Publications by authors named "Akshay Sharma"

126 Publications

Single-nucleotide-level mapping of DNA regulatory elements that control fetal hemoglobin expression.

Nat Genet 2021 May 6. Epub 2021 May 6.

Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Pinpointing functional noncoding DNA sequences and defining their contributions to health-related traits is a major challenge for modern genetics. We developed a high-throughput framework to map noncoding DNA functions with single-nucleotide resolution in four loci that control erythroid fetal hemoglobin (HbF) expression, a genetically determined trait that modifies sickle cell disease (SCD) phenotypes. Specifically, we used the adenine base editor ABEmax to introduce 10,156 separate A•T to G•C conversions in 307 predicted regulatory elements and quantified the effects on erythroid HbF expression. We identified numerous regulatory elements, defined their epigenomic structures and linked them to low-frequency variants associated with HbF expression in an SCD cohort. Targeting a newly discovered γ-globin gene repressor element in SCD donor CD34 hematopoietic progenitors raised HbF levels in the erythroid progeny, inhibiting hypoxia-induced sickling. Our findings reveal previously unappreciated genetic complexities of HbF regulation and provide potentially therapeutic insights into SCD.
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http://dx.doi.org/10.1038/s41588-021-00861-8DOI Listing
May 2021

Disease severity impacts plerixafor-mobilized stem cell collection in patients with sickle cell disease.

Blood Adv 2021 May;5(9):2403-2411

Cellular and Molecular Therapeutics Branch, NHLBI/NIDDK, National Institutes of Health, Bethesda, MD.

Recent studies suggest that plerixafor mobilization and apheresis in patients with sickle cell disease (SCD) is safe and can allow collection of sufficient CD34+ hematopoietic stem cell (HSC) collection for clinical gene therapy applications. However, the quantities of plerixafor-mobilized CD34+ cells vary between different SCD patients for unknown reasons. Twenty-three participants with SCD underwent plerixafor mobilization followed by apheresis, processing, and HSC enrichment under a phase 1 safety and efficacy study conducted at 2 institutions. Linear regression or Spearman's correlation test was used to assess the relationships between various hematologic and clinical parameters with total CD34+ cells/kg collected. Median CD34+ cells/kg after 2 or fewer mobilization and apheresis cycles was 4.0 × 106 (range, 1.5-12.0). Similar to what is observed generally, CD34+ yield correlated negatively with age (P < .001) and positively with baseline (P = .003) and preapheresis blood CD34+ cells/µL (P < .001), and baseline white blood cell (P = .01) and platelet counts (P = .03). Uniquely for SCD, CD34+ cell yields correlated positively with the number of days hydroxyurea was held (for up to 5 weeks, P = .01) and negatively with markers of disease severity, including hospitalization frequency within the preceding year (P = .01) and the number of medications taken for chronic pain (P = .002). Unique SCD-specific technical challenges in apheresis were also associated with reduced CD34+ cell collection efficiency and purification. Here, we describe factors that impact plerixafor mobilization success in patients with SCD, confirming known factors as described in other populations in addition to reporting previously unknown disease specific factors in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03226691.
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http://dx.doi.org/10.1182/bloodadvances.2021004232DOI Listing
May 2021

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Transplant Cell Ther 2021 Apr 22. Epub 2021 Apr 22.

CIBMTR® (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN.

Background: Young adult (YA) survivors of allogeneic hematopoietic cell transplant (HCT) are at risk for late psychosocial challenges, including inability to return to work post-HCT. However, work-related outcomes in this population remain understudied.

Objectives: To assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YA and analyze the patient-, disease-, and HCT-related factors associated with their work status at 1-year post-HCT.

Study Design: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we described post-HCT work status (full-time, part-time work, unemployed, and medical disability) of YA HCT survivors (N=1365) who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at four timepoints: 6-months, 1-, 2-, and 3-year post-HCT. Percentages of post-HCT work status categories at the 1-year timepoint were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression.

