22 results on '"Adissu H"'
Search Results
2. The epithelial polarity axis controls the resting membrane potential and Cl− cotransport in breast glandular structures
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Urazaev, A. K., primary, Wang, L., additional, Bai, Y., additional, Adissu, H. A., additional, and Lelièvre, S. A., additional
- Published
- 2023
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3. P277 Predicting disease relevant features in Crohn’s Disease and Ulcerative Colitis from Haematoxylin & Eosin stained whole slide images using self-supervised deep learning
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Mokhtari, R, primary, Hamidinekoo, A, additional, Lewis, A, additional, Sutton, D, additional, Angermann, B, additional, Gehrmann, U, additional, Lundin, P, additional, Khachapuridze, N, additional, Adissu, H, additional, Marks, D, additional, Cairns, J, additional, and Burlutskiy, N, additional
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- 2023
- Full Text
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4. Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis
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Dembowy, J, Adissu, H A, Liu, J C, Zacksenhaus, E, and Woodgett, J R
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- 2015
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5. Connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the breast epithelium.
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Bazzoun, D., primary, Adissu, H. A., additional, Wang, L., additional, Urazaev, A., additional, Tenvooren, I., additional, Fostok, S. F., additional, Chittiboyina, S., additional, Sturgis, J., additional, Hodges, K., additional, Chandramouly, G., additional, Vidi, P.-A., additional, Talhouk, R. S., additional, and Lelièvre, S. A., additional
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- 2019
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6. Right Ventricular Epicardial Fibrosis in Mice With Sternal Segment Dislocation
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Adissu, H. A., primary, Medhanie, G. A., additional, Morikawa, L., additional, White, J. K., additional, Newbigging, S., additional, and McKerlie, C., additional
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- 2014
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7. Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis
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Dembowy, J, primary, Adissu, H A, additional, Liu, J C, additional, Zacksenhaus, E, additional, and Woodgett, J R, additional
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- 2014
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8. Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling
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Louria-Hayon, I., primary, Frelin, C., additional, Ruston, J., additional, Gish, G., additional, Jin, J., additional, Kofler, M. M., additional, Lambert, J.-P., additional, Adissu, H. A., additional, Milyavsky, M., additional, Herrington, R., additional, Minden, M. D., additional, Dick, J. E., additional, Gingras, A.-C., additional, Iscove, N. N., additional, and Pawson, T., additional
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- 2013
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9. Lymphocytic Adenohypophysitis and Adrenalitis in a Dog With Adrenal and Thyroid Atrophy
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Adissu, H. A., primary, Hamel-Jolette, A., additional, and Foster, R. A., additional
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- 2010
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10. Cardiac Myxosarcoma With Adrenal Adenoma and Pituitary Hyperplasia Resembling Carney Complex in a Dog
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Adissu, H. A., primary, Hayes, G., additional, Wood, G. A., additional, and Caswell, J. L., additional
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- 2010
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11. Right Ventricular Epicardial Fibrosis in Mice With Sternal Segment Dislocation.
- Author
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Adissu, H. A., Medhanie, G. A., Morikawa, L., White, J. K., Newbigging, S., and McKerlie, C.
