Population screening for colorectal cancer (CRC) is expected to increase the number of pT1 CRCs. Local excision is an attractive treatment option, but is only oncologically safe in the absence of ...lymph node metastasis (LNM). A systematic review of the predictive value of pathological risk factors for LNM in pT1 CRC was conducted to provide data for an evidence-based decision regarding follow-up or radical surgery after local excision.
PubMed was searched for reports on predictors of LNM in pT1 CRC. Published papers written in English and containing at least 50 patients were included. Meta-analyses were performed using Review Manager 5.1.
A total of 17 studies were included involving a total of 3621 patients with available nodal status. The strongest independent predictors of LNM were lymphatic invasion (relative risk RR 5.2, 95 % confidence interval CI 4.0 - 6.8), submucosal invasion ≥ 1 mm (RR 5.2, 95 %CI 1.8 - 15.4), budding (RR 5.1, 95 %CI 3.6 - 7.3), and poor histological differentiation (RR 4.8, 95 %CI 3.3 - 6.9). Limitations of the study were: results could not be stratified according to location in the colon or rectum; very early tumors removed by polypectomy without surgical resection were not included in the meta-analysis; and included studies were primarily from Asian countries and results therefore need to be verified in Western populations.
The absence of lymphatic invasion, budding, submucosal invasion ≥ 1 mm, and poor histological differentiation were each associated with low risk of LNM. Risk stratification models integrating these factors need to be investigated further.
In many salmonid species, age and size at maturation is plastic and influenced by the interaction between genetic and environmental factors. Hatchery reared salmon often mature at an earlier age and ...smaller size than wild fish. Modern salmon conservation efforts have focused on managing the level of gene flow between hatchery and natural origin fish to minimize potential genotypic and phenotypic change. In salmonids, maturation probability is dependent on exceeding a genetically set threshold in growth rate and energetic status (and by association, body size) referred to as the probabalisitic maturation reaction norm (PMRN). Over fourteen years, we monitored the frequency of age-2 precocious male maturation (common term: age-2 minijack rate) and the PMRN of natural founder (FNDR), integrated natural-hatchery (INT), and segregated hatchery (SEG) broodlines of spring Chinook salmon, Oncorhynchus tshawytscha. The average age-2 minijack rate (± SEM) of the FNDR, INT and SEG broodlines was 48.2 ± 5.2%, 41.9 ± 3.6% and 30.9 ± 4.7%, respectively. Additionally, the PMRN WP50 (predicted weight at 50% maturation) of the SEG broodline was significantly greater (20.5 g) than that of the FNDR/INT broodlines (18.2 g). We also conducted a common garden experiment exploring the effects of less than one INT (0-1), one SEG (1) or two SEG (2) generations of hatchery culture on the age-2 minijack rate and PMRN WP50. Growth was not significantly different among broodlines, but age-2 minijack rates were significantly lower following two consecutive generations of hatchery culture: INT (0-1): 68.3 ± 1.7%, SEG (1): 70.3 ± 1.8% and SEG (2): 58.6 ± 0.4% and the PMRN WP50 was significantly higher by 6.1 g after two generations of SEG culture. These results indicate that managed gene flow reduces phenotypic divergence, but may serve to maintain potentially undesirably high age-2 minijack rates in salmon conservation hatchery programs.
Purpose
The genetic characteristics and mismatch repair (MMR) status of the primary tumor and corresponding metastases in colorectal cancer (CRC) are generally considered to be highly concordant. ...This implies that either the primary or metastatic tumor can be used for testing gene mutation and MMR status. However, whether this is also true for CRC and their ovarian metastases is currently unknown. Ovarian metastases generally show a poorer response to systemic therapy compared to other metastatic sites. Differences in biomarker status between primary CRC and ovarian metastases could possibly explain this difference in therapy response.
Methods
The study cohort was selected from CRC patients treated in two Dutch hospitals. Eligible patients with CRC and ovarian metastasis who were surgically treated between 2011 and 2018 were included. CRC and corresponding ovarian metastatic tissues were paired. Gene mutation status was established using next-generation sequencing, while the MMR status was established using either immunohistochemistry or microsatellite instability analysis.
Results
Matched samples of CRC and ovarian metastasis from 26 patients were available for analysis. A biomarker concordance of 100% was detected.
Conclusion
Complete biomarker concordance was found between MMR proficient CRC and their matching ovarian metastasis. Biomarker testing of MMR proficient CRC tissue appears to be sufficient, and additional testing of metastatic ovarian tissue is not necessary. Differences in therapy response between ovarian metastases and other metastases from CRC are thus unlikely to be caused by differences in the genetic status.
