To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.
Consecutive BRAF-tested Australian patients ...with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.
Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.
V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.
The tension biology of wound healing Harn, Hans I‐Chen; Ogawa, Rei; Hsu, Chao‐Kai ...
Experimental dermatology,
April 2019, Volume:
28, Issue:
4
Journal Article
Peer reviewed
Open access
Following skin wounding, the healing outcome can be: regeneration, repair with normal scar tissue, repair with hypertrophic scar tissue or the formation of keloids. The role of chemical factors in ...wound healing has been extensively explored, and while there is evidence suggesting the role of mechanical forces, its influence is much less well defined. Here, we provide a brief review on the recent progress of the role of mechanical force in skin wound healing by comparing laboratory mice, African spiny mice, fetal wound healing and adult scar keloid formation. A comparison across different species may provide insight into key regulators. Interestingly, some findings suggest tension can induce an immune response, and this provides a new link between mechanical and chemical forces. Clinically, manipulating skin tension has been demonstrated to be effective for scar prevention and treatment, but not for tissue regeneration. Utilising this knowledge, specialists may modulate regulatory factors and develop therapeutic strategies to reduce scar formation and promote regeneration.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The microbiome plays a fundamental role in how the immune system develops and how inflammatory responses are shaped and regulated. The "gut-lung axis" is a relatively new term that highlights a ...crucial biological crosstalk between the intestinal microbiome and lung. A growing body of literature suggests that dysbiosis, perturbation of the gut microbiome, is a driving force behind the development, and severity of allergic asthma. Animal models have given researchers new insights into how gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), influence the development of asthma. While the full understanding of how SCFAs influence allergic airway disease remains obscure, a recurring theme of epigenetic regulation of gene expression in several immune cell compartments is emerging. This review will address our current understanding of how SCFAs, and specifically butyrate, orchestrates cell behavior, and epigenetic changes and will provide a detailed overview of the effects of these modifications on immune cells in the context of allergic airway disease.
Recent work has shown that high-quality inline holographic microscopy images can be captured through fiber imaging bundles. Speckle patterns arising from modal interference within the bundle cores ...can be minimized by use of a partially-coherent optical source such as an LED delivered via a multimode fiber. This allows numerical refocusing of holograms from samples at working distances of up to approximately 1 mm from the fiber bundle before the finite coherence begins to degrade the lateral resolution. However, at short working distances the lateral resolution is limited not by coherence, but by sampling effects due to core-to-core spacing in the bundle. In this article we demonstrate that multiple shifted holograms can be combined to improve the resolution by a factor of two. The shifted holograms can be rapidly acquired by sequentially firing LEDs, which are each coupled to their own, mutually offset, illumination fiber. Following a one-time calibration, resolution-enhanced images are created in real-time at an equivalent net frame rate of up to 7.5 Hz. The resolution improvement is demonstrated quantitatively using a resolution target and qualitatively using mounted biological slides. At longer working distances, beyond 0.6 mm, the improvement is reduced as resolution becomes limited by the source spatial and temporal coherence.
Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic ...muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We identify candidate genes that may drive tissue specialization, including
,
, and
. By demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for studying the mechanisms of tissue specialization.
Purpose
Histopathological biomarkers guide breast cancer management. Testing histopathological biomarkers on both core needle biopsy (CNB) and surgical excision (SE) in patients who are treated with ...upfront surgery is unnecessary and costly if there is high concordance between the two. This study investigated the concordance between CNB and SE for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (HER2), tumor grade and Ki-67.
Methods
Histopathological biomarker information were retrospectively collected from preoperative CNB and SE on patients diagnosed with breast cancer through the BreastScreen Sydney West program over a four-year period between January 2017 and December 2020. Data were then analyzed to calculate percentage of agreement and concordance using kappa values for ER, PR, HER2, tumor grade and Ki-67.
Results
A total of 504 cases of invasive breast cancers were analyzed. There was substantial level of concordance for ER 96.7% (
κ
= 0.687) and PR 93.2% (
κ
= 0.69). Concordance for HER2 negative (IHC 0, IHC 1 +) or positive (IHC 3 +) tumor on CNB was 100% (
κ
= 1.00). Grade and Ki-67 showed moderate level of concordance, 72.6% (
κ
= 0.545) and 70.5% (
κ
= 0.453), respectively.
Conclusion
ER, PR and HER2 show high level of concordance. CNB is reliable in determining histopathological biomarkers for ER, PR positive and HER2 positive or negative tumors indicating that retesting these on SE may not be necessary.
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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
Introduction
Gastric electrical stimulation (GES) has been recommended for drug refractory patients with gastroparesis, but no clear baseline predictors of symptom response exist. We hypothesized ...that long‐term predictors to GES for foregut and hindgut symptoms exist, particularly when using augmented energies.