- Subjects
HEART fibrosis ,MOUSE diseases ,STERNUM ,JOINT dislocations ,CALLUS ,VETERINARY epidemiology ,VETERINARY pathophysiology ,WOUNDS & injuries - Abstract
We report coincident sternal segment dislocation and focally extensive right ventricular epicardial fibrosis observed during routine histopathology evaluation of C57BL/6N mice as part of a high throughput phenotyping screen conducted between 4 and 16 weeks of age. This retrospective case series study was conducted to determine whether cardiac fibrosis was a pathological consequence of sternal segment dislocation. We identified sternal segment dislocation in 51 of the total 1103 mice (4.6%) analyzed at 16 weeks of age. Males were more frequently affected. In all cases but 2, the dislocation occurred at the fourth intersternebral joint. In 42 of the 51 cases (82.4%), the dislocation was encased by regenerative cartilaginous callus that protruded internally into the thoracic cavity (intrathoracic callus) and/or externally to the outer aspect of the sternum (extrathoracic callus). Displacement of dislocated ends of the sternum into the thoracic cavity was present in 19 of 51 cases (36.5%). Coincident minimal or mild right ventricular epicardial and subepicardial fibrosis was observed in 22 of the 51 cases (43%) but was not observed in any of the mice in the absence of sternal segment dislocation. Our data suggest that right ventricular fibrosis was likely caused by direct injury of the right ventricle by the dislocated ends of the sternum and/or by intrathoracic callus that develops post dislocation. Potential pathogenesis for the sternal and cardiac lesions and their implication for the interpretation of phenotypes in mouse models of cardiopulmonary and skeletal disease are discussed. [ABSTRACT FROM AUTHOR]
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- 2015
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12. Factors necessary to produce basoapical polarity in human glandular epithelium formed in conventional and high-throughput three-dimensional culture: example of the breast epithelium
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Sturgis Jennifer, Urazaev Albert, Wang Lei, Adissu Hibret A, Chaboub Lesley S, Plachot Cedric, Asem Elikplimi K, and Lelièvre Sophie A
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Biology (General) ,QH301-705.5 - Abstract
Abstract Background Basoapical polarity in epithelia is critical for proper tissue function, and control of proliferation and survival. Cell culture models that recapitulate epithelial tissue architecture are invaluable to unravel developmental and disease mechanisms. Although factors important for the establishment of basal polarity have been identified, requirements for the formation of apical polarity in three-dimensional tissue structures have not been thoroughly investigated. Results We demonstrate that the human mammary epithelial cell line-3522 S1, provides a resilient model for studying the formation of basoapical polarity in glandular structures. Testing three-dimensional culture systems that differ in composition and origin of substrata reveals that apical polarity is more sensitive to culture conditions than basal polarity. Using a new high-throughput culture method that produces basoapical polarity in glandular structures without a gel coat, we show that basal polarity-mediated signaling and collagen IV are both necessary for the development of apical polarity. Conclusion These results provide new insights into the role of the basement membrane, and especially collagen IV, in the development of the apical pole, a critical element of the architecture of glandular epithelia. Also, the high-throughput culture method developed in this study should open new avenues for high-content screening of agents that act on mammary tissue homeostasis and thus, on architectural changes involved in cancer development.
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- 2009
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13. AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults.
- Author
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Cai Y, Diallo S, Rosenthal K, Ren K, Flores DJ, Dippel A, Oganesyan V, van Dyk N, Chen X, Cantu E, Choudhary R, Sulikowski M, Adissu H, Chawla B, Kar S, Liu C, Dijokaite-Guraliuc A, Mongkolsapaya J, Rajan S, Loo YM, Beavon R, Webber C, Chang LJ, Thomas S, Clegg L, Zhang H, Screaton GR, Philbin N, Harre M, Selim A, Martinez-Alier N, Uriel A, Cohen TS, Perez JL, Esser MT, Blair W, and Francica JR
- Subjects
- Animals, Humans, Cricetinae, COVID-19 Drug Treatment, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacokinetics, Mesocricetus, Female, Male, Adult, Antibodies, Viral immunology, Mutation genetics, Antibodies, Monoclonal, Angiotensin-Converting Enzyme 2 metabolism, Viral Load drug effects, SARS-CoV-2 drug effects, COVID-19 virology, Antibodies, Neutralizing immunology, Spike Glycoprotein, Coronavirus metabolism
- Abstract
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.
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- 2024
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14. Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function.
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Moore BA, Flenniken AM, Clary D, Moshiri AS, Nutter LMJ, Berberovic Z, Owen C, Newbigging S, Adissu H, Eskandarian M, McKerlie C, Thomasy SM, Lloyd KCK, Murphy CJ, and Moshiri A
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- Animals, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Knockout, Pigmentation genetics, Albinism, Oculocutaneous genetics, Integumentary System abnormalities
- Abstract
Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets.
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- 2019
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15. Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.
- Author
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Moore BA, Leonard BC, Sebbag L, Edwards SG, Cooper A, Imai DM, Straiton E, Santos L, Reilly C, Griffey SM, Bower L, Clary D, Mason J, Roux MJ, Meziane H, Herault Y, McKerlie C, Flenniken AM, Nutter LMJ, Berberovic Z, Owen C, Newbigging S, Adissu H, Eskandarian M, Hsu CW, Kalaga S, Udensi U, Asomugha C, Bohat R, Gallegos JJ, Seavitt JR, Heaney JD, Beaudet AL, Dickinson ME, Justice MJ, Philip V, Kumar V, Svenson KL, Braun RE, Wells S, Cater H, Stewart M, Clementson-Mobbs S, Joynson R, Gao X, Suzuki T, Wakana S, Smedley D, Seong JK, Tocchini-Valentini G, Moore M, Fletcher C, Karp N, Ramirez-Solis R, White JK, de Angelis MH, Wurst W, Thomasy SM, Flicek P, Parkinson H, Brown SDM, Meehan TF, Nishina PM, Murray SA, Krebs MP, Mallon AM, Kent Lloyd KC, Murphy CJ, and Moshiri A
- Abstract
[This corrects the article DOI: 10.1038/s42003-018-0226-0.].
