Individuals Of African Descent Research Articles

Updates on disorders in curly hair.

Hair disorders, including central centrifugal cicatricial alopecia (CCCA), traction alopecia (TA), and acquired trichorrhexis nodosa (ATN), commonly occur in individuals with curly textured hair. Curly textured hair in individuals of African descent has unique properties and can present diagnostic and therapeutic challenges. CCCA has been linked to uterine leiomyoma and type 2 diabetes mellitus, as well as fibroproliferation. TA often presents with a fringe sign and can arise from high-tension hairstyles presumed to be protective. Trichoscopy is useful in establishing a diagnosis; perifollicular halos are more commonly seen than perifollicular erythema or scale in CCCA. In TA, miniaturized follicles, hair casts, and "flambeau sign" can be seen. Hairstyling practices likely contribute to TA and ATN; however, the data are mixed on the role of chemical relaxers and heat styling in CCCA. Unique considerations in the presentation of frontal fibrosing alopecia in curly textured hair have also been published recently. This review provides a comprehensive, up-to-date summary of these disorders with an emphasis on their unique properties, as well as considerations in hair care for curly textured hair.

Abstract 2948: Unveiling hidden genomic diversity: Exploring epigenetic potential and gene expression in African Pan Genome contig sequences

Abstract An important consideration when studying cancer in diverse populations is the representativeness of the reference genome. Cancer genomics findings are largely based upon alignments to GRCh37 and GRCh38 references, and with the recent release of the telomere-to-telomere (T2T) and the Human Pangenome Reference Consortium references, analyses of sequences distinct from previous references in the cancer context provide exciting opportunities to identify novel targets that may be linked to cancer outcomes. Because GRCh38 and T2T are overwhelmingly Eurocentric, the question remains if these references have applicability outside the ancestral populations that comprise them. Prior to T2T and pangenome, whole genome sequencing of 910 individuals of African descent revealed 296.5 million distinct base pairs, which were assembled into 125,715 African Pan Genome (APG) contigs. These unique sequences represent African ancestry novel genomic sequences whose function was unclear. Here we present provisional efforts to determine the function of APG contigs, and whether they are represented in newer references. To determine the epigenetic potential of the 125,715 APG contigs, we used Emboss Cpgplot to predict CpG islands. We identified 8,353 potential CpG islands, where 6,352 contigs had at least 1 predicted CpG island, and 1 contig had 9. There was weak correlation between contig length, GC content and number of predicted CpG islands suggesting that these sequences represented potentially functional regions. Using unmapped transcriptomic reads from our published African ancestry triple negative breast cancer cohort, we sought to determine the expression potential of these contigs. Unmapped reads mapped to ~9% of the contigs, where ~1100 APG contigs had both predicted CpG islands and alignment of the unmapped transcriptomic reads. This strongly suggests that these APG contigs contain African ancestry-specific regulatory regions and functional gene coding sequences. Preliminary BLASTn queries of contigs with regulatory potential revealed that these sequences may be present in T2T. Mapping to T2T and visualization of expression and CpG islands showed that our predictions matched novel T2T sequences. We anticipated some contigs would map to T2T given one- or two-end placement in GRCh38 and wanted to determine if any of the ~1100 contigs mapped to T2T. Initial analysis of this contig subset shows ~15% fail to map to T2T, indicating that T2T may still fail to capture diversity across ancestry groups. These sequences represent previously unstudied expression and epigenetic potential not captured in the reference genome, and we are working to evaluate all 125,715 sequences. Capturing the diversity across the genome remains extremely important to contextualize these findings and build resources to continue moving precision medicine approaches forward across diverse ancestry groups. Citation Format: Rachel Martini, Kyriaki Founta, Sebastian Maurice, Jason White, Onyinye Balogun, Nyasha Chambwe, Melissa Davis. Unveiling hidden genomic diversity: Exploring epigenetic potential and gene expression in African Pan Genome contig sequences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2948.

