ABSTRACT
BACKGROUND: Breast cancer mortality rates are 39% higher in the African-American (AA) women compared to White-American (WA) women despite the advances in overall breast cancer screening and treatments. Several studies have undertaken to identify the factors leading to this disparity in United States with possible effects of lower socioeconomic status and underlying aggressive biology. METHODS: A retrospective analysis was done using a prospectively maintained database of a metropolitan health system. Patients were selected based on diagnosis of early-stage breast cancer between 10/1998 and 02/2017, and included women over age of 18 with clinically node-negative disease. Patients were then stratified by phenotype confirmed by pathology and patient-identified race. RESULTS: A total of 2,298 women were identified in the cohort with 39% AA and 61% WA women. The overall mean age at the time of diagnosis for AA women was slightly younger at 60 years compared to 62 years for WA women (p = 0.003). Follow-up time was longer for the WA women at 95 months vs. 86 months in AA women. The overall 5-year survival was analyzed for the entire cohort, with the lowest survival occurring in patients with triple-negative breast cancer (TNBC). Phenotype distribution revealed a higher incidence of TNBC in AA women compared to WA women (AA 16% vs. WA 10%; p < 0.0001). AA women also had higher incidence of HER2 positive cancers (AA 16.8% vs. WA 15.3%; p < 0.0001). WA women had a significantly higher distribution of Non-TNBC/HER2-negative phenotype (AA 55% vs. WA 65%; p < 0.0001). Furthermore, a subgroup analysis was done for a sentinel lymph node (SLN) negative cohort that showed higher rates of grade 3 tumors in AA (AA 35% vs. WA 23%; p < 0.0001); and higher rates of grade 1 and grade 2 tumors in WA (30% vs. 21% and 44% vs. 40%). Despite higher grade tumors in AA women, five-year overall survival outcomes in SLN-negative cohort did not differ between AA and WA women when stratifying based on tumor subtype. CONCLUSION: Breast cancer survival disparities in AA and WA women with SLN-negative breast cancer are diminished when evaluated at early-stage cancers defined by SLN-negative tumors. Our evaluation suggests that when diagnosed early, phenotype does not contribute to racial survival outcomes. The lower survival rate in AA women with breast cancer may be attributed to later stage biology between the two races, or underlying socioeconomic disparities.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Black or African American , Female , Humans , Phenotype , Retrospective Studies , United States/epidemiology , White PeopleABSTRACT
OBJECTIVE: To investigate subtype-specific risk of germline alleles associated with triple negative breast cancer (TNBC) in African ancestry populations. BACKGROUND: Breast cancer (BC) mortality is higher in African American (AA) compared to White American (WA) women; this disparity is partly explained by 2-fold higher TNBC incidence. METHODS: We used a surgically maintained biospecimen cohort of 2884 BC cases. Subsets of the total (760 AA; 962 WA; 910 West African/Ghanaian; 252 East African/Ethiopian) were analyzed for genotypes of candidate alleles. A subset of 417 healthy controls were also genotyped, to measure associations with overall BC risk and TNBC. RESULTS: TNBC frequency was highest in Ghanaian and AA cases (49% and 44% respectively; P < 0.0001) and lowest in Ethiopian and WA cases (17% and 24% respectively; P < 0.0001). TNBC cases had higher West African ancestry than non-TNBC (P < 0.0001). Frequency of the Duffy-null allele (rs2814778; an African ancestral variant adopted under selective pressure as protection against malaria) was associated with TNBC-specific risk (P < 0.0001), quantified West African Ancestry (P < 0.0001) and was more common in AA, Ghanaians, and TNBC cases. Additionally, rs4849887 was significantly associated with overall BC risk, and both rs2363956 and rs13000023 were associated with TNBC-specific risk, although none as strongly as the Duffy-null variant. CONCLUSIONS: West African ancestry is strongly correlated with TNBC status, as well as germline variants related to BC risk. The Duffy-null allele was associated with TNBC risk in our cohort.