- Published
- 2019
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16. Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma.
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Shao YW, Wood GA, Lu J, Tang QL, Liu J, Molyneux S, Chen Y, Fang H, Adissu H, McKee T, Waterhouse P, and Khokha R
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- Animals, Dogs, Genes, Tumor Suppressor, Genomics, Humans, Mice, Bone Neoplasms genetics, Guanylate Kinases genetics, Osteosarcoma genetics, Tumor Suppressor Proteins genetics
- Abstract
Leveraging the conserved cancer genomes across mammals has the potential to transform driver gene discovery in orphan cancers. Here, we combine cross-species genomics with validation across human-dog-mouse systems to uncover a new bone tumor suppressor gene. Comparative genomics of spontaneous human and dog osteosarcomas (OS) expose Disks Large Homolog 2 (DLG2) as a tumor suppressor candidate. DLG2 copy number loss occurs in 42% of human and 56% of canine OS. Functional validation through pertinent human and canine OS DLG2-deficient cell lines identifies a regulatory role of DLG2 in cell division, migration and tumorigenesis. Moreover, osteoblast-specific deletion of Dlg2 in a clinically relevant genetically engineered mouse model leads to acceleration of OS development, establishing DLG2 as a critical determinant of OS. This widely applicable cross-species approach serves as a platform to expedite the search of cancer drivers in rare human malignancies, offering new targets for cancer therapy.
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- 2019
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17. Identification of genes required for eye development by high-throughput screening of mouse knockouts.
- Author
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Moore BA, Leonard BC, Sebbag L, Edwards SG, Cooper A, Imai DM, Straiton E, Santos L, Reilly C, Griffey SM, Bower L, Clary D, Mason J, Roux MJ, Meziane H, Herault Y, McKerlie C, Flenniken AM, Nutter LMJ, Berberovic Z, Owen C, Newbigging S, Adissu H, Eskandarian M, Hsu CW, Kalaga S, Udensi U, Asomugha C, Bohat R, Gallegos JJ, Seavitt JR, Heaney JD, Beaudet AL, Dickinson ME, Justice MJ, Philip V, Kumar V, Svenson KL, Braun RE, Wells S, Cater H, Stewart M, Clementson-Mobbs S, Joynson R, Gao X, Suzuki T, Wakana S, Smedley D, Seong JK, Tocchini-Valentini G, Moore M, Fletcher C, Karp N, Ramirez-Solis R, White JK, de Angelis MH, Wurst W, Thomasy SM, Flicek P, Parkinson H, Brown SDM, Meehan TF, Nishina PM, Murray SA, Krebs MP, Mallon AM, Lloyd KCK, Murphy CJ, and Moshiri A
- Abstract
Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease., Competing Interests: The authors declare no competing interests.
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- 2018
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18. Topical Application of Culture-Expanded CD34+ Umbilical Cord Blood Cells from Frozen Units Accelerates Healing of Diabetic Skin Wounds in Mice.