Results: From 6 months to 3 years post-HCT, the percentage of survivors working full-time and part-time increased from 18.3% to 50.7%, and from 6.9% to 10.5%, respectively. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1-year post-HCT. Female sex (Odds ratio [OR] 0.55; 95% confidence interval [CI] 0.40-0.77), HCT-comorbidity index (HCT-CI) score ≥3 (OR 0.57; 95% CI 0.39-0.82), pre-HCT unemployment (OR 0.37; 95% CI 0.24-0.56), and medical disability (OR 0.44; 95% CI 0.28-0.70), development of grade 3-4 acute graft vs. host disease (OR 0.52; 95% CI 0.34-0.80), and relapse within one-year post-HCT (OR 0.34; 95% CI 0.21-0.56) were associated with lower likelihood of employment at 1-year post-HCT. Compared to myeloablative conditioning with total body irradiation (TBI), myeloablative conditioning without TBI (OR 1.71; 95% CI 1.16-2.53) was associated with higher likelihood of employment at 1-year post-HCT. Graduate school level education (OR 2.47; 95% CI 1.49-4.10) was also associated with higher likelihood of employment at 1-year post-HCT.

Conclusions: While the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective return to work supportive interventions in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.04.013DOI Listing
April 2021

Hematopoietic stem cell transplantation for people with β-thalassaemia.

Cochrane Database Syst Rev 2021 04 21;4:CD008708. Epub 2021 Apr 21.

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In β-thalassaemia there is an underproduction of β-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for β-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review.

Objectives: To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent β-thalassaemia.

Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021.

Selection Criteria: Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen).

Data Collection And Analysis: Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review.

Main Results: No relevant trials were retrieved after a comprehensive search of the literature.

Authors' Conclusions: We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent β-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.
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http://dx.doi.org/10.1002/14651858.CD008708.pub5DOI Listing
April 2021

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Apr 16. Epub 2021 Apr 16.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
April 2021

Genetic therapies for the first molecular disease.

J Clin Invest 2021 Apr;131(8)

Department of Hematology.

Sickle cell disease (SCD) is a monogenic disorder characterized by recurrent episodes of severe bone pain, multi-organ failure, and early mortality. Although medical progress over the past several decades has improved clinical outcomes and offered cures for many affected individuals living in high-income countries, most SCD patients still experience substantial morbidity and premature death. Emerging technologies to manipulate somatic cell genomes and insights into the mechanisms of developmental globin gene regulation are generating potentially transformative approaches to cure SCD by autologous hematopoietic stem cell (HSC) transplantation. Key components of current approaches include ethical informed consent, isolation of patient HSCs, in vitro genetic modification of HSCs to correct the SCD mutation or circumvent its damaging effects, and reinfusion of the modified HSCs following myelotoxic bone marrow conditioning. Successful integration of these components into effective therapies requires interdisciplinary collaborations between laboratory researchers, clinical caregivers, and patients. Here we summarize current knowledge and research challenges for each key component, emphasizing that the best approaches have yet to be developed.
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http://dx.doi.org/10.1172/JCI146394DOI Listing
April 2021

Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR.

Leukemia 2021 Mar 30. Epub 2021 Mar 30.

Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5-2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25-2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23-9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63-2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51-2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31-2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37-3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM.
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http://dx.doi.org/10.1038/s41375-021-01213-5DOI Listing
March 2021

Outcomes of pediatric patients who relapse after first HCT for acute leukemia or MDS.

Bone Marrow Transplant 2021 Mar 19. Epub 2021 Mar 19.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission.
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http://dx.doi.org/10.1038/s41409-021-01267-0DOI Listing
March 2021

Broad spectrum antibiotics and risk of graft-versus-host disease in pediatric patients transplanted for acute leukemia: association of carbapenem use with risk of acute GVHD.

