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Article ; Online: Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases.

Henderson, Scott H / Sorrell, Fiona J / Bennett, James M / Fedorov, Oleg / Hanley, Marcus T / Godoi, Paulo H / Ruela de Sousa, Roberta / Robinson, Sean / Navratilova, Iva Hopkins / Elkins, Jonathan M / Ward, Simon E

European journal of medicinal chemistry

2024 Volume 269, Page(s) 116292

Abstract: Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design ... ...

Abstract	Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.
MeSH term(s)	Humans ; Dyrk Kinases ; Diabetes Mellitus, Type 2/drug therapy ; Protein Kinase Inhibitors/chemistry ; Structure-Activity Relationship ; Pyridazines/chemistry ; Iohexol/analogs & derivatives
Chemical Substances	Dyrk Kinases (EC 2.7.1.-) ; compound 17 (31122-84-6) ; Protein Kinase Inhibitors ; Pyridazines ; Iohexol (4419T9MX03)
Language	English
Publishing date	2024-03-07
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2024.116292
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Article ; Online: Spatio-temporal home range of the dominant rodent species in Mabira central forest reserve, Uganda.

Ssuuna, James / Makundi, Rhodes H / Chidodo, Simon J / Isabirye, Moses / Mbije, Nsajigwa E / Mulungu, Loth S

BMC ecology and evolution

2023 Volume 23, Issue 1, Page(s) 40

Abstract: ... H. stella, L. striatus, L. stanleyi, M. natalensis, and P. jacksoni were most dominant during ... by calculating a minimum convex polygon with an added boundary strip of 5 m.: Results: Overall, the most ... Lophuromys ansorgei, and Lemniscomys striatus. H. stella dominated the intact forest habitat, while L ...

Abstract	Background: Rodents form the largest order among mammals in terms of species diversity, and home range is the area where an individual normally moves during its normal daily activities. Information about rodent home ranges is paramount in the development of effective conservation and management strategies. This is because rodent home range varies within species and different habitats. In Uganda, tropical high altitude forests such as the Mabira Central Forest Reserve are experiencing continuous disturbance. However, information on rodent home range is lacking. Therefore, a two year Capture-Mark-Release (CMR) of rodents was conducted in the intact forest habitat: Wakisi, regenerating forest habitat: Namananga, and the depleted forest habitat: Namawanyi of Mabira Central Forest Reserve in order to determine the dominant rodent species, their home ranges, and factors affecting these home ranges. The home ranges were determined by calculating a minimum convex polygon with an added boundary strip of 5 m. Results: Overall, the most dominant rodent species were: Lophuromys stanleyi, Hylomyscus stella, Praomys jacksoni Mastomys natalensis, Lophuromys ansorgei, and Lemniscomys striatus. H. stella dominated the intact forest habitat, while L. stanleyi was the most dominant both in the regenerating and the depleted forest habitats. L. stanleyi had a larger home range in the depleted forest, and the regenerating forest habitats, respectively. In the regenerating forest habitat, M. natalensis had a larger home range size, followed by L. stanleyi, and L. striatus. While in the intact forest habitat, H. stella had the largest home range followed by P. jacksoni. H. stella, L. striatus, L. stanleyi, M. natalensis, and P. jacksoni were most dominant during the wet season while L. ansorgei was relatively more dominant during the dry season. L. ansorgei, and P. jacksoni had a larger home range in the dry season, and a lower home range in the wet season. H. stella, L. stanleyi, M. natalansis and L.striatus had larger home ranges in the wet season, and lower home ranges in the dry season. The home ranges of the dominant rodent species varied across the three habitats in Mabira central forest reserve ([Formula: see text], [Formula: see text]). Conclusion: The significant variation in home ranges of the dominant rodent species in Mabira Central Forest Reserve depending on the type of habitat presupposes that the rodent management strategies in disturbed forest reserves should focus on the type of habitat.
MeSH term(s)	Animals ; Homing Behavior ; Uganda ; Forests ; Acetobacteraceae ; Murinae
Language	English
Publishing date	2023-08-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2730-7182
ISSN (online)	2730-7182
DOI	10.1186/s12862-023-02148-4
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Article ; Online: On the Design of Combination Cancer Therapy.

Doroshow, James H / Simon, Richard M

Cell

2017 Volume 171, Issue 7, Page(s) 1476–1478

Abstract: Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug ... ...

Abstract	Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug interactions rarely translate clinically and that the results of combination therapies in mouse models or human clinical trials, even if successful, are best explained by the independent activities of the individually administered drugs.
MeSH term(s)	Animals ; Combined Modality Therapy ; Humans ; Mice ; Neoplasms
Language	English
Publishing date	2017-12-13
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2017.11.035
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completionResearch in context

Marieke M. van der Zalm / Vita W. Jongen / Ruan Swanepoel / Klassina Zimri / Brian Allwood / Megan Palmer / Rory Dunbar / Pierre Goussard / H Simon Schaaf / Anneke C. Hesseling / James A. Seddon

EClinicalMedicine, Vol 67, Iss , Pp 102406- (2024)

2024

Abstract: Summary: Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. ... ...

Abstract	Summary: Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < −1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < −1.64). Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have ...
Keywords	Tuberculosis ; Adolescents ; Morbidity ; Lung health ; Post-tuberculosis ; Medicine (General) ; R5-920
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Difficult conversations: Management of estradiol deficiency.