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Whiteley J, Chow T, Adissu H, Keating A, and Rogers IM
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- Administration, Topical, Animals, Collagen Type IV metabolism, Diabetes Mellitus, Experimental complications, Disease Models, Animal, Fetal Blood cytology, Freezing, Keratin-6 metabolism, Keratinocytes metabolism, Male, Mice, Paracrine Communication, Skin Ulcer etiology, Skin Ulcer pathology, Stem Cells cytology, Transplantation, Heterologous, Antigens, CD34 metabolism, Skin Ulcer therapy, Stem Cell Transplantation, Stem Cells metabolism, Wound Healing
- Abstract
Chronic and nonhealing wounds are constant health issues facing patients with type 2 diabetes. As the incidence of type 2 diabetes mellitus (T2DM) increases, the incidence of chronic wounds and amputations will rise. T2DM is associated with peripheral arterial occlusive disease, which leads to the development of nonhealing skin ulcers after minor trauma. Patients develop severe pain limiting their mobility and ability to work and take care of themselves, thus putting a significant burden on the family and society. CD34+ cells from umbilical cord blood (UCB) grown in fibroblast growth factor-4 (FGF-4), stem cell factor, and Flt3-ligand produced a population of cells that have the ability to proliferate and develop properties enabling them to enhance tissue regeneration. The goal of this study was to assess in vitro cultured CD34+ cells in a setting where they would eventually be rejected so we could isolate paracrine signaling mediated therapeutic effect from the therapeutic effect due to engraftment and differentiation. To achieve this, we used db/db mice as a model for diabetic skin ulcers. Here, we report that in vitro cultured UCB CD34+ cells from frozen units can accelerate wound healing and resulted in the regeneration of full thickness skin. This study demonstrates a new indication for banked UCB units in the area of tissue regeneration. Stem Cells Translational Medicine 2018;7:591-601., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
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- 2018
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19. Corrigendum: High-throughput discovery of novel developmental phenotypes.
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Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, Meehan TF, Weninger WJ, Westerberg H, Adissu H, Baker CN, Bower L, Brown JM, Caddle LB, Chiani F, Clary D, Cleak J, Daly MJ, Denegre JM, Doe B, Dolan ME, Edie Helmut Fuchs SM, Gailus-Durner V, Galli A, Gambadoro A, Gallegos J, Guo S, Horner NR, Hsu CW, Johnson SJ, Kalaga S, Keith LC, Lanoue L, Lawson TN, Lek M, Mark M, Marschall S, Mason J, McElwee ML, Nutter SNLMJ, Peterson KA, Ramirez-Solis R, Rowland DJ, Ryder E, Samocha KE, Seavitt JR, Selloum M, Szoke-Kovacs Z, Tamura M, Trainor AG, Tudose I, Wakana S, Warren J, Wendling O, West DB, Wong L, Yoshiki A, Wurst W, MacArthur DG, Tocchini-Valentini GP, Gao X, Flicek P, Bradley A, Skarnes WC, Justice MJ, Parkinson HE, Moore M, Wells S, Braun RE, Svenson KL, de Angelis MH, Herault Y, Mohun T, Mallon AM, Henkelman RM, Brown SDM, Adams DJ, Lloyd KCK, McKerlie C, Beaudet AL, and Murray MBSA
- Abstract
This corrects the article DOI: 10.1038/nature19356.
- Published
- 2017
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20. Cancer incidence profile in sub-Saharan African-born blacks in the United States: Similarities and differences with US-born non-Hispanic blacks.
- Author
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Medhanie GA, Fedewa SA, Adissu H, DeSantis CE, Siegel RL, and Jemal A
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- Adult, Africa South of the Sahara ethnology, Africa, Eastern ethnology, Africa, Western ethnology, Aged, Black People statistics & numerical data, Colorectal Neoplasms epidemiology, Emigrants and Immigrants, Female, Humans, Incidence, Leukemia epidemiology, Liver Neoplasms epidemiology, Lung Neoplasms epidemiology, Lymphoma, Non-Hodgkin epidemiology, Male, Middle Aged, Prostatic Neoplasms epidemiology, SEER Program, Sarcoma, Kaposi epidemiology, Sex Factors, Stomach Neoplasms epidemiology, Thyroid Neoplasms epidemiology, United States epidemiology, Young Adult, Black or African American statistics & numerical data, Neoplasms epidemiology
- Abstract
Background: Sub-Saharan African-born blacks (ABs) are one of the fastest-growing populations in the United States. However, to the authors' knowledge, data regarding the cancer burden in this group are lacking, which would inform targeted cancer prevention and control., Methods: The authors calculated age-standardized proportional incidence ratios (PIRs) comparing the frequency of the top 15 cancers in ABs with that of US-born non-Hispanic blacks (USBs) by sex and region of birth using incidence data for 2000 through 2012 from the Surveillance, Epidemiology, and End Results (SEER 17) program., Results: Compared with USBs, ABs had significantly higher PIRs of infection-related cancers (liver, stomach, and Kaposi sarcoma), blood cancers (leukemia and non-Hodgkin lymphoma), prostate cancer, and thyroid cancers (females only). For example, the PIR for Kaposi sarcoma in AB versus USB women was 12.06 (95% confidence interval [95% CI], 5.23-18.90). In contrast, ABs had lower PIRs for smoking-related and colorectal cancers (eg, for lung cancer among men, the PIR was 0.30 [95% CI, 0.27-0.34]). Furthermore, cancer occurrence in ABs versus USBs varied by region of birth. For example, the higher PIRs for liver cancer noted among male ABs (PIR, 3.57; 95% CI, 1.79-5.35) and for thyroid cancer in female ABs (PIR, 3.03; 95% CI, 2.03-4.02) were confined to Eastern African-born blacks, whereas the higher PIR for prostate cancer (PIR, 1.90; 95% CI, 1.78, 2.02) was confined to Western African-born blacks., Conclusions: The cancer incidence profile of ABs is different from that of USBs and varies by region of birth, suggesting differences in environmental, cultural, social, and genetic factors. The findings of the current study could stimulate etiologic research and help to inform targeted interventions. Cancer 2017;123:3116-24. © 2017 American Cancer Society., (© 2017 American Cancer Society.)