Transplant Cell Ther 2021 Feb 21;27(2):177.e1-177.e8. Epub 2020 Dec 21.

Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA.

Variation in the gastrointestinal microbiota after hematopoietic cell transplantation has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD-risk in pediatric patients transplanted for acute leukemia. We performed a retrospective analysis in a dataset merged from two sources: (1) Center for International Blood and Marrow Transplant Research, an observational transplant registry, and (2) Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to three classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) anti-pseudomonal penicillins and (3) carbapenems. The primary outcome was grade 2-4 aGVHD; secondary outcomes were grade 3-4 aGVHD and lower gastrointestinal (GI) GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (sub-cohort) included transplant characteristics, GVHD-risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2,550 patients at 36 centers; the sub-cohort included 1,174 patients. In adjusted models, carbapenems were associated with an increased risk of grade 2-4 aGVHD in the full cohort (aOR 1.24, 95%CI 1.02-1.51) and sub-cohort (subHR 1.31, 95%CI 0.99-1.72), as well as with an increased risk of grade 3-4 aGVHD (subHR 1.77, 95%CI 1.25-2.52). Early carbapenem exposure (prior to day 0) especially impacted aGVHD-risk. For antipseudomonal penicillins the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad spectrum antibiotics, should be used judiciously in pediatric transplant patients to minimize aGVHD-risk. Further research is needed to clarify the mechanism underlying this association.
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http://dx.doi.org/10.1016/j.jtct.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946150PMC
February 2021

Proteomic analysis of TGFβ-induced A549 secretome identifies putative regulators of epithelial-mesenchymal transition.

Biotechnol Appl Biochem 2021 Feb 9. Epub 2021 Feb 9.

Division of Cancer Biology, CSIR-Central Drug Research Institute, CDRI, Lucknow, UP, India.

Imparting epithelial to mesenchymal transition (EMT) during cellular transformation, a major driving force behind tumor progression, is one of the notorious oncogenic activities of transforming growth factor β (TGFβ); however, the secretary factors released during TGFβ-induced EMT that may have role in potentiating EMT and tumor progression are poorly known. This study was undertaken to identify such secreted protein factors from TGFβ-induced A549 cells cultured in serum-free chemically defined medium (Freestyle ) using Matrix Assisted Laser Desorption Ionization-Time of flight/Time of flight (MALDI-TOF/TOF) mass spectrometry. We identified some of the potential factors such as ESR, ANXA2, ALDH1A, TGFβ-induced protein ig-h3, and PAI-1 that were not only secreted but some were also elevated in TGFβ-induced A549 cells. Interestingly, these factors are widely reported to play crucial role in EMT induction and progression, which not only validates our findings but also opens avenues for further investigation, if upon secretion they act exogenously through certain receptors to potentiate cellular signaling involved in EMT induction and tumor progression.
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http://dx.doi.org/10.1002/bab.2121DOI Listing
February 2021

Systematic reviews in hematopoietic cell transplantation and cellular therapy: considerations and guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research late effects and quality of life working committee.

Bone Marrow Transplant 2021 Apr 29;56(4):786-797. Epub 2021 Jan 29.

Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.
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http://dx.doi.org/10.1038/s41409-020-01199-1DOI Listing
April 2021

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study.

Lancet Haematol 2021 Mar 19;8(3):e185-e193. Epub 2021 Jan 19.

Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Background: Haematopoietic stem-cell transplantation (HSCT) recipients are considered at high risk of poor outcomes after COVID-19 on the basis of their immunosuppressed status, but data from large studies in HSCT recipients are lacking. This study describes the characteristics and outcomes of HSCT recipients after developing COVID-19.