Abstract 2702: Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive SMARCB1-deficient kidney cancer that mainly afflicts young individuals of African descent and has few treatment options. Despite the advancements in immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. The majority of RMC patients treated with ICT have experienced aggressively progressive disease as the best response. This hyperprogression was confirmed in our prospective clinical trial of nivolumab plus ipilimumab specifically designed for RMC patients (ClinicalTrials.gov identifier: NCT03274258). To elucidate the mechanisms of resistance to ICT in RMC, we generated high-quality single-cell RNA sequencing data on 23,880 cells from 7 patients at baseline and 2 patients exhibiting hyperprogression after ICT intervention. Our analysis revealed that RMC tumor cells undergo a distinct transcriptional reconfiguration following ICT therapy. This reconfiguration is manifested by upregulation of S100A9 and activation of the MEK/ERK pathway, indicating that RMC tumor cells adopt myeloid-affiliated transcriptional circuits, potentially promoting cell proliferation and leading to hyperprogression. Using a mouse model of RMC, we further demonstrated in a controlled setting that ICT causes hyperprogressive disease via activation of MEK/ERK pathway and an increase of S100A9 positive tumor cells. This process can be reversed by inhibiting master regulators of this “myeloid mimicry” mechanism, such as the CEBPB/p300 complex in our mouse model of RMC, thus restoring sensitivity to ICT. These findings provide novel insights into RMC resistance to ICT and suggest valuable directions for the development of therapeutic strategies. Citation Format: Melinda Soeung, Xinmiao Yan, Li Zhang, Luigi Perelli, Jianfeng Chen, Becky Slack Tidwell, Hania Khan, Courtney N. Le, Truong N. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Ziheng Chen, Sebastian R. Lundgren, Ningping Feng, Ciro Zanca, Menuka Karki, Niki Marie Zacharias Millward, Rong He, Rahul A. Sheth, Bathala K. Tharakeswara, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra-Cuentas, Hsinyi Lu, Cara Haymaker, Ignacio I. Wistuba, Andrew Futreal, Timothy Heffernan, Andrea Viale, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2702.

Epidemiological, immunological, and treatment response profile of patients with lupus nephritis in Brazil.

Brazil has the largest number of individuals of African descent outside Africa and a very admixed population. Among cases of lupus nephritis (LN) in the country, there are differences in incidence, and even in severity, depending on the location and characteristics of the population studied. The aim of this study was to describe the clinical and epidemiological characteristics of LN in Brazil, as well as to determine which of those characteristics would be risk factors for a poor renal prognosis. This was a retrospective, descriptive observational study of patients diagnosed with LN who underwent kidney biopsy between 1999 and 2015 in the Nephrology Department of the Hospital das Clínicas, in São Paulo, Brazil. Data were collected from electronic medical records. We evaluated 398 patients, among who 94.1% and 77.7% tested positive for antinuclear antibodies and anti-DNA antibodies, respectively, whereas 33.7% showed the full-house pattern. The time from LN symptom onset to biopsy was <6months in 47.5% (early biopsy group) and ≥6months in 52.5% (late biopsy group). In the early biopsy group, the chronicity index was lower and the activity index was higher. Multivariate analysis showed that a higher chronicity index was the only independent risk factor for progression to requiring kidney replacement therapy. Late biopsy seems to be associated with negative renal outcomes in LN. However, it seems that a higher chronicity index is the main predictor of a poor renal outcome among patients with LN in Brazil.

Clinicopathologic characteristics and treatment outcomes of pancreatic cancer patients at a tertiary referral hospital in Kenya.

