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The size and complexity of the human brain require optimally sized and myelinated fibers. White matter fibers facilitate fast communication between distant areas, but also connect adjacent cortical regions via short association fibers. The difference in length and packing density of long and short association fibers pose different requirements on their optimal size and degree of myelination. The fundamental questions of (i) how thick the short association fibers are and (ii) how strongly they are myelinated as compared to long fibers, however, remain unanswered. We present a comprehensive two-dimensional transmission electron microscopic analysis of ~400,000 fibers of human white matter regions with long (corpus callosum) and short fibers (superficial white matter). Using a deep learning approach, we demonstrate a substantially higher fiber diameter and higher myelination thickness (both approximately 25% higher) in corpus callosum than in superficial white matter. Surprisingly, we do not find a difference in the ratio between axon diameter and myelin thickness (g-ratio), which is close to the theoretically optimal value of ~0.6 in both areas (0.54). This work reveals a fundamental principle of brain organization that provides a key foundation for understanding the human brain.

The complexity of tumor histomorphology reflects underlying tumor biology impacting on natural course and response to treatment. This study presents a method of computer-aided analysis of tissue sections, relying on multifractal (MF) analyses, of cytokeratin-stained tumor sections which quantitatively evaluates of the morphological complexity of the tumor-stroma interface. This approach was applied to colon cancer collection, from an adjuvant treatment randomized study. Metrics obtained with the method acted as independent markers for natural course of the disease, and for benefit of adjuvant treatment. Comparative analyses demonstrated that MF metrics out-performed standard histomorphological features such as tumor grade, budding and configuration of invasive front. Notably, the MF analyses-derived “ α max ” –metric constitutes the first response-predictive biomarker in stage II-III colon cancer showing significant interactions with treatment in analyses using a randomized trial-derived study population. Based on these results the method appears as an attractive and easy-to-implement tool for biomarker identification.

This qualitative study delves into Incident Command System (ICS) training dynamics and its efficacy in enhancing collaborative efforts between non-governmental organizations (NGOs) and government agencies during emergency response operations. Anchored in a post-positivist paradigm, the research uncovers the complexities and variabilities of human and organizational behavior in crises through an in-depth thematic analysis of interviews with seasoned emergency response professionals. The analysis illuminates the pivotal role of communication, training, and collaborative strategies in enabling the effective integration of NGOs into emergency responses. It sheds light on the challenges of emergency management collaboration, particularly the issues of miscommunication, the need for a shared operational language, and the transformative potential of ICS training to address these issues. Research findings underscore the necessity for ICS training programs that are customized and adaptable to the diverse needs and operational contexts of NGOs. Structured collaboration and communication strategies are highlight for emergency professionals who navigate the complexities of varied operational languages and protocols. The study advocates a holistic approach to integrating NGOs into ICS-driven emergency responses, promoting cross-cultural communication, leadership across organizational boundaries, and responsive management strategies. It emphasizes the importance of specialized training and sophisticated communication strategies within a comprehensive collaborative framework to enhance NGO contributions to emergency responses. Recommendations include establishing an iterative learning and development cycle to refine collaboration mechanisms and continually, fostering ongoing dialogue and engagement between NGOs and government agencies. The study also identifies the need for adaptable emergency response frameworks, signaling the continuous need for research, improvement, and adaptation. By paving the way for practical applications, the research suggests longitudinal analyses to assess the long-term impact of ICS training, cross-jurisdictional comparisons to understand implementation benefits widely, and the development of training modules tailored specifically to the needs of NGOs. Additionally, the study points to the exploration of technology and digital communication tools as means to modernize emergency response infrastructures, contributing to a more resilient and collaborative national emergency response system.

Tumor budding and a proficient mismatch repair (pMMR) status are considered adverse prognostic factors in colorectal cancer (CRC). The aim of this pilot study was to assess tumor budding in primary CRC with pMMR versus that with deficient mismatch repair (dMMR). Tumor budding was retrospectively examined in the tumor from 134 patients with stage II and stage III CRC with known MMR status. The 29 available dMMR cases who developed recurrence or distant metastases (met+) were matched with a dMMR group with no recurrence or metastases (met-), and the pMMR/met+ group with pMMR/met- cases. Using tumor budding cut-offs of 5 and 10, a significantly higher percentage of high-grade tumor budding (≥5 and ≥10) was only found in the dMMR/met+ compared to pMMR/met+ subgroup (p=0.01 and p=0.02, respectively). A significantly higher grade of tumor budding was observed in the dMMR/met+ group, suggesting that tumor budding can provide prognostic information for patients with a dMMR status.

Background Identification of biomarkers associated with benefit of adjuvant chemotherapy in stage II/III colon cancer is an important task. Methods Vessel density (VD) and tumour stroma were analysed in a randomised-trial-derived discovery cohort ( n  = 312) and in a stage II/III group of a population-based validation cohort ( n  = 85). VD was scored separately in the tumour centre, invasive margin and peritumoral stroma compartments and quantitated as VD/total analysed tissue area or VD/stroma area. Results High stroma-normalised VD in the invasive margin was associated with significantly longer time to recurrence and overall survival (OS) ( p  = 0.002 and p  = 0.006, respectively) in adjuvant-treated patients of the discovery cohort, but not in surgery-only patients. Stroma-normalised VD in the invasive margin and treatment effect were significantly associated according to a formal interaction test ( p  = 0.009). Similarly, in the validation cohort, high stroma-normalised VD was associated with OS in adjuvant-treated patients, although statistical significance was not reached ( p  = 0.051). Conclusion Through the use of novel digitally scored vessel-density-related metrics, this exploratory study identifies stroma-normalised VD in the invasive margin as a candidate marker for benefit of adjuvant 5-FU-based chemotherapy in stage II/III colon cancer. The findings, indicating particular importance of vessels in the invasive margin, also suggest biological mechanisms for further exploration.