Subject(s)
Black or African American/genetics , Disease Susceptibility/epidemiology , Germ-Line Mutation/genetics , Receptor, ErbB-2/genetics , Triple Negative Breast Neoplasms/genetics , Adult , Africa South of the Sahara/ethnology , Aged , Case-Control Studies , Databases, Factual , Female , Ghana/ethnology , Humans , Incidence , Internationality , Middle Aged , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Risk Assessment , Triple Negative Breast Neoplasms/ethnology , Triple Negative Breast Neoplasms/pathology , United StatesABSTRACT
BACKGROUND: Little is known about general surgery trainees' education regarding management of breast problems. We sought to measure the impact of a dedicated breast surgery rotation on American Board of Surgery In-Service Examination (ABSITE) scores and operative volumes. METHODS: A breast surgery rotation was implemented at our program in July 2016. We obtained the January 2017 ABSITE scores for postgraduate year (PGY) 1-3 residents, and obtained the case volumes for PGY 1-3 residents during the years 2015-2016 and 2016-2017. RESULTS: We compared the performance on total questions and skin, soft tissue, and breast questions between the residents who had the breast rotation before the ABSITE to those that had it after. There was no difference in the average overall percentage (70.2% versus 71.7%, P = 0.55) or in the average skin, soft tissue, and breast percentage (70% versus 71.4%, P = 0.72). A postgraduate year-to-year comparison showed an increase in average total major cases among the PGY-1 residents (93.8 versus 166.8, P = 0.02), and an increase in average breast cases among the PGY-1 (17.8 versus 27 cases, P < 0.01) and PGY-2 (27.3 versus 47.7 cases, P = 0.02) years. There was an increase in the proportion of complex breast cases performed by PGY-3 residents (23.2% versus 33.1%, P = 0.01). CONCLUSIONS: A dedicated breast surgery rotation did not detract from the nonbreast general surgery educational experience of junior residents (as measured by ABSITE scores), and it increased the case volume of breast as well as total major cases among junior residents. A breast surgery rotation is valuable for strengthening surgical case volumes.
Subject(s)
Breast/surgery , General Surgery/education , Internship and Residency , Educational Measurement , HumansABSTRACT
We evaluated 328 patients (34.8% African American [AA]; 65.2% White American [WA]) with hormone receptor-positive, HER2/neu-negative breast cancer. Mean age (60 years); mean tumor size (1.6 and 1.7 cm for AA and WA, respectively) were similar, and mean BMI was higher for AA (33 vs 29.8; P = 0.001). Recurrence score (RS) distribution was similar- 8.3% AA and 5.9% WA with high RS (≥31). No significant differences were observed in delivery of chemotherapy stratified by score. With median follow-up 27.2 months for AA and 33.4 months for WA, distant recurrence occurred in 1.0% and 1.6%, respectively (P = 1). Our results suggest comparable RS utility in AA and WA patients.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Transcriptome , Adult , Black or African American/genetics , Aged , Aged, 80 and over , Breast Neoplasms/therapy , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Receptor, ErbB-2/metabolism , White People/geneticsABSTRACT
INTRODUCTION: The 21-gene expression profile [Oncotype DX Recurrence Score (RS)] stratifies benefit from adjuvant chemotherapy in hormone receptor (HR)-positive, HER2/neu-negative, node-negative breast cancer. It is not routinely applied to predict neoadjuvant chemotherapy (NACT) response; data in diverse patient populations also are limited. We developed a statistical model based on standard clinicopathologic features to identify high-risk cases (RS > 30) and then evaluated ability of predicted high RS to predict for NACT downstaging. METHODS: Primary surgery patients with Oncotype DX RS testing 2012-2016 were identified from a prospectively-maintained database. A RS predictive model was created and applied to a dataset of comparable NACT patients. Response was defined as tumor size decrease ≥ 1 cm. RESULTS: Of 394 primary surgery patients-60.4% white American; 31.0% African American-RS distribution was similar for both groups. No single feature reliably identified high RS patients; however, a model accounting for age, HR expression, proliferative index (MIB1/Ki67), histology, and tumor size was generated, with receiver operator area under the curve 0.909. Fifty-six NACT patients were identified (25 African American). Of 21 cases with all relevant clinicopathology, 14 responded to NACT and the model generated high-risk RS in 14 (100%); conversely, of 16 cases generating high-risk RS, only 2 did not respond. CONCLUSIONS: Predictive modelling can identify high RS patients; this model also can identify patients likely to experience primary tumor downstaging with NACT. Until this model is validated in other datasets, we recommend that Oncotype-eligible patients undergo primary surgery with decisions regarding chemotherapy made in the adjuvant setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Gene Expression Profiling , Neoadjuvant Therapy , Neoplasm Recurrence, Local/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/genetics , Carcinoma, Lobular/drug therapy , Carcinoma, Lobular/genetics , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Prognosis , Survival RateABSTRACT