The global incidence of pancreatic cancer (PC) continues to steadily increase whereas its prognosis remains poor. Previous studies have suggested worse outcomes among individuals of African descent. The characteristics of patients with PC in Kenya, and their contemporary management and survival outcomes remain largely unknown. This study aimed to describe the clinical and pathologic characteristics, management, and outcomes of patients diagnosed with PC at Kenyatta National Hospital (KNH), a tertiary referral hospital in Kenya. Records of 242 patients diagnosed with PC at KNH between 1st January 2014 and 30th September 2021 were assessed in this retrospective cohort study. Data on their clinical, histopathologic, and treatment characteristics was presented as mean (± standard deviation) and/or median (interquartile range) for continuous variables and frequency (percentage) for categorical variables. Kaplan-Meier and Cox proportional hazard ratios were used for survival analysis. PC occurred in a young population, the median age being 58.5 years (inter-quartile range 35-88). The majority of tumours (54%) were metastatic at diagnosis, while 28% and 14% were stage III and stage I/II, respectively. Surgical resections with curative intent were performed on 7% overall and 44% of stage I/II cases. The majority of patients with stage I/II disease (52.9%) received chemotherapy whereas the majority with stage III and IV disease received the best supportive care only (62.7% and 64.9%, respectively). Patients who underwent surgical resection (HR for mortality 0.20, 95% CI 0.05-0.83, p = 0.021) and chemotherapy (HR for mortality 0.15, 95% CI 0.08-0.29, p < 0.001) had significantly improved survival, reflecting a more favourable stage of the disease more amenable to aggressive therapies. The median survival time was 3 months and the 1-year survival rate was 32%.

Evaluation of Anthropometric Parameters and Lipid Profile in Subjects with Sickle Cell Traits at Madonna University, Elele, Nigeria

Sickle cell trait is a genetic condition that affects a substantial portion of the global population, particularly individuals of African descent. This study is aimed at evaluating anthropometric parameters and lipid profile parameters in subjects with sickle cell traits in Madonna University Teaching Hospital (MUTH), Elele. 72 subjects consisting of 30 HbAA (control), 21 HbAS, and 21 HbSS, all aged 18–40 years, were recruited for the study. Ethical clearance and informed consent were duly obtained from those involved. Blood samples were collected via venipuncture. Total cholesterol (TCH), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were analyzed using enzymatic spectrophotometric method. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Data were analyzed using Statistical Package for Social Sciences (SPSS) version 21 for Windows 7. The result from this study suggests that there are statistically significant differences (p &lt; 0.05) among the genotype variants, HbAA, HbAS, and HbSS, for the TCH, TG, HDL, LDL, and hemoglobin (Hb) levels. For the control group (HbAA), the TCH is 4.51 mmol/L, TG is 1.21 mmol/L, HDL is 0.95 mmol/L, LDL is 2.81 mmol/L, and Hb is 14.02 g/dL. For the HbAS, the TCH is 4.16 mmol/L, TG is 0.73 mmol/L, HDL is 0.92 mmol/L, LDL is 2.82 mmol/L, and Hb is 13.02 g/dL. For the HbSS, the TCH is 3.39 mmol/L, TG is 0.59 mmol/L, HDL is 0.63 mmol/L, LDL is 2.59 mmol/L, and Hb is 10.85 g/dL. Also, the BMI (kg/m2) showed no statistically significant differences among the genotype variants, HbAA, HbAS, and HbSS (p &gt; 0.05). This concludes that lipid metabolism may be altered in red cell genetic disorders such as sickle cell anemia.

Central Centrifugal Cicatricial Alopecia (CCCA): Unraveling the Complexities of a Scarring Hair Disorder

Central Centrifugal Cicatricial Alopecia (CCCA) represents a distinct form of scarring alopecia predominantly affecting individuals of African descent. This article provides an in-depth examination of the clinical characteristics, pathogenesis, diagnostic challenges, and evolving therapeutic strategies associated with CCCA. By synthesizing current research findings, we aim to enhance awareness, facilitate early diagnosis, and explore emerging interventions for this enigmatic hair disorder. A comprehensive understanding of CCCA is essential for clinicians to optimize patient care and contribute to ongoing efforts in advancing the field of trichology.

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Malarial Encounters and Shifting Racial Recruitment Strategies by the Basel Mission on the Gold Coast, 1828-1849.