Spencer, Hillary / Simon, James A / Nelson, Lawrence M

Maturitas

2023 Volume 171, Page(s) 24

MeSH term(s)	Humans ; Female ; Estradiol ; Primary Ovarian Insufficiency ; Osteoporosis, Postmenopausal ; Double-Blind Method ; Bone Density
Chemical Substances	Estradiol (4TI98Z838E)
Language	English
Publishing date	2023-03-20
Publishing country	Ireland
Document type	Letter ; Comment
ZDB-ID	80460-5
ISSN	1873-4111 ; 0378-5122
ISSN (online)	1873-4111
ISSN	0378-5122
DOI	10.1016/j.maturitas.2023.03.001
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Zs.A 1432: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 575: Show issues

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Article ; Online: Reply to Martinez-Garcia

Allinson, James P / Vlies, Ben H / Brill, Simon E / Law, Martin / Burnside, Girvan / Finney, Lydia J / Alves-Moreira, Luana / Calverley, Peter M A / Walker, Paul P / Wedzicha, Jadwiga A

American journal of respiratory and critical care medicine

2023 Volume 208, Issue 10, Page(s) 1144–1145

Language	English
Publishing date	2023-09-20
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202309-1604LE
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Article ; Online: Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.

Jansen, Rachel M / Peruzzo, Roberta / Fromm, Simon A / Yokom, Adam L / Zoncu, Roberto / Hurley, James H

Science advances

2022 Volume 8, Issue 37, Page(s) eadd2926

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)- ... ...

Abstract	The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagA
Language	English
Publishing date	2022-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.add2926
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Article ; Online: Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

van der Zalm, Marieke M / Jongen, Vita W / Swanepoel, Ruan / Zimri, Klassina / Allwood, Brian / Palmer, Megan / Dunbar, Rory / Goussard, Pierre / Schaaf, H Simon / Hesseling, Anneke C / Seddon, James A

EClinicalMedicine

2024 Volume 67, Page(s) 102406

Abstract: Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion.: Methods: ...

Abstract	Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity. Funding: EDCTP, National Institute of Health, Medical Research Council, BMBF.
Language	English
Publishing date	2024-01-03
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2023.102406
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Article ; Online: Blood Pressure Lowering in Patients With Central Hypertension: A randomized Clinical Trial.

Sharman, James E / Otahal, Petr / Stowasser, Michael / Stanton, Tony / Reid, Christopher M / Nolan, Mark / Roberts-Thomson, Philip / Negishi, Kazuaki / Greenough, Robert / Stewart, Simon / Marwick, Thomas H / Abhayaratna, Walter P

Hypertension (Dallas, Tex. : 1979)

2024

Abstract: ... a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m: Conclusions ...

Abstract	Background: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. Methods: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. Results: At 24-months, there was a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m Conclusions: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. Registration: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729.
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.123.21653
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Article ; Online: Associations of ambulatory blood pressure measurements with high-sensitivity troponin and natriuretic peptide levels in SPRINT.

Venishetty, Nikit / Berry, Jarett D / de Lemos, James A / Wu, Elaine / Lee, Min Jae / Drawz, Paul E / Nambi, Vijay / Ballantyne, Christie M / Killeen, Anthony A / Ix, Joachim H / Shlipak, Michael G / Ascher, Simon B

American journal of hypertension

2024

Abstract: Background: Nighttime blood pressure (BP) has greater prognostic importance for cardiovascular disease (CVD) than daytime BP, but less is known about nighttime and daytime BP associations with measures of subclinical CVD.: Methods: Among 897 Systolic ...

Abstract	Background: Nighttime blood pressure (BP) has greater prognostic importance for cardiovascular disease (CVD) than daytime BP, but less is known about nighttime and daytime BP associations with measures of subclinical CVD. Methods: Among 897 Systolic Blood Pressure Intervention Trial Study (SPRINT) participants with 24-hour ambulatory BP monitoring obtained near the 27-month study visit, 849 (95%) had N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) measured at the 24-month study visit. Multivariable linear regression analyses were performed to evaluate the associations of nighttime and daytime BP with cardiac biomarker levels. Results: Mean age was 69 ±12 years, 28% were African American, and mean nighttime and daytime SBP were 121 ±16 mm Hg and 132 ±14 mm Hg, respectively. In multivariable models, compared with the lowest tertile of nighttime systolic BP, the highest tertile was associated with 48% higher NT-proBNP levels (adjusted geometric mean ratio [GMR] = 1.48, 95% CI: 1.22, 1.79), and 19% higher hs-cTnT levels (adjusted GMR = 1.19, 95% CI: 1.07, 1.32). In contrast, the highest versus lowest tertile of daytime systolic BP was not associated with NT-proBNP (adjusted GMR = 1.09, 95% CI: 0.88, 1.34) but was associated with 16% higher hs-cTnT levels (adjusted GMR = 1.16, 95% CI: 1.04, 1.30). Similar results were observed using diastolic BP. Conclusion: In SPRINT, both higher nighttime and daytime BP were independently associated with higher hs-cTnT levels, but only higher nighttime BP was associated with higher NT-proBNP levels.
Language	English
Publishing date	2024-03-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	639383-4
ISSN	1941-7225 ; 1879-1905 ; 0895-7061
ISSN (online)	1941-7225 ; 1879-1905
ISSN	0895-7061
DOI	10.1093/ajh/hpae035
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