Many surgeons routinely use a single preoperative prophylactic dose of an antibiotic prior to needle-localized lumpectomy, despite the lack of evidence that this practice reduces the rate of infection. The aim of this study is to determine if antibiotic administration reduces wound infection for needle-localized lumpectomy. A retrospective chart review of patients that underwent needle-localized lumpectomy from 2010 to 2012 was conducted. Data regarding patient demographics, comorbid conditions, medical history, operative details, and pathology were collected. Surgical infections requiring opening of the wound or treatment with antibiotics were documented if occurred during the first 3 months following surgery. Fisher's exact tests were used for statistical analyses. Two hundred and twenty patients were identified. Thirty-six percent (80/220) of patients received preoperative prophylactic antibiotics. The antibiotic and the nonantibiotic group were similar in age, body mass index, tobacco use, history of radiation, history of neo-adjuvant chemotherapy, duration of surgery, duration needle in place, and pathology. Two percent (4/220) of patients had wound infections. Two percent (3/140) of patients in the nonantibiotic group had infections, versus 1% (1/80) in the antibiotic group. In an analysis of patients that developed infections (n = 4) and patients that did not (n = 216), there was no statistically significant difference in patient demographic, duration of surgery, duration of time needle in place, or pathology. It is safe to omit the use of antibiotics prior to needle-localized lumpectomy and avoid the cost of the medication, patient adverse reactions, and increase in resistant organisms.
Subject(s)
Antibiotic Prophylaxis , Breast Neoplasms/surgery , Mastectomy, Segmental/adverse effects , Mastectomy, Segmental/methods , Postoperative Complications/prevention & control , Surgical Wound Infection/prevention & control , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Female , Humans , Mastectomy, Segmental/instrumentation , Middle Aged , Needles , Retrospective Studies , Surgical Wound Infection/etiology , Time Factors , Treatment Outcome , Young AdultABSTRACT
Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.
ABSTRACT
As the ancestral homeland of our species, Africa contains elevated levels of genetic diversity and substantial population structure. Importantly, African genomes are heterogeneous: They contain mixtures of multiple ancestries, each of which have experienced different evolutionary histories. In this review, we view population genetics through the lens of admixture, highlighting how multiple demographic events have shaped African genomes. Each of these historical vignettes paints a recurring picture of population divergence followed by secondary contact. First, we give a brief overview of genetic variation in Africa and examine deep population structure within Africa, including the evidence of ancient introgression from archaic "ghost" populations. Second, we describe the genetic legacies of admixture events that have occurred during the past 10,000 years. This includes gene flow between different click-speaking Khoe-San populations, the stepwise spread of pastoralism from eastern to southern Africa, multiple migrations of Bantu speakers across the continent, as well as admixture from the Middle East and Europe into the Sahel region and North Africa. Furthermore, the genomic signatures of more recent admixture can be found in the Cape Peninsula and throughout the African diaspora. Third, we highlight how natural selection has shaped patterns of genetic variation across the continent, noting that gene flow provides a potent source of adaptive variation and that selective pressures vary across Africa. Finally, we explore the biomedical implications of population structure in Africa on health and disease and call for more ethically conducted studies of genetic variation in Africa.
Subject(s)
Genetic Variation , Genetics, Population , Africa, Southern , Biological Evolution , GenomeABSTRACT
Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. SIGNIFICANCE: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Female , Triple Negative Breast Neoplasms/genetics , Transcriptome , Black or African American/genetics , BiologyABSTRACT
BACKGROUND: Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. RESULTS: Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. CONCLUSIONS: Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.