In the early- to mid-nineteenth century, European mortality rates in West Africa were the highest in the world. Mortality estimates included nine missionaries sent from the Basel Mission (established in what is now Switzerland) to the Gold Coast (present-day Ghana), eight of whom died between 1828 and 1840, mostly from "fevers." In response to high mortality rates, the Basel Mission recruited several Afro-West Indians to work as Christian missionaries in the Gold Coast, mostly based on the presumption that individuals of African descent would better survive the environment. The decision to recruit Afro-West Indians to evangelize on the Gold Coast seemed to the mission to be a rational decision, one not in need of further justification or an overarching theory of race, environment, and disease. Surprisingly, the Basel Mission did not justify this position Biblically either. Once arrived, the West Indian Christian missionaries mostly lived in the Akwapem hills above Accra at an elevation that would have provided some protection against malaria; subsequently, their mortality rates were significantly lower than the European missionaries. After quinine came to be used as a prophylactic against malaria after 1850, thus lowering European missionary mortality rates, no more Afro-West Indians were recruited by the Basel Mission.

Returning personalized, genetic health test results to individuals of African descent or ancestry in precision medicine research.

Today, many epidemiological studies and biobanks are offering to disclose individual genetic results to their participants, including the National Institutes of Health's All of Us Research Program. Returning hereditary disease risks and pharmacogenetic test results to study participants from racial/ethnic groups that are historically underrepresented in biomedical research poses specific challenges to those participants and the health system writ large. For example, individuals of African descent are underrepresented in research about drug-gene interactions and have a relatively higher proportion of variants of unknown significance, affecting their ability to take clinical action following return of results. In this brief report, we summarize studies published to date concerning the perspectives and/or attitudes of African Americans engaged in genetic research programs to anticipate factors in disclosure protocols that would minimize risks and maximize benefits. A thematic analysis of studies identified (n = 6) lends to themes centered on motivations to engage or disengage in the return of results and integrating research and care. Actionable strategies determined in reaction to these themes center on ensuring adequate system and health education support for participants and personalizing the process for participants engaging in return of results. Overall, we offer these themes and actionable strategies as early guidance to research programs, and provide recommendations to policy makers focused on fair and equitable return of genetic research results to underrepresented research participants.

Paving the way while playing catch up: mitochondrial genetics in African ancestry primary open-angle glaucoma

Glaucoma, the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African descent. Specifically, previous research has indicated that primary open-angle glaucoma (POAG), the most common form of disease, is more prevalent, severe, early-onset, and rapidly-progressive in populations of African ancestry. Recent studies have identified genetic variations that may contribute to the greater burden of disease in this population. In particular, mitochondrial genetics has emerged as a profoundly influential factor in multiple neurodegenerative diseases, including POAG. Several hypotheses explaining the underlying mechanisms of mitochondrial genetic contribution to disease progression have been proposed, including nuclear-mitochondrial gene mismatch. Exploring the fundamentals of mitochondrial genetics and disease pathways within the understudied African ancestry population can lead to groundbreaking advancements in the research and clinical understanding of POAG. This article discusses the currently known involvements of mitochondrial genetic factors in POAG, recent directions of study, and potential future prospects in mitochondrial genetic studies in individuals of African descent.

FRI153 Genetic Variant In Armadillo Repeat Containing 5 Gene (ARMC5) Associates With Salt Sensitivity Of Blood Pressure And Aldosterone In A Caucasian Cohort