Patients
We evaluated 307 patients at baseline, 1 week post temporary GES, and one year after permanent GES. Baseline measures included upper and lower symptoms by patient‐reported outcomes (PRO), solid and liquid gastric emptying (GET), cutaneous, mucosal, and serosal electrophysiology (EGG, m/s EG), BMI, and response to temporary stimulation.
Methods
Foregut and hindgut PRO symptoms were analyzed for 12‐month patient outcomes. All patients utilized a standardized energy algorithm with the majority of patients receiving medium energy at 12 months. Patients were categorized based on change in average GI symptom scores at the time of permanent GES compared to baseline using a 10% decrease over time as the cutoff between improvers versus non‐improvers.
Results
By permanent GES implant, average foregut and hindgut GI symptom scores reduced 42% in improved patients (n = 199) and increased 27% in non‐improved patients (n = 108). Low BMI, baseline infrequent urination score, mucosal EG ratio, and proximal mucosal EG low‐resolution amplitude remained significant factors for improvement status.
Conclusions
GES, for patients responding positively, improved both upper/foregut and lower/hindgut symptoms with most patients utilizing higher than nominal energies. Low baseline BMI and the presence of infrequent urination along with baseline gastric electrophysiology may help identify those patients with the best response to GES/bio‐electric neuromodulation.
307 patients with gastroparetic symptoms underwent fore and hind gut patient reported outcomes (PRO) evaluation at baseline and after 1‐week temporary and 12‐months of permanent GES. Predictive factors at baseline for improvement with GES at one year included in‐frequent urination, low BMI and high proximal mucosal electrogram amplitude/ low frequency to amplitude mEG ratio. Patients were given nominal energy with temporary GES. Permanent GES patients had factory low energy setting at baseline and most patients with improvement in symptoms had augmented energy at last follow up.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
In a recent article in the American Journal of Epidemiology by Mendez et al. (Am J Epidemiol. 2011;173(4):448–458), the use of alternative approaches to the exclusion of implausible energy ...intakes led to significantly different cross-sectional associations between diet and body mass index (BMI), whereas the use of a simpler recommended criteria (<500 and >3,500 kcal/day) yielded no meaningful change. However, these findings might have been due to exclusions made based on weight, a primary determinant of BMI. Using data from 52,110 women in the Nurses' Health Study (1990), we reproduced the cross-sectional findings of Mendez et al. and compared the results from the recommended method with those from 2 weight-dependent alternative methods (the Goldberg method and predicted total energy expenditure method). The same 3 exclusion criteria were then used to examine dietary variables prospectively in relation to change in BMI, which is not a direct function of attained weight. We found similar associations using the 3 methods. In a separate cross-sectional analysis using biomarkers of dietary factors, we found similar correlations for intakes of fatty acids (n = 439) and carotenoids and retinol (n = 1,293) using the 3 methods for exclusions. These results do not support the general conclusion that use of exclusion criteria based on the alternative methods might confer an advantage over the recommended exclusion method.
Interest in the application of machine learning (ML) to the design, conduct, and analysis of clinical trials has grown, but the evidence base for such applications has not been surveyed. This ...manuscript reviews the proceedings of a multi-stakeholder conference to discuss the current and future state of ML for clinical research. Key areas of clinical trial methodology in which ML holds particular promise and priority areas for further investigation are presented alongside a narrative review of evidence supporting the use of ML across the clinical trial spectrum.
Conference attendees included stakeholders, such as biomedical and ML researchers, representatives from the US Food and Drug Administration (FDA), artificial intelligence technology and data analytics companies, non-profit organizations, patient advocacy groups, and pharmaceutical companies. ML contributions to clinical research were highlighted in the pre-trial phase, cohort selection and participant management, and data collection and analysis. A particular focus was paid to the operational and philosophical barriers to ML in clinical research. Peer-reviewed evidence was noted to be lacking in several areas.
ML holds great promise for improving the efficiency and quality of clinical research, but substantial barriers remain, the surmounting of which will require addressing significant gaps in evidence.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The digital environment has transformed how data on library material use is collected and reported, providing librarians with more information about usage but less clarity about how to interpret it. ...This article discusses current approaches to reporting and assessing library book use, addresses the question of what qualifies as a worthwhile use of library materials, and presents an analysis of four years of COUNTER 4 BR2 ebook reports at a single research institution to explore the reliability of page view-level usage data for collection assessment. It reveals ways assessment theory and practice fail to capture the value of library materials throughout the research lifecycle, and argues for an inclusive view of collections use.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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