Subject(s)
Genome-Wide Association Study , Prostatic Neoplasms , Africa South of the Sahara/epidemiology , Genetic Predisposition to Disease , Humans , Male , Prostatic Neoplasms/genetics , Risk FactorsABSTRACT
Histidine (His) plays a critical role in plant growth and development, both as one of the standard amino acids in proteins, and as a metal-binding ligand. While genes encoding seven of the eight enzymes in the pathway of His biosynthesis have been characterized from a number of plant species, the identity of the enzyme catalyzing the dephosphorylation of histidinol-phosphate to histidinol has remained elusive. Recently, members of a novel family of histidinol-phosphate phosphatase proteins, displaying significant sequence similarity to known myoinositol monophosphatases (IMPs) have been identified from several Actinobacteria. Here we demonstrate that a member of the IMP family from Arabidopsis (Arabidopsis thaliana), myoinositol monophosphatase-like2 (IMPL2; encoded by At4g39120), has histidinol-phosphate phosphatase activity. Heterologous expression of IMPL2, but not the related IMPL1 protein, was sufficient to rescue the His auxotrophy of a Streptomyces coelicolor hisN mutant. Homozygous null impl2 Arabidopsis mutants displayed embryonic lethality, which could be rescued by supplying plants heterozygous for null impl2 alleles with His. In common with the previously characterized HISN genes from Arabidopsis, IMPL2 was expressed in all plant tissues and throughout development, and an IMPL2:green fluorescent protein fusion protein was targeted to the plastid, where His biosynthesis occurs in plants. Our data demonstrate that IMPL2 is the HISN7 gene product, and suggest a lack of genetic redundancy at this metabolic step in Arabidopsis, which is characteristic of the His biosynthetic pathway.
Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/enzymology , Histidine/biosynthesis , Histidinol-Phosphatase/metabolism , Arabidopsis/genetics , Arabidopsis Proteins/genetics , DNA, Bacterial/genetics , DNA, Plant/genetics , Gene Expression Regulation, Plant , Genetic Complementation Test , Histidinol/metabolism , Histidinol-Phosphatase/genetics , Models, Molecular , Mutagenesis, Insertional , Mutation , Phosphorylation , Phylogeny , Protein Structure, Tertiary , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolismABSTRACT
Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry. Recently, there are new efforts to verify if these alleles increase risk in African American (AA) women as well. We investigated the effect of previously reported AA breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African-enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case-control, case-series and race-nested approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.420, p = 0.005). Our results suggest that an ancestry-specific Duffy-null allele and differential prevalence of a polymorphic gene variant of ANKLE1 may play a role in TNBC breast cancer outcomes. These findings present opportunities for therapeutic potential and future studies to address race-specific differences in TNBC risk and disease outcome.
Subject(s)
Black People/genetics , Duffy Blood-Group System/genetics , Endonucleases/genetics , Receptors, Cell Surface/genetics , Triple Negative Breast Neoplasms/genetics , White People/genetics , Alleles , Biomarkers, Tumor/genetics , Case-Control Studies , Cohort Studies , Female , Genotype , Humans , Internationality , Middle Aged , Risk Factors , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/pathologyABSTRACT
Active oxygen species (AOS) generated in response to stimuli and during development can function as signalling molecules in eukaryotes, leading to specific downstream responses. In plants these include such diverse processes as coping with stress (for example pathogen attack, wounding and oxygen deprivation), abscisic-acid-induced guard-cell closure, and cellular development (for example root hair growth). Despite the importance of signalling via AOS in eukaryotes, little is known about the protein components operating downstream of AOS that mediate any of these processes. Here we show that expression of an Arabidopsis thaliana gene (OXI1) encoding a serine/threonine kinase is induced in response to a wide range of H2O2-generating stimuli. OXI1 kinase activity is itself also induced by H2O2 in vivo. OXI1 is required for full activation of the mitogen-activated protein kinases (MAPKs) MPK3 and MPK6 after treatment with AOS or elicitor and is necessary for at least two very different AOS-mediated processes: basal resistance to Peronospora parasitica infection, and root hair growth. Thus, OXI1 is an essential part of the signal transduction pathway linking oxidative burst signals to diverse downstream responses.
Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/metabolism , MAP Kinase Signaling System , Protein Serine-Threonine Kinases/metabolism , Respiratory Burst , Arabidopsis/enzymology , Arabidopsis/genetics , Arabidopsis/parasitology , Arabidopsis Proteins/genetics , Cellulase/metabolism , Enzyme Activation/drug effects , Enzyme Induction/drug effects , Genes, Reporter , Genetic Complementation Test , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/pharmacology , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Phytophthora/physiology , Plant Diseases/genetics , Plant Diseases/parasitology , Plant Roots/enzymology , Plant Roots/growth & development , Plant Roots/metabolism , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.
