Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic ...level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance.
While ordered L12 or gamma prime precipitates in face centered cubic (FCC) based microstructures have been extensively used for strengthening nickel or cobalt base superalloys, and more recently in ...high entropy alloys (HEAs) or complex concentrated alloys (CCAs), the possibility of exploiting ordered B2 precipitates in FCC-based systems has been relatively less investigated. The present study shows the propensity of developing a heterogeneous microstructure, consisting of two different distributions of FCC grain sizes, and two different size scales of B2 precipitates, within an FCC-based Al0.5Co1.5CrFeNi1.5 HEA/CCA. This alloy composition has been designed using solution thermodynamics-based modeling such that it has a high phase fraction and solvus temperature of the B2 phase. The resulting heterogenous microstructure exhibited an approximately 400% increase in yield strength with respect to the single-phase FCC solid solution condition of the same alloy while maintaining very good tensile ductility ∼20%.
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•The HEA/CCA Al0.5Co1.5CrFeNi1.5 has been identified as a candidate alloy for studying FCC + B2 microstructure.•Single phase FCC, FCC + L12 and FCC + B2 microstructures have been obtained in this alloy via thermomechanical processing.•Precipitation annealing directly after rolling resulted in a heterogeneous microstructure with multiple length scales of B2.•The heterogeneous microstructure results in a 400% increase in yield stress when compared to the single phase FCC condition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol‐containing natural products such as cysteine. As such, these enzymes ...have relevance to the development of Alzheimer's and Parkinson's diseases in the brain. Recent crystal structure coordinates of cysteine and 3‐mercaptopropionate dioxygenase (CDO and MDO) showed major differences in the second‐coordination spheres of the two enzymes. To understand the difference in activity between these two analogous enzymes, we created large, active‐site cluster models. We show that CDO and MDO have different iron(III)‐superoxo‐bound structures due to differences in ligand coordination. Furthermore, our studies show that the differences in the second‐coordination sphere and particularly the position of a positively charged Arg residue results in changes in substrate positioning, mobility and enzymatic turnover. Furthermore, the substrate scope of MDO is explored with cysteinate and 2‐mercaptosuccinic acid and their reactivity is predicted.
Spheres of influence: Although cysteine and 3‐mercaptopropionate dioxygenase bind and react similar substrates, there are key differences in the first‐ and second‐coordination spheres that affect their catalytic reaction mechanism and reactivity, as highlighted by density functional theory studies on large enzyme clusters.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Current methods of chemical vapour deposition (CVD) of graphene on copper are complicated by multiple processing steps and by high temperatures required in both preparing the copper and inducing ...subsequent film growth. Here we demonstrate a plasma-enhanced CVD chemistry that enables the entire process to take place in a single step, at reduced temperatures (<420 °C), and in a matter of minutes. Growth on copper foils is found to nucleate from arrays of well-aligned domains, and the ensuing films possess sub-nanometre smoothness, excellent crystalline quality, low strain, few defects and room-temperature electrical mobility up to (6.0±1.0) × 10(4) cm(2) V(-1) s(-1), better than that of large, single-crystalline graphene derived from thermal CVD growth. These results indicate that elevated temperatures and crystalline substrates are not necessary for synthesizing high-quality graphene.
Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; ...myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases.
The fate of hematopoietic stem cells (HSCs) can be directed by microenvironmental factors including extracellular calcium ion concentration (Ca
), but the local Ca
around individual HSCs in vivo ...remains unknown. Here we develop intravital ratiometric analyses to quantify the absolute pH and Ca
in the mouse calvarial bone marrow, taking into account the pH sensitivity of the calcium probe and the wavelength-dependent optical loss through bone. Unexpectedly, the mean Ca
in the bone marrow (1.0 ± 0.54 mM) is not significantly different from the blood serum, but the HSCs are found in locations with elevated local Ca
(1.5 ± 0.57 mM). With aging, a significant increase in Ca
is found in M-type cavities that exclusively support clonal expansion of activated HSCs. This work thus establishes a tool to investigate Ca
and pH in the HSC niche with high spatial resolution and can be broadly applied to other tissue types.
Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and mortality in women. We review recent literature published on treatment of endometrial cancer and ...highlight areas of active interest.
There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains controversial and continues to be investigated. Progress has been made to establish consensus on endometrial cancer risk classification to promote consistency for future trial design. Molecular characterization of endometrial cancer and its integration into clinicopathological profiling to develop predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment strategy in high-risk endometrial cancer remains to be defined with recognition of treatment-related toxicity. Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer, no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically validated therapy with predictive biomarkers.
