The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF ...protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient's tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.
Abstract Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to ...this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment.
Purpose
To investigate the global burden of sepsis in hospitalized adults by updating and expanding a systematic review and meta-analysis and to compare findings with recent Institute for Health ...Metrics and Evaluation (IHME) sepsis estimates.
Methods
Thirteen electronic databases were searched for studies on population-level sepsis incidence defined according to clinical criteria (Sepsis-1, -2: severe sepsis criteria, or sepsis-3: sepsis criteria) or relevant ICD-codes. The search of the original systematic review was updated for studies published 05/2015–02/2019 and complemented by a search targeting low- or middle-income-country (LMIC) studies published 01/1979–02/2019. We performed a random-effects meta-analysis with incidence of hospital- and ICU-treated sepsis and proportion of deaths among these sepsis cases as outcomes.
Results
Of 4746 results, 28 met the inclusion criteria. 21 studies contributed data for the meta-analysis and were pooled with 30 studies from the original meta-analysis. Pooled incidence was 189 95% CI 133, 267 hospital-treated sepsis cases per 100,000 person-years. An estimated 26.7% 22.9, 30.7 of sepsis patients died. Estimated incidence of ICU-treated sepsis was 58 42, 81 per 100,000 person-years, of which 41.9% 95% CI 36.2, 47.7 died prior to hospital discharge. There was a considerably higher incidence of hospital-treated sepsis observed after 2008 (+ 46% compared to the overall time frame).
Conclusions
Compared to results from the IHME study, we found an approximately 50% lower incidence of hospital-treated sepsis. The majority of studies included were based on administrative data, thus limiting our ability to assess temporal trends and regional differences. The incidence of sepsis remains unknown for the vast majority of LMICs, highlighting the urgent need for improved epidemiological sepsis surveillance.
Psychiatry is in one of its regular crises. It is a crisis of its diagnostic systems despite – perhaps because – of the recurrent claims about the extent of diagnosable ‘brain disorders’. It is a ...crisis of its explanatory systems despite – perhaps because – of its current wager on the brain as the ultimate locus for explanations of mental disorders. It is a crisis of its therapeutic capacities despite – perhaps because – more and more people are making use of its primary mode of intervention focussed on the brain – psychiatric drugs. In this editorial, I will suggest that this triple crisis of diagnosis, explanation and therapeutics arises from the dominant reductionist approaches to the role of neurobiology in psychiatry that priorities the analysis of brain mechanisms, at the expense of an understanding of the whole living organism in its milieu, and the processes which social experience shapes neurobiology from the moment of conception if not before. I shall suggest a different approach that starts from the experience of persons coping with adversity in their forms of life. This approach does not require giving up on our search for plausible explanations of mental health problems that engage neurobiological mechanisms, but it begins from a commitment to understanding, and hence intervening in, the ways in which social adversity shapes and blights the lives of so many of our fellow citizens.
Plants grow in multi-species communities rather than monocultures. Yet most studies on the emission of volatile organic compounds (VOCs) from plants in response to insect herbivore feeding focus on ...one plant species. Whether the presence and identity of neighboring plants or plant community attributes, such as plant species richness and plant species composition, affect the herbivore-induced VOC emission of a focal plant is poorly understood.
We established experimental plant communities in pots in the greenhouse where the focal plant species, red clover (Trifolium pratense), was grown in monoculture, in a two species mixture together with Geranium pratense or Dactylis glomerata, or in a mixture of all three species. We measured VOC emission of the focal plant and the entire plant community, with and without herbivory of Spodoptera littoralis caterpillars caged on one red clover individual within the communities.
Herbivory increased VOC emission from red clover, and increasing plant species richness changed emissions of red clover and also from the entire plant community. Neighbor identity strongly affected red clover emission, with highest emission rates for plants growing together with D. glomerata.
The results from this study indicate that the blend of VOCs perceived by host searching insects can be affected by plant-plant interactions.
Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and ...metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment.
We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro.
GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.
As one of the main knowledge producers, researchers can play an important role in contributing to efforts that bridge the gap between knowledge, policy and practice. However, for researchers to play ...this role, they need knowledge translation (KT) capacities that many typically lack. Furthermore, research has confirmed that little is known on KT training approaches for LMICs researchers and their effectiveness. This paper seeks to contribute to filling this knowledge gap on KT training approaches for LMIC researchers by assessing the effectiveness of a training and mentorship intervention to build African researchers' KT capacity. We conducted KT training and mentorship for 23 early and mid-career researchers from 20 universities in sub-Saharan Africa. This comprised a 5-day intense residential training workshop, followed by a 6-months mentorship. A pre- and post-training test was used to assess the immediate effect of the workshop. The intermediate effect of the training following a 6-month mentorship was assessed by the number of researchers who completed policy briefs during this period and those who participated in the webinar series conducted during this period. Overall, the aggregate average point change in the self-reported learning between the pre-training and the post-training survey was 1.9, which demonstrated the effectiveness of the training workshop. This was confirmed by a 33.7% increase in the aggregate average percentage of participants that responded correctly to questions assessing topics covered in the training between the pre-training and the post-training survey. During the mentorship period, 19 of the 23 researchers prepared and submitted complete drafts of their policy briefs within two months after the training. Fewer (4) researchers revised and submitted final policy briefs. More than half of the trained researchers participated in the webinars conducted in the first three months of the mentorship, whereas less than half of the researchers participated in the webinars conducted in the last three months. KT training and mentorship can be an effective intervention for addressing researchers' KT capacity gaps. For sustainability, KT training and mentorship need to be integrated in graduate training programmes in universities so that future LMIC researchers leave training institutions with the KT capacities they need for influencing policy and programme decisions and actions.
Objective This study examined diabetes knowledge, health fatalism (the belief that health outcomes are outside one's control), and their interaction, as predictors of Type 2 Diabetes preventive ...behavior. Participants: Ethnically diverse college students (N = 345) without prior diagnosis of diabetes. Methods: Cross-sectional design using validated self-report measures. Results: Respondents answered approximately half of the diabetes knowledge items correctly. Physical activity and sedentary behavior were not predicted by diabetes knowledge, fatalism, or their interaction. Higher diabetes knowledge was associated with a healthier diet among individuals with low fatalism. Greater fatalism was associated with a poorer diet among individuals with moderate or high diabetes knowledge. Conclusions: Diabetes knowledge was moderate in this college student sample. Greater knowledge was linked with a healthier diet among those with sense of personal control over their health. College health educators may consider emphasizing modifiability of health behaviors in conjunction with Type 2 diabetes education efforts.
Spheroidal carbonaceous particles (SCPs) are a component of fly-ash, the particulate by-product of industrial high temperature combustion of fuel-oil and coal-series fuels. We provide the first ...evidence that these indelible markers of industrialisation have been deposited in Antarctic ice, thousands of kilometres from any potential source. The earliest observed particle was deposited in an ice layer from 1936 CE. While depositional fluxes are low, chemical analysis of individual SCPs indicates a coal combustion origin.
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