Subject(s)
Black People/genetics , Genetic Predisposition to Disease , Neoplasms/epidemiology , Neoplasms/genetics , Polymorphism, Single Nucleotide , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/genetics , Case-Control Studies , Cohort Studies , Genetic Loci , Genetics, Population , Genome-Wide Association Study , Humans , Male , Neoplasms/classification , Prostatic Neoplasms/classification , Risk Factors , South Africa/epidemiologyABSTRACT
Expression of the Arabidopsis Oxidative Signal-Inducible1 (OXI1) serine/threonine protein kinase gene (At3g25250) is induced by oxidative stress. The kinase is required for root hair development and basal defence against the oomycete pathogen Hyaloperonospora parasitica, two separate H(2)O(2)-mediated processes. In this study, the role of OXI1 during pathogenesis was characterized further. Null oxi1 mutants are more susceptible to both virulent and avirulent strains of the biotrophic bacterial pathogen Pseudomonas syringae compared with the wild type, indicating that OXI1 positively regulates both basal resistance triggered by the recognition of pathogen-associated molecular patterns, as well as effector-triggered immunity. The level of OXI1 expression appears to be critical in mounting an appropriate defence response since OXI1 overexpressor lines also display increased susceptibility to biotrophic pathogens. The induction of OXI1 after P. syringae infection spatially and temporally correlates with the oxidative burst. Furthermore, induction is reduced in atrbohD mutants and after application of DPI (an inhibitor of NADPH oxidases) suggesting that reactive oxygen species produced through NADPH oxidases drives OXI1 expression during this plant-pathogen interaction.
Subject(s)
Arabidopsis Proteins/immunology , Arabidopsis/immunology , Arabidopsis/microbiology , Plant Diseases/immunology , Protein Serine-Threonine Kinases/immunology , Pseudomonas syringae/physiology , Arabidopsis/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Gene Expression Regulation, Plant , Immunity , Immunity, Innate , Oxidative Stress , Plant Diseases/microbiology , Protein Serine-Threonine Kinases/genetics , Pseudomonas syringae/pathogenicity , VirulenceABSTRACT
INTRODUCTION: The optimal structure for survivorship care plan (SCP) programs and methodology for generating treatment summaries (TSs) has not yet been defined, but the Commission on Cancer and the National Accreditation Program for Breast Centers both mandate that participating oncology programs implement SCP-TS processes for patients that have completed treatment. METHODS: We used the Institute for Healthcare Improvement's Plan-Do-Study-Act model for conducting a quality improvement project evaluating two different SCP-TS programs implemented at the Henry Ford Health System/Henry Ford Cancer Institute's Breast Oncology Program in Detroit, Michigan. System I involved TSs drafted by nonspecialist breast clinic staff; System II involved TSs vetted through a multidisciplinary breast specialist conference approach. Accuracy of basic documentation entries related to dates and components of treatment were compared for the two approaches. RESULTS: Seventy-one System I and 93 System II documents were reviewed. Documentation was accurate in at least 90% of documents for both systems regarding delivery of chemotherapy and/or endocrine therapy and for documenting the identity of the various members of the cancer treatment team. Both systems had notable inaccuracies in documenting type of surgery performed, but System II had fewer inaccuracies than System I (33.78% v 51.67%, respectively; P = .05). System II, compared with System I, had fewer inaccuracies in documenting date of diagnosis (9.68% v 25.35%, respectively; P = .01) and had less missing information for dose of radiation delivered (9.33% v 33.9%, respectively; P < .01). CONCLUSION: A multidisciplinary team approach to drafting and reviewing SCP-TS documents improved content accuracy for our program, but ongoing education regarding documentation of various surgical procedures is warranted.