Abstract Disclosure: W.W. Parksook: None. M. Heydarpour: None. L. Pojoga: None. A. Gaye: None. G.H. Gibbons: None. G.H. Williams: Advisory Board Member; Self; Cereno. Consulting Fee; Self; Alnylam, Crinetics, Damian, KBP bioscience, Paxel, Relapsa, Unicycive. Grant Recipient; Self; NIH 2 grants. J.S. Williams: Advisory Board Member; Self; Mellicell, Inc. Background: Genetic alterations of ARMC5 have been reported in various adrenal disorders, particularly in primary bilateral macronodular adrenal hyperplasia. Increasing evidence shows that polymorphic variants in ARMC5 are also associated with blood pressure (BP), hypertension, and the renin-angiotensin-aldosterone-system (RAAS) in individuals of African descent; however, little is known about these relationships in Caucasians. Herein, we conducted a deep phenotyping study to assess the association of ARMC5 variants with BP, salt sensitivity of BP (SSBP), and components of the RAAS in Caucasians. Methods: Normotensive and hypertensive, non-diabetic, non-chronic kidney disease, Caucasian participants underwent two dietary interventions at 5-7 days apart (200 mmol/day and 10 mmol/day sodium) to assess SSBP and other hormonal parameters. All participants were genotyped using a Multi-Ethnic-Genotyping-Array. Association analysis and the quality control of the genomic data were assessed by PLINK. Participants with complete data for SSBP and hormonal parameters, who were in salt balance, were included in the analysis (n= 306). Multiple linear regression models were used to assess the association between the genetic variant and outcome parameters. Results: There were 5 single nucleotide polymorphisms in the ARMC5 region. rs4889660 was significantly associated with SSBP in additive and dominant models when adjusted by Bonferroni correction. In a candidate gene analysis, rs4889660 risk allele carriers had greater SSBP than non-risk allele homozygotes (β= 4 mmHg, P= 0.03). Following dietary sodium restriction, rs4889660 risk allele carriers had lower serum aldosterone levels in an upright position (β= -6.9 ng/dl, P= 0.04) and serum aldosterone levels after angiotensin II stimulation (β= -3.0 ng/dl, P= 0.02). There were no differences between plasma renin activity, serum and urinary cortisol levels, and renal plasma flows between genotypes. Conclusions: There was an association between the ARMC5 rs4889660 variant and SSBP in Caucasians. With dietary sodium restriction, aldosterone responses to both upright posture and angiotensin II infusion were lower in the risk allele carriers. The reduced aldosterone responses suggest that an alteration in the RAAS system is not the cause of the SSBP, but is in response to a defect in another sodium-mediated homeostatic mechanism. Presentation: Friday, June 16, 2023

Associations of smoking and alcohol consumption with the development of open angle glaucoma: a retrospective cohort study

ObjectivesTo investigate the associations of alcohol consumption and smoking with the development of perimetric glaucoma in patients with suspected glaucoma.DesignA retrospective cohort study of patients suspected to have glaucoma enrolled...

Racial Differences in the Diagnostic Accuracy of OCT Angiography Macular Vessel Density for Glaucoma

To evaluate and compare the diagnostic accuracy of macular vessel density (VD) measured by OCT angiography (OCTA) in individuals of African descent (AD) and European descent (ED) with open-angle glaucoma. Observational, cross sectional study. A total of 176 eyes of 123 patients with glaucoma and 140 eyes of 88 healthy participants from the Diagnostic Innovations in Glaucoma Study. Whole-image ganglion cell complex (wiGCC) thickness and macular VD (parafoveal VD and perifoveal VD) were obtained from 6× 6 macula scans. Area under the receiver operating characteristic (AUROC) curves were used to evaluate the diagnostic accuracy of macular VD and ganglion cell complex (GCC) thickness in AD and ED participants after adjusting for confounders such as age, visual field mean deviation (VF MD), signal strength index, axial length, self-reported hypertension and diabetes. Macular VD and wiGCC measurements. Parafoveal and perifoveal VD were significantly lower in ED than AD patients with glaucoma. Parafoveal and perifoveal VD performed significantly worse in AD participants compared with ED participants for detection of glaucoma (adjusted AUROC, 0.75 [95% confidence interval (CI), 0.62, 0.87], 0.85 [95% CI, 0.79, 0.90], P= 0.035; and 0.82 [95% CI, 0.70, 0.92], 0.91 [95% CI, 0.87, 0.94], respectively; P= 0.020). In contrast to VD, diagnostic accuracy of GCC thickness was similar in AD and ED individuals (adjusted AUROC, 0.89 [95% CI, 0.79, 0.96], 0.92 [95% CI, 0.86, 0.96], respectively; P= 0.313). The diagnostic accuracies of both macular VD and GCC thickness for differentiating between glaucoma and healthy eyes increased with increasing VF MD in both AD and ED participants. Diagnostic performance of OCTA macular VD, but not GCC thickness, for glaucoma detection varies by race. Moreover, macular VD parameters had lower accuracy for detecting glaucoma in AD individuals than in ED individuals. The diagnostic performance of macular VD is race-dependent, and, therefore, race should be taken into consideration when interpreting macular OCTA results. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract IA028: Renal medullary carcinoma: Discovery and validation of tailored treatment strategies