Methods: In response to the pandemic, the Center for International Blood and Marrow Transplant Research (CIBMTR) implemented a special form for COVID-19-related data capture on March 27, 2020. All patients-irrespective of age, diagnosis, donor type, graft source, or conditioning regimens-were included in the analysis with data cutoff of Aug 12, 2020. The main outcome was overall survival 30 days after a COVID-19 diagnosis. Overall survival probabilities were calculated using Kaplan-Meier estimator. Factors associated with mortality after COVID-19 diagnosis were examined using Cox proportional hazard models.

Findings: 318 HSCT recipients diagnosed with COVID-19 were reported to the CIBMTR. The median time from HSCT to COVID-19 diagnosis was 17 months (IQR 8-46) for allogeneic HSCT recipients and 23 months (8-51) for autologous HSCT recipients. The median follow-up of survivors was 21 days (IQR 8-41) for allogeneic HSCT recipients and 25 days (12-35) for autologous HSCT recipients. 34 (18%) of 184 allogeneic HSCT recipients were receiving immunosuppression within 6 months of COVID-19 diagnosis. Disease severity was mild in 155 (49%) of 318 patients, while severe disease requiring mechanical ventilation occurred in 45 (14%) of 318 patients-ie, 28 (15%) of 184 allogeneic HSCT recipients and 17 (13%) of 134 autologous HSCT recipients. At 30 days after the diagnosis of COVID-19, overall survival was 68% (95% CI 58-77) for recipients of allogeneic HSCT and 67% (55-78) for recipients of autologous HSCT. Age 50 years or older (hazard ratio 2·53, 95% CI 1·16-5·52; p=0·020); male sex (3·53; 1·44-8·67; p=0·006), and development of COVID-19 within 12 months of transplantation (2·67, 1·33-5·36; p=0·005) were associated with a higher risk of mortality among allogeneic HSCT recipients, and a disease indication of lymphoma was associated with a higher risk of mortality compared with plasma cell disorder or myeloma (2·41, [1·08-5·38]; p=0·033) in autologous HSCT recipients.

Interpretation: Recipients of autologous and allogeneic HSCT who develop COVID-19 have poor overall survival. These data emphasise the need for stringent surveillance and aggressive treatment measures in HSCT recipients who develop COVID-19.

Funding: American Society of Hematology; Leukemia and Lymphoma Society; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Cancer Institute; Health Resources and Services Administration; Office of Naval Research.
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http://dx.doi.org/10.1016/S2352-3026(20)30429-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816949PMC
March 2021

Therapeutic gene editing strategies using CRISPR-Cas9 for the β-hemoglobinopathies.

J Biomed Res 2020 Nov;35(2):115-134

Department of Cellular and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

With advancements in gene editing technologies, our ability to make precise and efficient modifications to the genome is increasing at a remarkable rate, paving the way for scientists and clinicians to uniquely treat a multitude of previously irremediable diseases. CRISPR-Cas9, short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9, is a gene editing platform with the ability to alter the nucleotide sequence of the genome in living cells. This technology is increasing the number and pace at which new gene editing treatments for genetic disorders are moving toward the clinic. The β-hemoglobinopathies are a group of monogenic diseases, which despite their high prevalence and chronic debilitating nature, continue to have few therapeutic options available. In this review, we will discuss our existing comprehension of the genetics and current state of treatment for β-hemoglobinopathies, consider potential genome editing therapeutic strategies, and provide an overview of the current state of clinical trials using CRISPR-Cas9 gene editing.
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http://dx.doi.org/10.7555/JBR.34.20200096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038529PMC
November 2020

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.

N Engl J Med 2021 01 5;384(3):252-260. Epub 2020 Dec 5.