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- 2017
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21. High-throughput discovery of novel developmental phenotypes.
- Author
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Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, Meehan TF, Weninger WJ, Westerberg H, Adissu H, Baker CN, Bower L, Brown JM, Caddle LB, Chiani F, Clary D, Cleak J, Daly MJ, Denegre JM, Doe B, Dolan ME, Edie SM, Fuchs H, Gailus-Durner V, Galli A, Gambadoro A, Gallegos J, Guo S, Horner NR, Hsu CW, Johnson SJ, Kalaga S, Keith LC, Lanoue L, Lawson TN, Lek M, Mark M, Marschall S, Mason J, McElwee ML, Newbigging S, Nutter LM, Peterson KA, Ramirez-Solis R, Rowland DJ, Ryder E, Samocha KE, Seavitt JR, Selloum M, Szoke-Kovacs Z, Tamura M, Trainor AG, Tudose I, Wakana S, Warren J, Wendling O, West DB, Wong L, Yoshiki A, MacArthur DG, Tocchini-Valentini GP, Gao X, Flicek P, Bradley A, Skarnes WC, Justice MJ, Parkinson HE, Moore M, Wells S, Braun RE, Svenson KL, de Angelis MH, Herault Y, Mohun T, Mallon AM, Henkelman RM, Brown SD, Adams DJ, Lloyd KC, McKerlie C, Beaudet AL, Bućan M, and Murray SA
- Subjects
- Animals, Conserved Sequence genetics, Disease, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Imaging, Three-Dimensional, Mice, Mice, Inbred C57BL, Mice, Knockout, Penetrance, Polymorphism, Single Nucleotide genetics, Sequence Homology, Embryo, Mammalian embryology, Embryo, Mammalian metabolism, Genes, Essential genetics, Genes, Lethal genetics, Mutation genetics, Phenotype
- Abstract
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
- Published
- 2016
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22. The role of sphingosine-1-phosphate transporter Spns2 in immune system function.
- Author
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Nijnik A, Clare S, Hale C, Chen J, Raisen C, Mottram L, Lucas M, Estabel J, Ryder E, Adissu H, Adams NC, Ramirez-Solis R, White JK, Steel KP, Dougan G, and Hancock RE
- Subjects
- Animals, Anion Transport Proteins deficiency, Anion Transport Proteins genetics, Cell Differentiation genetics, Cell Differentiation immunology, Crosses, Genetic, Gene Targeting, Immunophenotyping, Lymphocyte Subsets metabolism, Lymphopenia genetics, Lymphopenia immunology, Lymphopenia pathology, Lysophospholipids genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Insertional immunology, Protein Transport genetics, Protein Transport immunology, Sphingosine genetics, Sphingosine metabolism, Anion Transport Proteins physiology, Lymphocyte Subsets immunology, Lymphocyte Subsets pathology, Lysophospholipids metabolism, Sphingosine analogs & derivatives
- Abstract
Sphingosine-1-phosphate (S1P) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of S1P transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate S1P transport in cell culture. Spns2 was also shown to control S1P activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different S1P-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2(tm1a(KOMP)Wtsi) allele (Spns2(tm1a)). The Spns2(tm1a/tm1a) animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2(tm1a/tm1a) mice closely mimicked the phenotypes of partial S1P deficiency and impaired S1P-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2(tm1a/tm1a) resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the S1P signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard.
- Published
- 2012
- Full Text
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