Claudin-2 is a trans-membrane protein—component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU±irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.

CYP2W1 is a novel enzyme shown to be selectively expressed in rat fetal colon and in human colon cancer and has previously been suggested as a potential drug target for cancer therapy. Here, the expression and gene methylation of CYP2W1 were analyzed in human colon carcinoma cell lines, colon tumors and in corresponding normal colon tissue. CYP2W1 mRNA and protein expression in HepG2 and Caco-2TC7 cells and normal colon and colon tumor tissue samples were analyzed using real-time PCR and Western blotting. gene methylation status in the same samples was analyzed using the sodium bisulfite sequencing method. CYP2W1 mRNA was detected in all (n  =  39) tumor samples analyzed. Moreover, in 60% (12/20) of the colon tumors, CYP2W1 mRNA levels were substantially higher than in corresponding normal tissues. CYP2W1 protein was detected in most of the colon tumor samples analyzed (n  =  16), which appeared to be of two apparent phenotypes: those with five- to ten-fold induced CYP2W1 (approximately 50% of the tumors), and those with low expression, harboring similar or only slightly higher amounts of CYP2W1 as compared with surrounding control tissue. Methylation analysis of the CpG island in the exon  1-–intron 1 junction of the gene from both cell lines, tumors and normal tissues revealed that demethylated CpG dinucleotides appeared as a requirement for high gene expression. The expression of CYP2W1 is colon tumor-specific and is associated with methylation status of the gene, suggesting a potential causal link between the gene hypomethylation and its enhanced expression.

This study aims to investigate the possible association between the risk of colorectal cancer (CRC) and allelic variants of CYP2W1 and their functional properties. The distribution of three different CYP2W1 alleles (CYP2W1*1, CYP2W1*2 and CYP2W1*6) in 1785 CRC patients and 1761 healthy blood donors was determined using the TaqMan(®) (Applied Biosystems, CA, USA) allelic discrimination assay or allele-specific amplification. Corresponding gene products (CYP2W1.1, CYP2W1.2 and CYP2W1.6) were expressed in human colon cancer SW480 cells and their activities towards two different substrates, the duocarmycin analogs ICT2706 and ICT2726, were monitored. No significant differences in the distribution of CYP2W1*1, CYP2W1*2 and CYP2W1*6 alleles were found between CRC patients and controls. The CYP2W1.1, CYP2W1.2 and CYP2W1.6 variant enzymes were expressed at the similar levels in the transfected SW480 cells and had comparable kinetics in terms of the metabolism of the duocarmycin ICT2726, as well as in the bioactivation of ICT2706 into a cytotoxic product. These epidemiological data obtained from a large population of CRC patients and controls cannot confirm the previously suggested decreased risk for CRC among carriers of CYP2W1*2. On the molecular level, this conclusion is further supported by the similar catalytic characteristics of the CYP2W1.1, CYP2W1.2 and CYP2W1.6 variants of CYP2W1.

A novel set of integrated procedures for quantification of fibroblast‐rich stroma and vascular characteristics has recently been presented allowing discovery of novel perivascular and stromal biomarkers in colorectal, renal cell, and ovarian cancer. In the present study, data obtained through these procedures from clinically well‐annotated collections of these three tumour types have been used to address two novel questions. First, data have been used to investigate if the three tumour types demonstrate significant differences regarding features such as vessel diameter, vessel density, and perivascular marker expression. Second, analyses of the cohorts have been used to explore the prognostic significance of a novel vascular metric, ‘vessel distance inter‐quartile range (IQR)’ that describes intra‐case heterogeneity regarding vessel distribution. The comparisons between the three tumour types demonstrated a set of significant differences. Vessel density of renal cell cancer was statistically significantly higher than in colorectal and ovarian cancer. Vessel diameter was statistically significantly higher in ovarian cancer. Concerning perivascular status, colorectal cancer displayed significantly higher levels of perivascular PDGFR‐β expression than the other two tumour types. Intra‐case heterogeneity of perivascular PDGFR‐β expression was also higher in colorectal cancer. Notably, these fibroblast‐dominated stroma phenotypes matched previously described experimental tumour stroma characteristics, which have been linked to differential sensitivity to anti‐VEGF drugs. High ‘vessel distance IQR’ was significantly associated with poor survival in both renal cell cancer and colorectal cancer. In renal cell cancer, this characteristic also acted as an independent prognostic marker according to multivariate analyses including standard clinico‐pathological characteristics. Explorative subset analyses indicated particularly strong prognostic significance of ‘vessel distance IQR’ in T stage 4 of this cancer type. Together, these analyses identified tumour‐type‐specific vascular‐stroma phenotypes of possible functional significance, and suggest ‘vessel distance IQR’ as a novel prognostic biomarker.

Yes there are security measures and of course short of wandering near naked through the security devices, it is a given of 21st travel that no matter how much change and keys you remove from your pockets those security lights will always go off, but it''s a minor inconvenience compared to the cattle-like conditions that air travellers are faced with nowadays and yippee I can take a bottle of water on without being arrested.