From the Sarah Cannon Center for Blood Cancer at the Children's Hospital at TriStar Centennial, Nashville (H.F., J.D.), and St. Jude Children's Research Hospital, Memphis (A.S.) - both in Tennessee; Vertex Pharmaceuticals (D.A., B.K.E., J.L.-H., A.Y.) and Boston University School of Medicine (M.H.S.), Boston, and CRISPR Therapeutics, Cambridge (Y.-S.C., T.W.H., A. Kernytsky, S. Soni) - both in Massachusetts; the University of Milan, Milan (M.D.C.), and Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Rome (F.L.); the University of Regensburg, Regensburg (J. Foell, S.C.), and Children's University Hospital, University of Tübingen, Tübingen (R.H.) - both in Germany; Imperial College Healthcare NHS Trust, St. Mary's Hospital, London (J. de la Fuente); Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.G.); the University of Athens, Athens (A. Kattamis); BC Children's Hospital, University of British Columbia, Vancouver (A.M.L.), and the Hospital for Sick Children-University of Toronto, Toronto (D.W.) - both in Canada; Columbia University (M.Y.M.) and the Joan and Sanford I. Weill Medical College of Cornell University (S. Sheth), New York; Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris (M.M.); and the University of Illinois at Chicago, Chicago (D.R.).

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
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http://dx.doi.org/10.1056/NEJMoa2031054DOI Listing
January 2021

FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1.

Mol Cancer Res 2021 02 13;19(2):261-273. Epub 2020 Nov 13.

Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.

Glycogen synthase kinase 3β (GSK3β), an ubiquitously expressed serine/threonine kinase is reported to be overexpressed and hyperactivated in cancers including acute myeloid leukemia (AML) where it promotes self-renewal, growth, and survival of AML cells. Therefore, GSK3β inhibition results in AML cell growth inhibition and myeloid differentiation. Here we identified master transcription factor PU.1 of monocyte-macrophage differentiation pathway as potential GSK3β target. We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. This GSK3-dependent degradation of PU.1 by FBW7 inhibited monocyte-macrophage differentiation. We further showed that a phospho-deficient PU.1 mutant (PU.1-S41, S140A) neither bound to FBW7 nor was degraded by it. Consequently, PU.1-S41, S140A retained its transactivation, DNA-binding ability and promoted monocyte-macrophage differentiation of U937 cells even without phorbol 12-myristate 13-acetate (PMA) treatment. We further showed that FBW7 overexpression inhibited both PMA as well as M-CSF-induced macrophage differentiation of myeloid cell lines and peripheral blood mononuclear cells (PBMC) from healthy volunteers, respectively. Contrarily, FBW7 depletion promoted differentiation of these cells even without any inducer suggesting for a robust role of GSK3β-FBW7 axis in negatively regulating myeloid differentiation. Furthermore, we also recapitulated these findings in PBMCs isolated from patients with leukemia where FBW7 overexpression markedly inhibited endogenous PU.1 protein levels. In addition, PBMCs also showed enhanced differentiation when treated with M-CSF and GSK3 inhibitor (SB216763) together compared with M-CSF treatment alone. IMPLICATIONS: Our data demonstrate a plausible mechanism behind PU.1 restoration and induction of myeloid differentiation upon GSK3β inhibition and further substantiates potential of GSK3β as a therapeutic target in AML.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0268DOI Listing
February 2021

Neighborhood poverty and pediatric allogeneic hematopoietic cell transplantation outcomes: a CIBMTR analysis.

Blood 2021 01;137(4):556-568

CIBMTR, National Marrow Donor Program/Be The Match, Minneapolis, MN.

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.
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http://dx.doi.org/10.1182/blood.2020006252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845011PMC
January 2021

Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States.

Cancer 2021 Feb 21;127(4):609-618. Epub 2020 Oct 21.

Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.

Methods: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.

Results: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.

Conclusions: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.
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http://dx.doi.org/10.1002/cncr.33232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855526PMC
February 2021

Chebulinic acid inhibits MDA-MB-231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy.

Cell Biol Int 2020 Dec 16;44(12):2553-2569. Epub 2020 Sep 16.

Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.

