Socioeconomic status and breast cancer treatment Dreyer, Marie S.; Nattinger, Ann B.; McGinley, Emily L. ...
Breast cancer research and treatment,
01/2018, Letnik:
167, Številka:
1
Journal Article
Recenzirano
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Purpose
Evidence suggests substantial disparities in breast cancer survival by socioeconomic status (SES). We examine the extent to which receipt of newer, less invasive, or more effective ...treatments—a plausible source of disparities in survival—varies by SES among elderly women with early-stage breast cancer.
Methods
Multivariate regression analyses applied to 11,368 women (age 66–90 years) identified from SEER-Medicare as having invasive breast cancer diagnosed in 2006–2009. Socioeconomic status was defined based on Medicaid enrollment and level of poverty of the census tract of residence. All analyses controlled for demographic, clinical health status, spatial, and healthcare system characteristics.
Results
Poor and near-poor women were less likely than high SES women to receive sentinel lymph node biopsy and radiation after breast-conserving surgery (BCS). Poor women were also less likely than near-poor or high SES women to receive any axillary surgery and adjuvant chemotherapy. There were no significant differences in use of aromatase inhibitors (AI) between poor and high SES women. However, near-poor women who initiated hormonal therapy were more likely to rely exclusively on tamoxifen, and less likely to use the more expensive but more effective AI when compared to both poor and high SES women.
Conclusions
Our results indicate that SES disparities in the receipt of treatments for incident breast cancer are both pervasive and substantial. These disparities remained despite women’s geographic area of residence and extent of disease, suggesting important gaps in access to effective breast cancer care.
Background
Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large‐scale genomic studies have improved ...understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas.
Methods
Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study.
Results
Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole‐genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial‐to‐mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer.
Conclusion
PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.
Worse genetic profile in tail
This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in ...non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of ‘all-comer’ treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.
•Molecular diversity of pancreatic cancer requires a paradigm shift towards a genomic-driven therapeutic approach.•Unselected treatment strategies demonstrate only limited efficacy in early-stage pancreatic cancer.•Personalised treatment in non-metastatic disease has potential to reduce pancreatic cancer mortality.•It is fundamental to implement preoperative clinical studies enriched for potential prognostic/predictive biomarkers.•Novel models of therapeutic development are warranted to accelerate progress in pancreatic cancer care and research.
The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin ...effector paxillin to recruit and activate TNFα converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNFα and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNFα. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment.
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► HIV-Nef translocates activated TACE/ADAM17 into extracellular vesicles (EVs) ► The mechanism is initiated by interaction of Eed and paxillin with TACE ► Translocation of TACE into EVs is regulated by Pak2 ► Melanoma cells activate the same mechanism to upload activated ADAM10 into EVs
Abstract
Background
Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare ...survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis.
Methods
An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan–Meier method and Cox regression analyses.
Results
Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy.
Conclusion
Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.
Graphical Abstract
In this retrospective international multicentre study, patients with resected ampullary adenocarcinoma of the pancreaticobiliary/mixed subtype demonstrated a survival benefit from adjuvant chemotherapy. No benefit seemed present for the intestinal subtype.
Graphical Abstract
Selection is key
Although the issue of transformation has always been on the agenda of higher education since the transition to a democratic government in 1994, it is only since the student protests in 2015 and 2016 ...that the call for decolonisation of higher education in South Africa attracted much attention. The aim of this article is to reflect on the discipline of practical theology in South Africa in view of this call for decolonisation. Looking through the theoretical lens of decolonial theory, the author opts for an epistemological perspective on decolonisation. More particularly, the call for decolonisation of knowledge implies a struggle for epistemic justice. With this understanding of the call for decolonisation, the author reflects on the situation of practical theology in South Africa. The article concludes with three proposals for the decolonisation of practical theological research.
Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 ...patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.
is an important pathogen for both humans and animals. It can infect livestock, as well as pets and wild animals. During recent years, a number of reports have described the isolation of
from zoo ...animals, mainly birds and mammals, for which the infection was mostly lethal. Between 2005 and 2019, there were at least 17 cases of deceased mammals, belonging to five different species, which suffered from a
infection at the Zoo Wuppertal, Germany. Since only scarce information exists on the properties of
from zoo animals, we characterized eight isolates, covering all infected species, in detail. All isolates were members of biotype 1, but belonged to five serotypes, five sequence types (STs), and seven core-genome multilocus sequence types (cgMLSTs). Using pulsed-field gel electrophoresis (PFGE) analysis and whole-genome sequencing (WGS), the seven isolates could be discriminated from each other. They differed significantly regarding their virulence genes and mobile genetic elements. While the virulence plasmid pYV existed in all serotypes (five isolates), a complete high-pathogenicity island (HPI) was detected only in the serotypes O:1a, O:1b, and O:13 (four isolates), but not in O:2a and O:2b. Similarly, the content of other plasmids and prophages varied greatly between the isolates. The data demonstrate that the deceased mammals were infected by seven individual isolates and not by a single type predominating in the zoo animals.
Microbially-produced ice nucleating proteins (INpro) are unique molecular structures with the highest known catalytic efficiency for ice formation. Airborne microorganisms utilize these proteins to ...enhance their survival by reducing their atmospheric residence times. INpro also have critical environmental effects including impacts on the atmospheric water cycle, through their role in cloud and precipitation formation, as well as frost damage on crops. INpro are ubiquitously present in the atmosphere where they are emitted from diverse terrestrial and marine environments. Even though bacterial genes encoding INpro have been discovered and sequenced decades ago, the details of how the INpro molecular structure and oligomerization foster their unique ice-nucleation activity remain elusive. Using machine-learning based software AlphaFold 2 and trRosetta, we obtained and analysed the first
ab initio
structural models of full length and truncated versions of bacterial INpro. The modeling revealed a novel beta-helix structure of the INpro central repeat domain responsible for ice nucleation activity. This domain consists of repeated stacks of two beta strands connected by two sharp turns. One beta-strand is decorated with a TxT amino acid sequence motif and the other strand has an SxLT/I motif. The core formed between the stacked beta helix-pairs is unusually polar and very distinct from previous INpro models. Using synchrotron radiation circular dichroism, we validated the β-strand content of the central repeat domain in the model. Combining the structural model with functional studies of purified recombinant INpro, electron microscopy and modeling, we further demonstrate that the formation of dimers and higher-order oligomers is key to INpro activity. Using computational docking of the new INpro model based on rigid-body algorithms we could reproduce a previously proposed homodimer structure of the INpro CRD with an interface along a highly conserved tyrosine ladder and show that the dimer model agrees with our functional data. The parallel dimer structure creates a surface where the TxT motif of one monomer aligns with the SxLT/I motif of the other monomer widening the surface that interacts with water molecules and therefore enhancing the ice nucleation activity. This work presents a major advance in understanding the molecular foundation for bacterial ice-nucleation activity.
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