Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic ...instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
Abstract
The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours ...including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
•Few studies elicited the public’s vaccine beliefs using open-ended questions.•Concerns about vaccine safety are the most commonly stated beliefs.•Mistrust in physicians, pharma, and the government ...may exacerbate hesitancy.•The majority of studies (57%) focused on HPV vaccines.•Nearly a third of the studies exclusively examined Latinos and African Americans.
While childhood vaccines are safe and effective, some parents remain hesitant to vaccinate their children, which has led to outbreaks of vaccine preventable diseases. The goal of this systematic review was to identify and summarize the range of beliefs around childhood vaccines elicited using open-ended questions, which are better suited for discovering beliefs compared to closed-ended questions.
PubMed, Embase, and PsycINFO were searched using keywords for childhood vaccines, decision makers, beliefs, and attitudes to identify studies that collected primary data using a variety of open-ended questions regarding routine childhood vaccine beliefs in the United States. Study designs, population characteristics, vaccine types, and vaccine beliefs were abstracted. We conducted a qualitative analysis to conceptualize beliefs into themes and generated descriptive statistics.
Of 1727 studies identified, 71 were included, focusing largely on parents (including in general, and those who were vaccine hesitant or at risk of hesitancy). Seven themes emerged: Adverse effects was most prominent, followed by mistrust, perceived lack of necessity, pro-vaccine opinions, skepticism about effectiveness, desire for autonomy, and morality concerns. The most commonly described beliefs included that vaccines can cause illnesses; a child’s immune system can be overwhelmed if receiving too many vaccines at once; vaccines contain harmful ingredients; younger children are more susceptible to vaccine adverse events; the purpose of vaccines is profit-making; and naturally developed immunity is better than that acquired from vaccines. Nearly a third of the studies exclusively assessed minority populations, and more than half of the studies examined beliefs only regarding HPV vaccine.
Few studies used open-ended questions to elicit beliefs about vaccines. Many of the studies that did so, focused on HPV vaccine. Concerns about vaccine safety were the most commonly stated beliefs about childhood vaccines, likely because studies were designed to capture barriers and challenges to vaccination.
Social networks can consist of close friends, family members, and neighbors as well as peripheral others. Studies of social networks and associations with well-being have mostly focused on ...age-restricted samples of older adults or specific geographic areas, thus limiting their generalizability. We analyzed 2 online surveys conducted with RAND's American Life Panel, a national adult life span sample recruited through multiple probability-based approaches. In Survey 1, 496 participants assessed the sizes of their social networks, including the number of close friends, family members, neighbors, and peripheral others. Of those, 287 rated their social satisfaction and well-being on Survey 2. Older participants reported smaller social networks, largely because of reporting fewer peripheral others. Yet older age was associated with better well-being. Although the reported number of close friends was unrelated to age, it was the main driver of well-being across the life span-even after accounting for the number of family members, neighbors, and peripheral others. However, well-being was more strongly related to social satisfaction than to the reported number of close friends-suggesting that it is the perception of relationship quality rather than the perception of relationship quantity that is relevant to reporting better well-being. We discuss implications for social network interventions that aim to promote well-being.
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Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive ...byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K
(KCNK) potassium channel class comprises an ...ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K
s contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K
s have established the basic architecture of this channel family, revealed key moving parts involved in K
function, uncovered the importance of asymmetric pinching and dilation motions in the K
selectivity filter (SF) C-type gate, and defined two K
structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K
:modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K
activity. Such knowledge should catalyze development of new K
modulators to probe function and treat a wide range of disorders.
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•K2P structures reveal unique features of this ‘leak’ potassium channel family.•K2Ps have three moving – M2 and M4 transmembrane helices and the SF gate.•The absence or presence of an ...inner gate defines two K2P structural subfamilies.•K2P channels have a polysite pharmacology comprising five modulator binding sites.•Frontiers involve defining modulator interplay and membrane and heterodimerization effects
Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K2P (KCNK) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K2Ps contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K2Ps have established the basic architecture of this channel family, revealed key moving parts involved in K2P function, uncovered the importance of asymmetric pinching and dilation motions in the K2P selectivity filter (SF) C-type gate, and defined two K2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K2P:modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K2P activity. Such knowledge should catalyze development of new K2P modulators to probe function and treat a wide range of disorders.
Objective: Flu vaccinations are recommended for almost everyone, but uptake may vary because of perceived social norms. We aimed to examine the relationship between perceived social circle vaccine ...coverage (including family, friends, and acquaintances) and own vaccination behavior as well as potential mediators. Methods: In 2011, 357 participants from RAND's American Life Panel reported perceived social circle vaccine coverage for the 2010-2011 flu season, own vaccination behavior for the 2009-2010 and 2010-2011 flu seasons, perceived flu risk without and with vaccination, and perceived vaccine safety. In 2012 and 2016, respectively, participants returned to report their own vaccination behavior for the 2011-2012 flu season (N = 338) and 2015-2016 flu season (N = 216). Results: Perceiving greater percentage of 2010-2011 social circle vaccine coverage was associated with a greater likelihood of getting vaccinated in the 2010-2011 flu season (odds ratio OR = 1.03, 95% confidence interval CI = 1.01, 1.04) and the subsequent 2011-2012 flu season (OR = 1.02, 95% CI = 1.01, 1.03) but not the 2015-2016 flu season (OR = 1.00, 95% CI = .99, 1.01), as seen in logistic regressions that controlled for demographics and 2009-2010 vaccination behavior. All significant relationships between social circle vaccine coverage and own vaccination behavior were mediated by perceived flu risk without vaccination. Conclusions: Perceived social circle vaccine coverage is associated with own vaccination behavior in the current and subsequent flu season, establishing behavior patterns that may persist into the future. People's vaccination decisions may be informed by their perceptions of their peers' beliefs and behaviors. We discuss intervention strategies for promoting vaccine uptake by counteracting negative and promoting positive perceived social norms.
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Acute liver failure (ALF) is defined as the development of severe liver injury with associated hepatic encephalopathy and synthetic dysfunction in a patient without known cirrhosis or other ...preexisting liver disease. Definitions of acute-on-chronic liver failure (ACLF) vary, but generally describe a syndrome marked by acutely decompensated cirrhosis and extrahepatic organ dysfunction. Here, Han et al offer guidelines that seek to address the distinct pathophysiology of ALF and ACLF, focusing on the cardiovascular, endocrine, hematologic, pulmonary, and renal systems.
We sought to evaluate longitudinal trends in people's risk perceptions and vaccination intentions during the 2009 H1N1 pandemic.
We used data from 10 waves of a US national survey focusing on the ...H1N1 pandemic (administered between May 2009 and January 2010) to conduct a longitudinal analysis of adult respondents' risk perceptions and vaccination intentions.
Self-reported perceived risk of becoming infected with H1N1 paralleled H1N1 activity throughout the pandemic's first year. However, intention to be vaccinated declined from 50% (May 2009) to 16% (January 2010) among those who remained unvaccinated (27% had been vaccinated by January 2010). Respondents who indicated that they had previously been vaccinated against seasonal influenza reported significantly higher H1N1 vaccination intentions than those who had not been vaccinated (67% vs 26%; P < .001).
Reported intention to be vaccinated declined well before vaccine became available and decreased throughout the pandemic year. To the extent that prior vaccination for seasonal influenza vaccination is a strong correlate of H1N1 risk perceptions, encouraging seasonal influenza vaccination may benefit pandemic preparedness efforts.
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