Within the European Epidemiological Study to Quantify Risks for Paediatric Computerized Tomography (EPI-CT study), a cohort was assembled comprising nearly one million children, adolescents and young ...adults who received over 1.4 million computed tomography (CT) examinations before 22 years of age in nine European countries from the late 1970s to 2014. Here we describe the methods used for, and the results of, organ dose estimations from CT scanning for the EPI-CT cohort members. Data on CT machine settings were obtained from national surveys, questionnaire data, and the Digital Imaging and Communications in Medicine (DICOM) headers of 437,249 individual CT scans. Exposure characteristics were reconstructed for patients within specific age groups who received scans of the same body region, based on categories of machines with common technology used over the time period in each of the 276 participating hospitals. A carefully designed method for assessing uncertainty combined with the National Cancer Institute Dosimetry System for CT (NCICT, a CT organ dose calculator), was employed to estimate absorbed dose to individual organs for each CT scan received. The two-dimensional Monte Carlo sampling method, which maintains a separation of shared and unshared error, allowed us to characterize uncertainty both on individual doses as well as for the entire cohort dose distribution. Provided here are summaries of estimated doses from CT imaging per scan and per examination, as well as the overall distribution of estimated doses in the cohort. Doses are provided for five selected tissues (active bone marrow, brain, eye lens, thyroid and female breasts), by body region (i.e., head, chest, abdomen/pelvis), patient age, and time period (1977-1990, 1991-2000, 2001-2014). Relatively high doses were received by the brain from head CTs in the early 1990s, with individual mean doses (mean of 200 simulated values) of up to 66 mGy per scan. Optimization strategies implemented since the late 1990s have resulted in an overall decrease in doses over time, especially at young ages. In chest CTs, active bone marrow doses dropped from over 15 mGy prior to 1991 to approximately 5 mGy per scan after 2001. Our findings illustrate patterns of age-specific doses and their temporal changes, and provide suitable dose estimates for radiation-induced risk estimation in epidemiological studies.
Prostate multiparametric MRI (mpMRI) with subsequent targeted biopsy of suspicious lesions has a critical role in the diagnostic workup of prostate cancer. The objective was to evaluate the ...diagnostic accuracy of systematic biopsies, targeted biopsies, and the combination of both in prostate cancer detection.
From January 1, 2013 to June 1, 2022, biopsy-naïve and prior biopsy-negative patients who underwent both systematic and targeted biopsies were included. MRIs were evaluated according to PI-RADS with biopsy threshold set at PI-RADS ≥3. Systematic biopsies consisted of 8-12 cores, based on prostate volume. Overall prostate cancer and clinically significant cancer (Gleason Score ≥3 + 4) detection rates were stratified based on PI-RADS and location within the prostate, and compared between biopsy types using McNemar test.
Among 867 patients, 615 had prostate cancer, with 434 clinically significant cases. Overall detection rates were: PI-RADS 3 48%, PI-RADS 4 72%, and PI-RADS 5 90%. Detection rates for clinically significant cancer were 21%, 53%, and 72%, respectively. The combination of biopsy methods was most accurate in detecting clinically significant prostate cancer (P < .001). Targeted biopsies alone detected more clinically significant prostate cancer than systematic biopsies alone (43.1% vs 40.3%, P = .046). For posterior PI-RADS 5 lesions, no statistically significant difference was found between all biopsy methods.
In the detection of clinically significant prostate cancer, the combination of systematic and targeted biopsies proves most effective. Targeted biopsies rarely missed significant cancer for posterior PI-RADS 5 lesions, suggesting systematic biopsies could be reserved for instances where targeted biopsy results are negative.
This study emphasizes on the efficacy of mpMRI and targeted biopsies in suspected prostate cancer in real-world clinical context. For PI-RADS 5 lesions, systematic biopsies provide limited clinical benefit and may only be necessary when targeted biopsy results are negative.
Bone marrow mesenchymal stem cells (MSCs) are adult pluripotent cells that are considered to be an important resource for
human cell-based therapies. Understanding the clinical potential of MSCs may ...require their use in preclinical large-animal
models, such as pigs. The objectives of the present study were 1) to establish porcine MSC (pMSC) cultures; 2) to optimize
in vitro pMSC culture conditions, 3) to investigate whether pMSCs are amenable to genetic manipulation, and 4) to determine
pMSC reprogramming potential using somatic cell nuclear transfer (SCNT). The pMSCs isolated from bone marrow grew, attached
to plastic with a fibroblast-like morphology, and expressed the mesenchymal surface marker THY1 but not the hematopoietic
marker ITGAM. Furthermore, pMSCs underwent lipogenic, chondrogenic, and osteogenic differentiation when exposed to specific
inducing conditions. The pMSCs grew well in a variety of media, and proliferative capacity was enhanced by culture under low
oxygen atmosphere. Transient transduction of pMSCs and isogenic skin fibroblasts (SFs) with a human adenovirus carrying the
gene for green fluorescent protein (GFP; Ad5-F35eGFP) resulted in more pMSCs expressing GFP compared with SFs. Cell lines
with stable genetic modifications and extended expression of transgene were obtained when pMSCs were transfected with a plasmid
containing the GFP gene. Infection of pMSC and SF cell lines by an adeno-associated virus resulted in approximately 12% transgenic cells, which
formed transgenic clonal lines after propagation as single cells. The pMSCs can be expanded in vitro and used as nuclear donors
to produce SCNT embryos. Thus, pMSCs are an attractive cell type for large-animal autologous and allogenic cell therapy models
and for SCNT transgenesis.
