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Defining curative endpoints for transfusion-dependent β-thalassemia in the era of gene therapy and gene editing.
Corbacioglu, S, Frangoul, H, Locatelli, F, Hobbs, W, Walters, M
American journal of hematology. 2024;(3):422-429
Abstract
β-thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion-dependent β-thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life-long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end-organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing-based treatments for patients with TDT with the potential to provide a one-time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.
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When and what to eat? A scoping review of health outcomes of fasting in conjunction with a low-carbohydrate diet.
Salehi, N, Walters, M
The British journal of nutrition. 2023;(10):1677-1692
Abstract
Over the last several decades, there has been an increase in chronic diseases such as neurodegenerative, inflammatory, cardiovascular disease (CVD) and cancer. Two eating patterns, a low-carbohydrate diet (LCD) and fasting, have been researched independently over this period and found to be beneficial in reducing many of these chronic diseases' detrimental effects. However, there have been limited studies about the synergy of these eating patterns. This current scoping review aims to explore the evidence of the health outcomes of using a LCD in conjunction with fasting. Four databases were searched, and fifteen articles were found that fit the inclusion criteria. The articles reported positive effects of combining the two eating patterns for type 2 diabetes, CVD, inflammatory conditions and weight reduction and maintenance. LCD and fasting together provide synergy in decreasing metabolic syndrome (as the key causes of chronic illnesses), such as insulin levels, fasting glucose, blood pressure, TAG and regulating lipid profile. Due to the paucity of research, further high-quality studies are needed to substantiate this evidence.
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Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.
Willeit, P, Tschiderer, L, Allara, E, Reuber, K, Seekircher, L, Gao, L, Liao, X, Lonn, E, Gerstein, HC, Yusuf, S, et al
Circulation. 2020;(7):621-642
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BACKGROUND To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.
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Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.
Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, van der Laan, SW, Gretarsdottir, S, et al
Nature genetics. 2019;(7):1192-1193
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area.
Mosconi, L, Walters, M, Sterling, J, Quinn, C, McHugh, P, Andrews, RE, Matthews, DC, Ganzer, C, Osorio, RS, Isaacson, RS, et al
BMJ open. 2018;8(3):e019362
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Plain language summary
Alzheimer’s disease (AD) is the most common form of dementia, affecting nearly 34 million people worldwide. It has been estimated that one in every three cases of AD may be attributable to diet and lifestyle factors. The aim of this study was to investigate the effects of lifestyle and vascular-related risk factors for AD. Researchers studied the brain scans of 116 healthy adults aged 30-60 years. They collected information on factors related to lifestyle, such as diet, physical activity and intellectual enrichment. They also looked at markers for vascular risk such as body mass index (BMI), cholesterol and homocysteine, as well as cognitive function. The researchers found that a Mediterranean-style diet and good insulin sensitivity were both associated with a healthier brain structure. A better score for intellectual enrichment and lower BMI were both associated with better cognition. They concluded that adopting a Mediterranean-style diet and maintaining a healthy weight might reduce the risk of developing AD.
Abstract
OBJECTIVE To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN Cross-sectional, observational. SETTING Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: βs≥0.26, insulin sensitivity βs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (βs≥0.25 P≤0.001), as were those between overweight and lower cognition (βs≥-0.22, P≤0.01). CONCLUSIONS In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.
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Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.
Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, van der Laan, SW, Gretarsdottir, S, et al
Nature genetics. 2018;(4):524-537
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Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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One-unit versus two-unit cord-blood transplantation for hematologic cancers.
Wagner, JE, Eapen, M, Carter, S, Wang, Y, Schultz, KR, Wall, DA, Bunin, N, Delaney, C, Haut, P, Margolis, D, et al
The New England journal of medicine. 2014;(18):1685-94
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BACKGROUND Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. METHODS Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival. RESULTS Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit. CONCLUSIONS We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00412360.).
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Quorum sensing in Escherichia coli and Salmonella.
Walters, M, Sperandio, V
International journal of medical microbiology : IJMM. 2006;(2-3):125-31
Abstract
Quorum sensing in Escherichia coli and Salmonella has been an elusive topic for a long time. However, in the past 8 years, several research groups have demonstrated that these bacteria use several quorum-sensing systems, such as: the luxS/AI-2, AI-3/epinephrine/norepinephrine, indole, and the LuxR homolog SdiA to achieve intercellular signaling. The majority of these signaling systems are involved in interspecies communication, and the AI-3/epinephrine/norepinephrine signaling system is also involved in interkingdom communication. Both E. coli and Salmonella reside in the human intestine, which is the largest and most complex environment in the mammalian host. The observation that these bacteria evolved quorum-sensing systems primarily involved in interspecies communication may constitute an adaptation to this environment. The gastrointestinal tract harbors a high density and diversity of bacterial cells, with the majority of the flora residing in the colon (10(11)-10(12) bacterial cells/ml). Given the enormous number and diversity of bacteria inhabiting the gastrointestinal environment, it should not be surprising that the members of this community communicate amongst themselves and with the host itself to coordinate a variety of adaptive processes.