Subject(s)
Breast Neoplasms/epidemiology , Delivery of Health Care , Patient Care Planning , Patient Care Team , Survivorship , Breast Neoplasms/diagnosis , Breast Neoplasms/etiology , Breast Neoplasms/therapy , Disease Management , Female , Humans , Medical Oncology/methods , Medical Oncology/standardsABSTRACT
PURPOSE: Health research in low- and middle-income countries can generate novel scientific knowledge and improve clinical care, fostering population health improvements to prevent premature death. Project management is a critical part of the success of this research, applying knowledge, skills, tools, and techniques to accomplish required goals. Here, we describe the development and implementation of tools to support a multifaceted study of prostate cancer in Africa, focusing on building strategic and operational capacity. METHODS: Applying a learning organizational framework, we developed and implemented a project management toolkit (PMT) that includes a management process flowchart, a cyclical center-specific schedule of activities, periodic reporting and communication, and center-specific monitoring and evaluation metrics. RESULTS: The PMT was successfully deployed during year one of the project with effective component implementation occurring through periodic cycles of dissemination and feedback to local center project managers. A specific evaluation was conducted 1 year after study initiation to obtain enrollment data, evaluate individual quality control management plans, and undertake risk log assessments and follow-up. Pilot data obtained identified areas in which centers required mentoring, strengthening, and capacity development. Strategies were implemented to improve project goals and operational capacity through local problem solving, conducting quality control checks and following compliancy with study aims. Moving forward, centers will perform quarterly evaluations and initiate strengthening measures as required. CONCLUSION: The PMT has fostered the development of both strategic and operational capacity across project centers. Investment in project management resources is essential to ensuring high-quality, impactful health research in low- and middle-income countries.
Subject(s)
Carcinoma/epidemiology , Prostatic Neoplasms/epidemiology , Black People , Carcinoma/pathology , Developing Countries , Humans , Income , Male , Prostate/pathology , Prostatic Neoplasms/pathology , South Africa/epidemiologyABSTRACT
PURPOSE: Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA. METHODS: We established the Men of African Descent and Carcinoma of the Prostate Network, which includes seven SSA centers partnering with five US centers to study the genetics and epidemiology of CaP in SSA. We developed common data elements and instruments, regulatory infrastructure, and biosample collection, processing, and shipping protocols. We tested this infrastructure by collecting epidemiologic, medical record, and genomic data from a total of 311 patients with CaP and 218 matched controls recruited at the seven SSA centers. We extracted genomic DNA from whole blood, buffy coat, or buccal swabs from 265 participants and shipped it to the Center for Inherited Disease Research (Baltimore, MD) and the Centre for Proteomics and Genomics Research (Cape Town, South Africa), where genotypes were generated using the UK Biobank Axiom Array. RESULTS: We used common instruments for data collection and entered data into the shared database. Double-entered data from pilot participants showed a 95% to 98% concordance rate, suggesting that data can be collected, entered, and stored with a high degree of accuracy. Genotypes were obtained from 95% of tested DNA samples (100% from blood-derived DNA samples) with high concordance across laboratories. CONCLUSION: We provide approaches that can produce high-quality epidemiologic and genomic data in multicenter studies of cancer in SSA.
Subject(s)
Carcinoma/epidemiology , Carcinoma/genetics , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/genetics , Baltimore , Black People , Carcinoma/pathology , Genomics , Genotype , Humans , Male , Prostate/pathology , Prostatic Neoplasms/pathology , South Africa/epidemiologyABSTRACT
Basal resistance is the ultimately unsuccessful plant defense response to infection with a virulent pathogen. It is thought to be triggered by host recognition of pathogen-associated molecular patterns, with subsequent suppression of particular components by pathogen effectors. To identify novel components of Arabidopsis basal resistance against the bacterial pathogen Pseudomonas syringae pv. tomato, microarray expression profiling was carried out on the cirl mutant, which displays enhanced resistance against P. syringae pv. tomato. This identified two genes, At4g23810 and At2g40000, encoding the transcription factor WRKY53 and the nematode resistance protein-like HSPRO2, whose expression was upregulated in cir1 prior to pathogen infection and in wild-type plants after P. syringae pv. tomato infection. WRKY53 and HSPRO2 are positive regulators of basal resistance. Knockout mutants of both genes were more susceptible to P. syringae pv. tomato infection than complemented lines, with increased growth of the pathogen in planta. WRKY53 and HSPRO2 appear to function downstream of salicylic acid and to be negatively regulated by signaling through jasmonic acid and ethylene.