Triple-negative breast cancers (TNBC) are highly aggressive and drug resistant accounting for majority of cases with poor outcome. Purified natural compounds display substantial anticancer activity with reduced cytotoxicity providing a new avenue to combat TNBC. Chebulinic acid (CA), a polyphenol derived from the fruits of various medicinal plants has potent anticancer activity. Here, we demonstrate that CA shows significant cytotoxicity against triple negative MDA-MB-231 cells. CA exhibited cytotoxicity to MDA-MB-231 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Further, CA mitigated MDA-MB-231 cells viability and proliferation as shown by reduced live cell count, crystal violet staining, colony formation assay, soft agar assay and cell cycle analysis. Wound healing assay and trans-well migration assay demonstrated that CA significantly inhibited migration of MDA-MB-231 cells. Also reduced MMP9 expression was observed in CA-treated cells by gelatin zymography. CA negatively regulated mesenchymal characteristics of MDA-MB-231 cells demonstrated by F-actin staining and reduced expression of N-cadherin by confocal microscopy and western blot analysis. Annexin V/propidium iodide (PI) and active caspase-3 staining showed that CA was able to induce apoptosis in MDA-MB-231 cells but did not activate caspase-3. Two-dimensional gel electrophoresis based proteomic analysis demonstrated that CA regulated proteins belonging to the oxidative stress pathway, apoptotic pathway and proteins with antiproliferative activity. Western blot analysis analysis revealed that CA negatively regulated superoxide dismutase 1 (SOD1) and enhanced oxidative stress in MDA-MB-231 cells. SOD1 in-gel activity assay also showed reduced SOD1 activity upon CA treatment. Overexpression studies with GFP-LC3 and tandem tagged RFP-GFP-LC-3 also demonstrated enhanced autophagy upon CA treatment.
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http://dx.doi.org/10.1002/cbin.11463DOI Listing
December 2020

Germline Gene Editing for Sickle Cell Disease.

Am J Bioeth 2020 08;20(8):46-49

St. Jude Children's Research Hospital.

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http://dx.doi.org/10.1080/15265161.2020.1781970DOI Listing
August 2020

Willingness of Adults in the United States to Receive HIV Testing in Dental Care Settings: Cross-Sectional Web-Based Study.

JMIR Public Health Surveill 2020 07 21;6(3):e17677. Epub 2020 Jul 21.

Center for Sexuality and Health Disparities, University of Michigan School of Nursing, Ann Arbor, MI, United States.

Background: The Centers for Disease Control and Prevention estimates that 1.1 million people in the United States are living with HIV and 1 in 8 are estimated to be unaware of their serostatus. Little is known about whether individuals would consider being tested for HIV in nontraditional health care settings such as a dentist's office. Studies in selected US cities have indicated high acceptability of receiving an HIV test among people attending dental clinics. However, we are not aware of studies that have assessed willingness to receive HIV testing in dental care settings at a national level.

Objective: Using a web-based sample of adult residents of the United States, we sought to assess the self-reported willingness to receive any type of HIV testing (ie, oral fluid rapid testing, finger-stick blood rapid testing, or venipuncture blood testing) in a dental care setting and evaluate independent associations of willingness with the extent to which dental care providers were perceived as knowledgeable about HIV and how comfortable participants felt discussing HIV with their dental care providers.

Methods: Participants were recruited using banner advertisements featured on social networking platforms (Facebook and Instagram) from December 2018 to February 2019. Demographic and behavioral data including information on sexual behaviors in the past 6 months, HIV testing history, and dental/health care-seeking history were collected using an anonymous web-based survey. Willingness to receive any type of HIV testing in a dental care setting was assessed on 4-point scale from very willing to very unwilling. Factors independently associated with participants' willingness were identified using a multivariable logistic regression model.

