Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA ...methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.
Background
Breast surgeons have a wide variety of intraoperative techniques available to help achieve low rates for positive margins of excision, with variable levels of evidence.
Methods
A ...systematic review of the medical literature from 1995 to July 2016 was conducted, with 434 abstracts identified and evaluated. The analysis included 106 papers focused on intraoperative management of breast cancer margins and contained actionable data.
Results
Ultrasound-guided lumpectomy for palpable tumors, as an alternative to palpation guidance, can lower positive margin rates, but the effect when used as an alternative to wire localization (WL) for nonpalpable tumors is less certain. Localization techniques such as radioactive seed localization and radioguided occult lesion localization were found potentially to lower positive margin rates as alternatives to WL depending on baseline positive margin rates. Intraoperative pathologic methods including gross histology, frozen section analysis, and imprint cytology all have the potential to lower the rates of positive margins. Cavity-shave margins and the Marginprobe device both lower rates of positive margins, with some potential for negative cosmetic effects. Specimen radiography and multiple miscellaneous techniques did not affect positive margin rates or provided too little evidence for formation of a conclusion.
Conclusions
A systematic review of the literature showed evidence that several intraoperative techniques and actions can lower the rates of positive margins. These results are presented together with graded recommendations.
The purpose of this article is to discuss whether the sensitivity and specificity of contrast-enhanced digital mammography (CEDM) render it a viable diagnostic alternative to breast MRI.
That CEDM ...couples low-energy images (comparable to the diagnostic quality of standard mammography) and subtracted contrast-enhanced mammograms make it a cost-effective modality and a realistic substitute for the more costly breast MRI.
The Choosing Wisely Organization and the American College of Surgeons have issued recommendations for patients >70 with breast cancer involving screening and use of radiation therapy (RT) and ...sentinel lymph node biopsies (SNLB) in early stage tumors. This study evaluated compliance and implementation of these recommendations.
A database of patients undergoing breast cancer surgery was retrospectively queried from 2002 to 2017. Patients were divided into cohorts before and after the year of each guideline publication.
The rate of presentation on mammography was not different before 2009 (65%) vs. after 2009 (66%). RT was given to 57% of patients with T1 ER + Her2-prior to 2013 vs. 27% after (p=<0.001). SLNB was performed in 91% of patients with T1, grade1/2, ER + Her2-tumors prior to 2016 vs. 56% after (p=<0.001).
Rates of mammography detected breast cancer have not decreased but adjuvant RT and SLNB are less frequently performed in low risk breast cancer in the elderly.
•There are no defined diagnostic or treatment algorithms for the elderly with breast cancer.•Screening mammogram utilization in the elderly with a life expectancy of less than 10 years has not decreased since 2009.•Radiation therapy in low risk estrogen receptor positive breast cancer can be obviated without compromising outcomes.•Utilization of sentinel lymph node biopsy in low risk elderly breast cancer has decreased over time as per recommendations.
We aimed to identify opioid prescribing practices across surgical specialties and institutions.
In an effort to minimize the contribution of prescription narcotics to the nationwide opioid epidemic, ...reductions in postoperative opioid prescribing have been proposed. It has been suggested that a maximum of 7 days, or 200 mg oral morphine equivalents (OME), should be prescribed at discharge in opioid-naïve patients.
Adults undergoing 25 common elective procedures from 2013 to 2015 were identified from American College of Surgeons National Surgical Quality Improvement Program data from 3 academic centers in Minnesota, Arizona, and Florida. Opioids prescribed at discharge were abstracted from pharmacy data and converted into OME. Wilcoxon Rank-Sum and Kruskal-Wallis tests assessed variations.
Of 7651 patients, 93.9% received opioid prescriptions at discharge. Of 7181 patients who received opioid prescriptions, a median of 375 OME (interquartile range 225-750) were prescribed. Median OME varied by sex (375 men vs 390 women, P = 0.002) and increased with age (375 age 18-39 to 425 age 80+, P < 0.001). Patients with obesity and patients with non-cancer diagnoses received more opioids (both P < 0.001). Subset analysis of the 5756 (75.2%) opioid-naïve patients showed the majority received >200 OME (80.9%). Significant variations in opioid prescribing practices were seen within each procedure and between the 3 medical centers.
The majority of patients were overprescribed opioids. Significant prescribing variation exists that was not explained by patient factors. These data will guide practices to optimize opioid prescribing after surgery.
There has been a dramatic rise in opioid abuse, and diversion of excess, unused prescriptions is a major contributor. We assess the impact of implementing a new standardized pain care bundle to ...reduce postoperative opioids in outpatient general surgical procedures.
This study was designed to demonstrate non-inferiority for the primary end point: patient-reported average pain in the first 7 postoperative days. We prospectively evaluated 224 patients who underwent laparoscopic cholecystectomy or open hernia repair (inguinal, umbilical) pre-intervention to 192 patients post-intervention. We implemented a multimodal intra- and postoperative analgesic bundle, including promoting co-analgesia, opioid-reduced prescriptions, and patient education designed to clarify patient expectations. Patients completed a brief pain inventory at their first postoperative visit. Groups were compared using chi-square test, Mann-Whitney U test, and independent samples t-test, where appropriate.
No difference was seen in average postoperative pain scores in the pre- vs post-intervention groups (2.3 vs 2.1 of 10; p = 0.12). The reported quality of pain control improved post-intervention (good/very good pain control in 69% vs 85%; p < 0.001). The median total morphine equivalents for prescriptions filled in the post-intervention group were significantly less (100; interquartile range 75 to 116 pre-intervention vs 50; interquartile range 50 to 50 post-intervention; p < 0.001). Only 78 of 172 (45%) patients filled their opioid prescription in the post-intervention group (p < 0.001), with no significant difference in prescription renewals (3.5% pre-intervention vs 2.6% post-intervention; p = 0.62).
