin and MMP-7 was performed on 51 tumours, including 26 polypoid tumours and 25 ulcerative tumours. Protein truncation tests and single-strand conformational polymorphism for mutation of the adenomatous polyposis coli tumour suppressor gene, as well as single-strand conformational polymorphism for the mutation of β-catenin exon 3 were also done. Nuclear expression of β-catenin was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A significant relationship of nuclear β-catenin expression with ulcerative colorectal cancer was found (P<0.001). However, this finding was independent of adenomatous polyposis coli tumour suppressor gene mutation and E-cadherin expression. Together with previous data, we propose that different combinations of genetic alterations may underlie different morphological types of colorectal cancer. These findings should be taken into consideration whenever developing a new genetic diagnosis or therapy for colorectal cancer

Structural and Functional Analysis of Phytotoxin Toxoflavin-Degrading Enzyme

Pathogenic bacteria synthesize and secrete toxic low molecular weight compounds as virulence factors. These microbial toxins play essential roles in the pathogenicity of bacteria in various hosts, and are emerging as targets for antivirulence strategies. Toxoflavin, a phytotoxin produced by Burkholderia glumae BGR1, has been known to be the key factor in rice grain rot and wilt in many field crops. Recently, toxoflavin-degrading enzyme (TxDE) was identified from Paenibacillus polymyxa JH2, thereby providing a possible antivirulence strategy for toxoflavin-mediated plant diseases. Here, we report the crystal structure of TxDE in the substrate-free form and in complex with toxoflavin, along with the results of a functional analysis. The overall structure of TxDE is similar to those of the vicinal oxygen chelate superfamily of metalloenzymes, despite the lack of apparent sequence identity. The active site is located at the end of the hydrophobic channel, 9 Å in length, and contains a Mn(II) ion interacting with one histidine residue, two glutamate residues, and three water molecules in an octahedral coordination. In the complex, toxoflavin binds in the hydrophobic active site, specifically the Mn(II)-coordination shell by replacing a ligating water molecule. A functional analysis indicated that TxDE catalyzes the degradation of toxoflavin in a manner dependent on oxygen, Mn(II), and the reducing agent dithiothreitol. These results provide the structural features of TxDE and the early events in catalysis

Value of ADC measurements for nodal staging after chemoradiation in locally advanced rectal cancer—a per lesion validation study

OBJECTIVES: To evaluate the performance of diffusion-weighted MRI (DWI) in addition to T2-weighted (T2W) MRI for nodal restaging after chemoradiation in rectal cancer. METHODS: Thirty patients underwent chemoradiation followed by MRI (1.5 T) and surgery. Imaging consisted of T2W-MRI and DWI (b0, 500, 1000). On T2W-MRI, nodes were scored as benign/malignant by two independent readers (R1, R2). Mean apparent diffusion coefficient (ADC) was measured for each node. Diagnostic performance was compared for T2W-MRI, ADC and T2W+ADC, using a per lesion histological validation. RESULTS: ADC was higher for the malignant nodes (1.43 +/- 0.38 vs 1.19 +/- 0.27 *10(-3) mm(2)/s, p < 0.001). Area under the ROC curve/sensitivity/specificity were 0.88/65%/93% (R1) and 0.95/71%/91% (R2) using T2W-MRI; 0.66/53%/82% using ADC (mean of two readers); and 0.91/56%/98% (R1) and 0.96/56%/99% (R2) using T2W+ADC. There was no significant difference between T2W-MRI and T2W+ADC. Interobserver reproducibility was good for T2W-MRI (kappa0.73) and ADC (intraclass correlation coefficient 0.77). CONCLUSIONS: After chemoradiation, ADC measurements may have potential for nodal characterisation, but DWI on its own is not reliable. Addition of DWI to T2W-MRI does not improve accuracy and T2W-MRI is already sufficiently accurate

“In the Beginning, It Was Little Whispers...Now, We’re Almost a Roar”: Conceptualizing a Model for Community and Self in LGBTQ+ Health Information Practices

Although LGBTQ+ populations experience significant health challenges, little research exists that investigates their health from an informational perspective. Our study addresses this gap by exploring the health information practices of LGBTQ+ communities in South Carolina, focusing on how sociocultural context shapes these practices. Thirty semi-structured interviews with South Carolina LGBTQ+ community leaders analyzed using open qualitative coding informed the development of a conceptual framework describing their information practices. Findings show that participants engaged in two broad types of practices – protective and defensive – as responses to risks and barriers experienced, which are in turn produced by social and structural factors. Findings advance information practices and marginalization approaches and offer ways for medical professionals to improve service to LGBTQ+ populations