Results: Of the 421 participants in our study aged 18 to 73 years, 271 (64.4%) reported having oral sex, 197 (46.8%) reported having vaginal sex, and 136 (32.3%) reported having anal sex in the past 6 months. Approximately one-third had never been tested for HIV (137/421, 32.5%), and the same proportion had not been tested in the past year (137/421, 32.5%). Most participants had dental insurance coverage (356/421, 84.6%), and more than three-fourths reported being very or somewhat willing (326/421, 77.4%) to receive any type of HIV testing in a dental care setting. Higher levels of willingness were associated with being 18 to 24 years versus ≥35 years (aOR 3.22, 95% CI 1.48-6.98), 25 to 34 years versus ≥35 years (aOR 5.26, 95% CI 2.52-10.98), believing that one's dental care provider is knowledgeable about HIV (aOR 2.04, 95% CI 1.06-3.92), and feeling comfortable discussing HIV with one's dental care provider (aOR 9.84, 95% CI 3.99-24.27).

Conclusions: Our data indicate high acceptability of receiving HIV testing in a dental care setting, especially among those who report having a positive patient-provider relationship. Future research should focus on assessing dental care providers' attitudes, self-efficacy, and beliefs about whether HIV testing fits into the scope of dentistry.
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http://dx.doi.org/10.2196/17677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404012PMC
July 2020

Sexual Agreements and Intimate Partner Violence Among Male Couples in the U.S.: An Analysis of Dyadic Data.

Arch Sex Behav 2021 Apr 23;50(3):1087-1105. Epub 2020 Jul 23.

Center for Sexuality and Health Disparities, School of Nursing, University of Michigan, 400 N. Ingalls St., Ann Arbor, MI, 48109, USA.

Prior research with male couples has focused on how sexual agreements can influence relationship dynamics, sexual risk taking, and health promoting behaviors. Little is known about the association between sexual agreements and the experience or perpetration of intimate partner violence (IPV) in this population. Our study sought to evaluate these associations using dyadic data from a sample of 386 male couples residing in the U.S. Both partners independently reported on their relationship characteristics, sexual agreements, and specific acts reflecting physical, emotional, controlling, and monitoring IPV in separate surveys. Participants were more likely to have experienced IPV in the past year if they were in a relationship for ≥ 3 years versus < 3 years (aOR = 1.62, 95% CI = 1.03-2.53). Among 278 couples who had formulated sexual agreements, men who concurred with their partners on being in an "open" relationship were less likely to have experienced IPV versus those in a "closed" relationship (aOR = 0.47, 95% CI = 0.25-0.89). However, participants were more likely to have experienced IPV if their partners believed they had previously broken their sexual agreement (aOR = 2.79, 95% CI = 1.03-7.52). The verbal explicitness and duration of sexual agreements were not associated with either experiencing or perpetrating IPV in the past year. However, increasing levels of depressive symptomatology were associated with a greater likelihood of both experiencing and perpetrating IPV. Our findings highlight the need to prioritize dyadic interventions for male couples that focus on skills building around enhancing mutual communication and negotiating sexual agreements to reduce IPV.
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http://dx.doi.org/10.1007/s10508-020-01783-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855288PMC
April 2021

E3 ligase SCF ubiquitinates and degrades tumor suppressor C/EBPα in acute myeloid leukemia.

Life Sci 2020 Sep 2;257:118041. Epub 2020 Jul 2.

Room No. LSS008, Division of Cancer Biology, CSIR-Central Drug Research Institute, CDRI Sector-10, Jankipuram Extension, Lucknow, 226031, UP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India. Electronic address:

Aim: Transcription factor CCAAT/Enhancer binding protein alpha (C/EBPα) is a key regulator of myeloid differentiation, granulopoiesis in particular. Although CEBPA mutations are found in more than 10% in AML, functional inhibition of C/EBPα protein is also widely observed in AML. Here, we sought to examine if SKP2, an aberrantly enhanced E3 ubiquitin ligase in primary AMLs inhibits C/EBPα stability to induce differentiation block.

Main Methods: Here we employed cell based assays such as transfections, immunoblotting, co-immunoprecipitation, luciferase and gel shift assays along with differentiation assays to investigate SKP2 regulated C/EBPα protein stability in acute myeloid leukemia.