For outpatient open hernia repair and cholecystectomy, a standardized pain care bundle decreased opioid prescribing significantly and frequently eliminated opioid use, while adequately treating postoperative pain and improving patient satisfaction.
Models and Mechanisms of Stomatal Mechanics Woolfenden, Hugh C.; Baillie, Alice L.; Gray, Julie E. ...
Trends in plant science,
September 2018, 2018-09-00, 20180901, Letnik:
23, Številka:
9
Journal Article
Recenzirano
The mechanism of stomatal function (control of gas flux through the plant surface via regulation of pore size) is fundamentally mechanical. The material properties of the pore-forming guard cells ...must play a key role in setting the dynamics and degree of stomatal opening/closure, but our understanding of the molecular players involved and resultant mechanical performance has remained limited. The application of indentation techniques and computational modelling, combined with molecular tools for imaging and manipulating guard cells and their constituent cell walls, has opened the way to a systems approach to analysing this problem. The outcomes of these investigations have led to a reassessment of accepted paradigms and are providing a new understanding of the mechanism of stomatal mechanics.
Combined measurement and manipulation of guard cell mechanics, via manipulation of the cell wall, along with computational modelling of the cellular complex, is challenging textbook descriptions of how stomata work.
Finite element modelling supports an important role for cellulose-based anisotropy in the wall in guard cell movement.
Imaging the guard cell wall reveals novel patterns of molecular components and changing these patterns alters stomatal function.
Atomic force microscopy reveals polar stiffening of stomata, which modelling and experimentation reveal facilitates stomatal opening.
Radial stiffening of the guard cells is not required for stomatal opening.
There is a concerted global effort to digitize biodiversity occurrence data from herbarium and museum collections that together offer an unparalleled archive of life on Earth over the past few ...centuries. The Global Biodiversity Information Facility provides the largest single gateway to these data. Since 2004 it has provided a single point of access to specimen data from databases of biological surveys and collections. Biologists now have rapid access to more than 120 million observations, for use in many biological analyses. We investigate the quality and coverage of data digitally available, from the perspective of a biologist seeking distribution data for spatial analysis on a global scale. We present an example of automatic verification of geographic data using distributions from the International Legume Database and Information Service to test empirically, issues of geographic coverage and accuracy. There are over 1/2 million records covering 31% of all Legume species, and 84% of these records pass geographic validation. These data are not yet a global biodiversity resource for all species, or all countries. A user will encounter many biases and gaps in these data which should be understood before data are used or analyzed. The data are notably deficient in many of the world's biodiversity hotspots. The deficiencies in data coverage can be resolved by an increased application of resources to digitize and publish data throughout these most diverse regions. But in the push to provide ever more data online, we should not forget that consistent data quality is of paramount importance if the data are to be useful in capturing a meaningful picture of life on Earth.
A substantial amount of organismal complexity is thought to be encoded by enhancers which specify the location, timing, and levels of gene expression. In mammals there are more enhancers than ...promoters which are distributed both between and within genes. Here we show that activated, intragenic enhancers frequently act as alternative tissue-specific promoters producing a class of abundant, spliced, multiexonic poly(A)+ RNAs (meRNAs) which reflect the host gene's structure. meRNAs make a substantial and unanticipated contribution to the complexity of the transcriptome, appearing as alternative isoforms of the host gene. The low protein-coding potential of meRNAs suggests that many meRNAs may be byproducts of enhancer activation or underlie as-yet-unidentified RNA-encoded functions. Distinguishing between meRNAs and mRNAs will transform our interpretation of dynamic changes in transcription both at the level of individual genes and of the genome as a whole.
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► Intragenic enhancers act as unidirectional, cell-specific, alternative promoters ► Activated intragenic enhancers produce a class of multiexonic poly(A)+ RNAs, meRNAs ► meRNAs appear as isoforms of the host gene ► meRNAs add significantly to transcriptome complexity
Background
Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma with few studies reporting on patient outcomes and prognostic variables.
Methods
A retrospective ...review of 175 patients diagnosed with MPNST from 1985 to 2010 was performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables.
Results
The median age of our study population was 44 years, and 51% were female. Median tumor size was 6 cm, and 61% of patients had high-grade tumors. Tumors were most commonly located on the extremities (45%), then trunk (34%) and head/neck (19%). The majority of patients underwent surgical resection (95%) and adjuvant treatment with chemotherapy (6%), radiation (42%) or both (22%). Margin status was R0 in 69%, R1 in 2%, R2 in 9%, and unknown in 20%. The local recurrence rate was 22%, and 5- and 10-year disease-specific survival (DSS) were 60% and 45%, respectively. On univariate analysis, no predictors for local recurrence were identified. Tumor size ≥5 cm, high tumor grade, tumor location, presence of neurofibromatosis type 1, local recurrence, and adjuvant chemotherapy were all associated with DSS. On multivariate analysis, size ≥5 cm hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.5–25.0, local recurrence (HR = 4.4, 95% CI 1.7–11.4), high tumor grade (HR = 3.8, 95% CI 1.1–13.2), and truncal location (HR = 3.7, 95% CI 1.1–12.7) were poor prognostic indicators for DSS.
Conclusions
High tumor grade and tumor size ≥5 cm predict adverse DSS for MPNST. In the context of a multidisciplinary treatment regimen, local recurrence and survival outcomes at 5 and 10 years were better than previously reported for MPNST.
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