Abstract
Marrow-derived porcine mesenchymal stem cells can be expanded in vitro, genetically modified, and used as nuclear donors to
produce somatic cell nuclear transfer embryos and, in the future, to serve as a large animal model for gene and cell therapies.
The evolution of eusociality is one of the major transitions in evolution, but the underlying genomic changes are unknown. We compared the genomes of 10 bee species that vary in social complexity, ...representing multiple independent transitions in social evolution, and report three major findings. First, many important genes show evidence of neutral evolution as a consequence of relaxed selection with increasing social complexity. Second, there is no single road map to eusociality; independent evolutionary transitions in sociality have independent genetic underpinnings. Third, though clearly independent in detail, these transitions do have similar general features, including an increase in constrained protein evolution accompanied by increases in the potential for gene regulation and decreases in diversity and abundance of transposable elements. Eusociality may arise through different mechanisms each time, but would likely always involve an increase in the complexity of gene networks.
To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity ...in normal Fallopian tube epithelium (FTE).
We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways.
There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression.
Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.
•Aberrant PI3K, HH and ER pathway activity might be putative early drivers of neoplastic transformation of FTE into STIC.•STIC and concurrent HGSC showed loss of FOXO3a protein expression in comparison to normal FTE.•Loss of AR and Wnt pathway activity are more likely to be contributors of HGSC progression.
The majority of islands surrounding the Antarctic continent are poorly characterized in terms of microbial macroecology due to their remote locations, geographical isolation and access difficulties. ...The 2016/2017 Antarctic Circumnavigation Expedition (ACE) provided unprecedented access to a number of these islands. In the present study we use metagenomic methods to investigate the microbial ecology of soil samples recovered from 11 circum‐Antarctic islands as part of ACE, and to investigate the functional potential of their soil microbial communities. Comparisons of the prokaryote and lower eukaryote phylogenetic compositions of the soil communities indicated that the various islands harbored spatially distinct microbiomes with limited overlap. In particular, we identified a high prevalence of lichen‐associated fungal taxa in the soils, suggesting that terrestrial lichens may be one of the key drivers of soil microbial ecology on these islands. Differential abundance and redundancy analyses suggested that these soil microbial communities are also strongly shaped by multiple abiotic factors, including soil pH and average annual temperatures. Most importantly, we demonstrate that the islands sampled in this study can be clustered into three distinct large‐scale biogeographical regions in a conservation context, the sub‐, Maritime and Continental Antarctic, which are distinct in both environmental conditions and microbial ecology, but are consistent with the widely‐used regionalization applied to multicellular Antarctic terrestrial organisms. Functional profiling of the island soil metagenomes from these three broad biogeographical regions also suggested a degree of functional differentiation, reflecting their distinct microbial ecologies. Taken together, these results represent the most extensive characterization of the microbial ecology of Antarctic island soils to date.
The aim of this study is to analyze the histopathological features of endometrial samples obtained by aspiration when performed before or after the saline contrast sonohysterography in women with ...postmenopausal bleeding and a thickened endometrium. Hypothetically, the saline infusion could disrupt the tissue and therefore affect the quality of the sample. Furthermore, we want to determine which histological features have impact on the quality of the endometrial sample.
We performed a randomized controlled trial (ESPRESSO trial) in which we analyzed the aspiration samples in two groups. Women were allocated either to saline contrast sonohysterography and subsequent endometrial sampling (SCSH-Sampling group) or to the opposite order (Sampling-SCSH group). Dedicated gyneco-pathologists retrospectively assessed the specimens and recorded the type (blood, mucus, epithelium, intact glands, stroma and tissue context) and quantity (on a scale of 0-3) of material that was found in the specimens.
This analysis consisted of 197 samples, with 101 women in the SCSH-Sampling group and 96 women in the Sampling-SCSH group. No significant differences were found in the histological features between the two groups. All significant histological features differed significantly in the sufficient samples compared to the insufficient samples: higher amounts of blood, more endometrial epithelium, presence of intact endometrial glands, better stroma and tissue context. Oppositely, a significantly higher amount of mucus was found in the insufficient samples.
This study shows that the histological features of the endometrial sample were not affected by the saline contrast sonohysterography, when performed prior to the tissue sampling. Trial registration ESPRESSO TRIAL, NTR5690, registered 16 February 2016, https://trialsearch.who.int/Trial2.aspx?TrialID=NTR5690 .
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