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that predominantly afflicts young individuals of African descent harboring the sickle cell trait and is defined by loss of the SMARCB1 tumor suppressor. Notably, the anti-VEGF and mTOR targeted therapies and standard immune checkpoint inhibitor strategies developed for clear cell renal cell carcinoma (ccRCC) are completely ineffective against RMC. Conversely, platinum-based cytotoxic chemotherapy regimens are the preferred first-line therapy yielding a response rate of 29% and median survival of 13 months from diagnosis. There is clearly a need for tailored treatment strategies for this deadly disease. To meet this challenge, we have developed a dedicated research and clinical team and bench-to-bedside pipeline that supported the comprehensive profiling of patient samples and the development of multiple RMC cell lines, three patient-derived xenografts, and the first genetically engineered mouse model of RMC. These tools informed the development of the first three clinical trials dedicated to RMC (NCT03587662, NCT03274258, and NCT05347212 at clinicaltrials.gov), as well as the establishment of effective second-line, and more recently third-line, therapeutic strategies that produce objective responses and occasionally cures for this deadly disease. Using these approaches, the majority of patients diagnosed with RMC today will survive beyond a year from diagnosis. The progress made has been supported by a passionate patient advocacy group and the awareness raised has resulted in our current clinical volume of caring for 3-5 patients with RMC per week. Emerging insights into the pathophysiology of RMC have allowed us to uncover an "exercise paradox" whereby the hypoxia induced by high-intensity exercise in the setting of sickle cell trait may be the strongest modifiable risk factor for RMC. The unique biological processes behind the exercise paradox also underlie the distinct biological adaptation of RMC to true hypoxia via the loss of SMARCB1, as opposed to the pseudohypoxia observed in ccRCC driven by VHL loss. Whereas pseudohypoxic tumors are sensitive to VEGF targeting, SMARCB1 loss confers resistance to the hypoxia induced by in vivo inhibition of angiogenesis. These insights have allowed us to identify immediately actionable therapeutic targets paving the way for the next generation of clinical trials for RMC. The benchmark goal is to improve the median survival of patients with RMC to 24 months by 2025 and to 5 years by 2030. Citation Format: Pavlos Msaouel. Renal medullary carcinoma: Discovery and validation of tailored treatment strategies [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA028.

Stroke Experiences and Unmet Needs of Individuals of African Descent Living in High-Income Economy Countries: a Qualitative Meta-Synthesis.

Stroke service disparities experienced by individuals of African descent highlight the need to optimize services. While qualitative studies have explored participants' unique experiences and service needs, a comprehensive synthesis is lacking. To address current knowledge gaps, this review aimed to synthesize existing literature on the experiences of individuals of African descent impacted by a stroke living in high-income economy countries in terms of stroke prevention, management, and care. A qualitative meta-synthesis incorporating a meta-study approach was conducted to obtain comprehensive and interpretive insights on the study topic. Four databases were searched to identify qualitative English-language studies published in the year 2022 or earlier on the experiences of adults of African descent who were at risk or impacted by a stroke and living in high-income economy countries. Study methods, theory, and data were analyzed using descriptive and interpretive analyses. Thirty-seven studies met our inclusion criteria, including 29 journal articles and 8 dissertations. Multiple authors reported recruitment as a key challenge in study conduct. Multiple existing theories and frameworks of health behaviours, beliefs, self-efficacy, race, and family structure informed research positionality, questions, and analysis across studies. Participant experiences were categorized as (1) engagement in stroke prevention activities and responses to stroke symptoms, (2) self-management and self-identity after stroke, and (3) stroke care experiences. This study synthesizes the experiences and needs of individuals of African descent impacted by stroke. Findings can help tailor stroke interventions across the stroke care continuum, as they suggest the need for intersectional and culturally humble care approaches.