Key Findings: Here we discovered that oncogenic E3 ubiquitin ligase SCF ubiquitinates and destabilizes C/EBPα in a proteasome-dependent manner. Our data demonstrates that SKP2 physically interacts with C-terminal of C/EBPα and promotes its K48-linked ubiquitination-mediated degradation leading to its reduced transactivation potential, DNA binding ability and cellular functions. We further show that while overexpression of SKP2 inhibits both ectopic as well as endogenous C/EBPα in heterologous (HEK293T) as well as myeloid leukemia cells respectively, SKP2 depletion restores endogenous C/EBPα leading to reduced colony formation and enhanced myeloid differentiation of myeloid leukemia cells. Using Estradiol-inducible K562-C/EBPα-ER cells as yet another model of granulocytic differentiation, we further confirmed that SKP2 overexpression indeed inhibits granulocytic differentiation by mitigating C/EBPα stability.

Significance: Our findings identify SKP2 as a potential negative regulator of C/EBPα stability and function in AML which suggests that SKP2 can be potentially targeted in AML to restore C/EBPα and overcome differentiation block.
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http://dx.doi.org/10.1016/j.lfs.2020.118041DOI Listing
September 2020

Comparison of total body irradiation versus non- total body irradiation containing regimens for de novo acute myeloid leukemia in children.

Haematologica 2020 06 18. Epub 2020 Jun 18.

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.
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http://dx.doi.org/10.3324/haematol.2020.249458DOI Listing
June 2020

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

(7)Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

Gene therapy for haemophilia.

Cochrane Database Syst Rev 2020 04 28;4:CD010822. Epub 2020 Apr 28.

Hematology Department, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation. This is an update of a published Cochrane Review.

Objectives: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.

Search Methods: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020.

Selection Criteria: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.

Data Collection And Analysis: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.

Main Results: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.

Authors' Conclusions: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.
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http://dx.doi.org/10.1002/14651858.CD010822.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192367PMC
April 2020

The conduct of thoracic organ procurement.

Asian Cardiovasc Thorac Ann 2020 Mar 13;28(3):158-167. Epub 2020 Feb 13.

UT Southwestern Medical Center, Dallas, Texas, USA.

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http://dx.doi.org/10.1177/0218492320906687DOI Listing
March 2020

The Influence of Relationship Dynamics and Sexual Agreements on Perceived Partner Support and Benefit of PrEP Use Among Same-Sex Male Couples in the U.S.

AIDS Behav 2020 Jul;24(7):2169-2177

Center for Sexuality and Health Disparities, School of Nursing, University of Michigan, Ann Arbor, USA.

Use of Pre-exposure prophylaxis (PrEP) for HIV prevention by men who have sex with men (MSM) may be impacted by relationship dynamics. We assessed perceived partner support of PrEP use and benefit of PrEP by relationship characteristics among male couples. Baseline data from a randomized control trial of video-based HIV counseling and testing among male couples in the U.S. were used in adjusted multilevel regression models to assess individual and dyadic characteristics. Among 659 participants, 73.3% thought their partner would be supportive of their PrEP use; 26.7% reported their partner would not support PrEP use, which was significantly associated with intimate partner violence (IPV) (p = 0.008). Most (57.7%) did not believe PrEP would be beneficial to them or their partner. Couples with a sexual agreement allowing outside partners were significantly associated with higher perceived support of partners for PrEP (p < 0.001) and benefit of PrEP use (p < 0.001). Perceived partner support of PrEP was high but perceived benefit of PrEP was low, both shaped by relationship dynamics that highlight the need for tailored dyadic interventions. The association between perceived PrEP support and IPV points to the need to integrate relationship contexts in HIV prevention programs.
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http://dx.doi.org/10.1007/s10461-020-02782-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319880PMC
July 2020