Our understanding of endometrial cancer has evolved through improvements in molecular biology, allowing improved definition of target-specific therapies. The precise role and sequence of conventional and targeted therapies, including immunotherapy, will require careful attention to the design of clinical trials with translational emphasis to allow the discovery, validation, and implementation of predictive biomarkers into clinical care.
Background and Objectives
The purpose of this study was to investigate the relationship between periodontitis, dental scaling (DS) and pyogenic liver abscesses (PLAs).
Material and Methods
A ...nationwide population‐based case‐control study was applied using data from the National Health Insurance Research Database in Taiwan. We identified and enrolled 691 PLA patients, who were individually matched by age and sex to 2764 controls.
Results
Conditional logistic regression was applied to estimate adjusted odds ratios (aORs) in patients with exposure to periodontitis and DS before PLA. After adjusting for other confounding factors, periodontitis remained a risk factor for PLA among patients aged 20‐40 years, with an aOR of 2.31 (95% confidence interval CI = 1.37‐3.90, P = .0018). In addition, the average aOR for PLA was significantly lower among patients with one DS (aOR = 0.76, 95% CI = 0.59‐0.96) and more than one DS (aOR = 0.61, 95% CI = 0.39‐0.95) within 1 year before the index date.
Conclusion
According to these results, we concluded that adult patients with periodontitis aged <50 years old are more at risk for PLA than controls, particularly when they have no DS. Moreover, from 20 years of age, non‐periodontal patients subjected to at least 2 DS per year are less at risk for PLA than controls.
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Osteoarthritis (OA) is a common degenerative joint disease, and total knee replacement (TKR) is a successful surgical intervention for knee OA treatment. However, the risks of mortality and major ...cardiovascular events (MACEs) in patients receiving TKR remain unclear. This study investigated the risks of mortality and MACEs in knee OA patients who received TKR.
For this population-based cohort study, the Longitudinal Health Insurance Database 2000 was used. Two million individuals with knee OA defined by ICD-9-CM codes who received physical therapy between 1999 and 2017 were selected. For propensity score matching (PSM), we considered the year of knee OA diagnosis, demographics, comorbidities, co-medications, and knee OA–related hyaluronic acid or physical therapy at baseline. After PSM, regression analyses were performed to assess the association of mortality or MACEs with TKR and non-TKR individuals.
We identified patients (n = 189,708) with a new diagnosis of knee OA between 2000 and 2017. In total, 10,314 propensity-score-paired TKR and non-TKR individuals were selected. The PSM cohort algorithm revealed that the risk of mortality or MACEs was lower in the TKR group (adjusted hazard ratio: 0.791; 95% confidence interval: 0.755–0.830) than in the non-TKR group.
Patients with knee OA who received TKR had decreased risks of mortality and MACEs than those who did not receive TKR. Moreover, the TKR group received a reduced dosage of nonsteroidal anti-inflammatory drugs at the 1-year follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Despite its recognized importance, there is currently no reliable tool for surgical quality assurance (SQA) of gastrectomy in surgical oncology. The aim of this study was to develop an SQA ...tool for gastrectomy and to apply this tool within the ADDICT Trial in order to assess the extent and completeness of lymphadenectomy.
Methods
The operative steps for D1+ and D2 gastrectomy have been previously described in the literature and ADDICT trial manual. Two researchers also performed fieldwork in the UK and Japan to document key operative steps through photographs and semi-structured interviews with expert surgeons. This provided the steps that were used as the framework for the SQA tool. Sixty-two photographic cases from the ADDICT Trial were rated by three independent surgeons. Generalizability (G) theory determined inter-rater reliability. D-studies examined the effect of varying the number of assessors and photographic series they rated. Chi-square assessed intra-rater reliability, comparing how the individual assessor’s responses corresponded to their global rating for extent of lymphadenectomy.
Results
The tool comprised 20 items, including 19 anatomical landmarks and a global rating score. Overall reliability had G-coefficient of 0.557. Internal consistency was measured with a Cronbach’s alpha score of 0.869 and Chi-square confirmed intra-rater reliability for each assessor as < 0.05.
Conclusions
A photographic surgical quality assurance tool is presented for gastrectomy. Using this tool, the assessor can reliably determine not only the quality but also the extent of the lymphadenectomy performed based on remaining anatomy rather than the excised specimen.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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