Reducing saturated fat intake lowers LDL-C but increases Lp(a) levels in African Americans: the GET-READI feeding trial

Reducing dietary saturated fatty acids (SFA) intake results in a clinically significant lowering of low-density lipoprotein cholesterol (LDL-C) across ethnicities. In contrast, dietary SFA’s role in modulating emerging cardiovascular risk factors in different ethnicities remains poorly understood. Elevated levels of lipoprotein(a) [Lp(a)], an independent cardiovascular risk factor, disproportionally affect individuals of African descent. Here, we assessed the responses in Lp(a) levels to dietary SFA reduction in 166 African Americans enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Participants were fed two diets in random order for 5 weeks each: 1) an average American diet (AAD) (37% total fat: 16% SFA), and 2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) diet (25% total fat: 6% SFA). The participants’ mean age was 35 years, 70% were women, the mean BMI was 28 kg/m2, and the mean LDL-C was 116 mg/dl. Compared to the AAD diet, LDL-C was reduced by the DASH-type diet (mean change: −12 mg/dl) as were total cholesterol (−16 mg/dl), HDL-C (−5 mg/dl), apoA-1 (−9 mg/dl) and apoB-100 (−5 mg/dl) (all P < 0.0001). In contrast, Lp(a) levels increased following the DASH-type diet compared with AAD (median: 58 vs. 44 mg/dl, P < 0.0001). In conclusion, in a large cohort of African Americans, reductions in SFA intake significantly increased Lp(a) levels while reducing LDL-C. Future studies are warranted to elucidate the mechanism(s) underlying the SFA reduction-induced increase in Lp(a) levels and its role in cardiovascular risk across populations.

Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells

Canonical splice site variants affecting the 5' GT and 3' AG nucleotides of introns result in severe missplicing and account for about 10% of disease-causing genomic alterations. Treatment of such variants has proven challenging due to the unstable mRNA or protein isoforms that typically result from disruption of these sites. Here, we investigate CRISPR-Cas9-mediated adenine base editing for such variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We validate a CFTR expression minigene (EMG) system for testing base editing designs for two different targets. We then use the EMG system to test non-standard single-guide RNAs with either shortened or lengthened protospacers to correct the most common cystic fibrosis-causing variant in individuals of African descent (c.2988+1G>A). Varying the spacer region length allowed placement of the editing window in a more efficient context and enabled use of alternate protospacer adjacent motifs. Using these modifications, we restored clinically significant levels of CFTR function to human airway epithelial cells from two donors bearing the c.2988+1G>A variant.

Illuminating a Hidden Site

This study was provoked by the recent detection of 541 unmarked burials signifying the recovery of the African American Burial Ground (AABG) on the grounds of Woodland Cemetery (WC) at Clemson University, South Carolina. A case study analysis of this coexistent sacred burial ground, initially for enslaved individuals of African descent interred during the pre-emancipation plantation era, seeks answers to fundamental questions: Was Clemson University aware of the AABG’s existence, and why did it take so long to act on preserving this sacred ground, historically known to the local descendant community? This study reveals that Clemson University’s negligence and cultural erasure during the 20th century has in the present day given way to an institutional commitment to truth-telling brought on by student activism and concerns about long-standing social inequities. The recovery of the AABG aligns with and contributes to work on “Black Geographies” and “Black Landscapes” (Woods, 2000; McKittrick &amp; Woods, 2007; Boone, 2020; Hood 2020). The study examines the national reckoning among universities as they consider the legacy of slavery at their institutions and navigate justice (Wilder, 2014; Harris, et al., 2019). This research draws upon the author’s larger study on South Carolina’s landscape legacy and the synthesis of novel typologies beyond the normative classification of cultural landscapes (Padua, 2020). The commemoration of the AABG on campus is explored as a potential “reconciliatory landscape” conceptualized through the lens of “retrospective justice” drawn from the human rights literature (Russell, 2003; Roth, 2004). Status-quo attitudes are questioned as disruption to the norm instigates change and asserts social justice.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N=20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.